Patterns of inheritance

Patterns of Inheritance

Concept Outline

Mendel solved the mystery of heredity.Early Ideas about Heredity: The Road to Mendel. Before

Mendel, biologists believed in the direct transmission of traits.Mendel and the Garden Pea. Mendel, a monk, experimented

with heredity in edible peas, as had many others, but hecounted his results.

What Mendel Found. Mendel found that contrasting traitssegregated among second-generation progeny in the ratio 3:1.

Mendel's Model of Heredity. Mendel proposed thatinformation rather than the trait itself is inherited, with eachparent contributing one copy.

How Mendel Interpreted His Results. Mendel found thatone alternative of a trait could mask the other inheterozygotes, but both could subsequently be expressed inhomozygotes of future generations.

Mendelian Inheritance Is Not Always Easy to Analyze.A variety of factors can disguise the Mendelian segregationof alleles.

Genes are on chromosomes.Chromosomes: The Vehicles of Mendelian Inheritance.

Mendelian segregation reflects the random assortment ofchromosomes in meiosis.

Genetic Recombination. Crossover frequency indicates thephysical distance between genes and is used to constructgenetic maps.

13.3 Human genetics follows Mendelian principles.Multiple Alleles: The ABO Blood Groups. The human ABO

blood groups are determined by three / gene alleles.Human Chromosomes. Humans possess 2 3 pairs of

chromosomes, one of them determining the sex.Human Abnormalities Due to Alterations in Chromosome

Number. Loss or addition of chromosomes has seriousconsequences.

Human Genetic Disorders. Many heritable human disordersare the result of recessive mutations in genes.

Genetic Counseling. Some gene defects can be detected earlyin pregnancy.

„

FIGURE 13.1Human beings are extremely diverse in appearance. Thedifferences between us are partly inherited and partly the resultof environmental factors we encounter in our lives.

Every living creature is a product of the long evolution-ary history of life on earth. While all organisms share

this history, only humans wonder about the processes thatled to their origin. We are still far from understandingeverything about our origins, but we have learned a greatdeal. Like a partially completed jigsaw puzzle, the bound-aries have fallen into place, and much of the internal struc-ture is becoming apparent. In this chapter, we will discussone piece of the puzzle—the enigma of heredity. Why dogroups of people from different parts of the world oftendiffer in appearance (figure 13.1)? Why do the members ofa family tend to resemble one another more than they re-semble members of other families?

241

heredity.

Early Ideas about Heredity:The Road to MendelAs far back as written records go, patterns of resemblanceamong the members of particular families have been notedand commented on (figure 13.2). Some familial features areunusual, such as the protruding lower lip of the Europeanroyal family Hapsburg, evident in pictures and descriptionsof family members from the thirteenth century onward.Other characteristics, like the occurrence of redheadedchildren within families of redheaded parents, are morecommon (figure 13.3). Inherited features, the buildingblocks of evolution, will be our concern in this chapter.

Like many great puzzles, the riddle of heredity seemssimple now that it has been solved. The solution was not aneasy one to find, however. Our present understanding isthe culmination of a long history of thought, surmise, andinvestigation. At every stage we have learned more, and aswe have done so, the models we use to describe the mecha-nisms of heredity have changed to encompass new facts.

Classical Assumption 1: Constancy of Species

Two concepts provided the basis for most of the thinkingabout heredity before the twentieth century. The first isthat heredity occurs within species. For a very long time peo-ple believed that it was possible to obtain bizarre compos-ite animals by breeding (crossing) widely different species.The minotaur of Cretan mythology, a creature with thebody of a bull and the torso and head of a man, is one ex-ample. The giraffe was thought to be another; its scientificname, Giraffa camelopardalis, suggests the belief that it wasthe result of a cross between a camel and a leopard. Fromthe Middle Ages onward, however, people discovered thatsuch extreme crosses were not possible and that variationand heredity occur mainly within the boundaries of a par-ticular species. Species were thought to have been main-tained without significant change from the time of theircreation.

Classical Assumption 2: Direct Transmissionof Traits

The second early concept related to heredity is that traitsare transmitted directly. When variation is inherited by off-spring from their parents, what is transmitted? The ancientGreeks suggested that the parents' body parts were trans-mitted directly to their offspring. Hippocrates called thistype of reproductive material gonos, meaning "seed."Hence, a characteristic such as a misshapen limb was theresult of material that came from the misshapen limb of aparent. Information from each part of the body was sup-posedly passed along independently of the information

FIGURE 13.2Heredity is responsible for family resemblance. Familyresemblances are often strong—a .visual manifestation of themechanism of heredity. This is the Johnson family, the wife anddaughters of one of the authors. While each daughter is different,all clearly resemble their mother.

FIGURE 13.3Red hair is inherited. Many different traits are inherited inhuman families. This redhead is exhibiting one of these traits.

from the other parts, and the child was formed after thehereditary material from all parts of the parents' bodies hadcome together.

242 Part IV Reproduction and Heredity

This idea was predominant until fairlyrecently. For example, in 1868, CharlesDarwin proposed that all cells and tissuesexcrete microscopic granules, or "gem-mules," that are passed to offspring, guid-ing the growth of the corresponding part inthe developing embryo. Most similar theo-ries of the direct transmission of hereditarymaterial assumed that the male and femalecontributions blend in the offspring. Thus,parents with red and brown hair wouldproduce children with reddish brown hair,and tall and short parents would producechildren of intermediate height.

Koelreuter DemonstratesHybridization between Species

Taken together, however, these two con-cepts lead to a paradox. If no variation en-ters a species from outside, and if the varia-tion within each species blends in everygeneration, then all members of a speciesshould soon resemble one another exactly.Obviously, this does not happen. Individu-als within most species differ widely fromeach other, and they differ in characteristicsthat are transmitted from generation togeneration.

How could this paradox be resolved? Ac-tually, the resolution had been providedlong before Darwin, in the work of theGerman botanist Josef Koelreuter. In 1760,Koelreuter carried out the first successful hybridizationsof plant species, crossing different strains of tobacco andobtaining fertile offspring. The hybrids differed in appear-ance from both parent strains. When individuals within thehybrid generation were crossed, the offspring were highlyvariable. Some of these offspring resembled plants of thehybrid generation (their parents), but a few resembled theoriginal strains (their grandparents).

The Classical Assumptions Fail

Koelreuter's work represents the beginning of moderngenetics, the first clues pointing to the modern theory ofheredity. Koelreuter's experiments provided an impor-tant clue about how heredity works: the traits he wasstudying could be masked in one generation, only toreappear in the next. This pattern contradicts the theoryof direct transmission. How could a trait that is transmit-ted directly be latent and then reappear? Nor were thetraits of Koelreuter's plants blended. A contemporary ac-count stated that the traits reappeared in the third gener-ation "fully restored to all their original powers andproperties."

FIGURE 13.4The garden pea, Pimmsativum. Easy to cultivate andable to produce many distinctivevarieties, the garden pea was apopular experimental subject ininvestigations of heredity as longas a century before GregorMendel's experiments.

It is worth repeating that the offspringof Koelreuter's crosses were not identicalto one another. Some resembled the hy-brid generation, while others did not. Thealternative forms of the traits Koelreuterwas studying were distributed among theoffspring. A modern geneticist would saythe alternative forms of each trait weresegregating among the progeny of a mat-ing, meaning that some offspring exhibitedone alternative form of a trait (for example,hairy leaves), while other offspring fromthe same mating exhibited a different alter-native (smooth leaves). This segregation ofalternative forms of a trait provided theclue that led Gregor Mendel to his under-standing of the nature of heredity.

Knight Studies Heredity in Peas

Over the next hundred years, other investi-gators elaborated on Koelreuter's work.Prominent among them were English gen-tleman farmers trying to improve varietiesof agricultural plants. In one such series ofexperiments, carried out in the 1790s,T. A. Knight crossed two true-breedingvarieties (varieties that remain uniformfrom one generation to the next) of thegarden pea, Pisum sativum (figure 13.4).One of these varieties had purple flowers,and the other had white flowers. All of theprogeny of the cross had purple flowers.

Among the offspring of these hybrids, however, were someplants with purple flowers and others, less common, withwhite flowers. Just as in Koelreuter's earlier studies, a traitfrom one of the parents disappeared in one generationonly to reappear in the next.

In these deceptively simple results were the makings of ascientific revolution. Nevertheless, another century passedbefore the process of gene segregation was fully appreci-ated. Why did it take so long? One reason was that earlyworkers did not quantify their results. A numerical recordof results proved to be crucial to understanding the process.Knight and later experimenters who carried out othercrosses with pea plants noted that some traits had a"stronger tendency1'" to appear than others, but they did notrecord the numbers of the different classes of progeny. Sci-ence was young then, and it was not obvious that the num-bers were important.

Early geneticists demonstrated that some forms ofan inherited trait (1) can disappear in one generationonly to reappear unchanged in future generations;(2) segregate among the offspring of a cross; and (3) aremore likely to be represented than their alternatives.

Chapter 13 Patterns of Inheritance 243

Mendel and the Garden PeaThe first quantitative studies of inheritance were carriedout by Gregor Mendel, an Austrian monk (figure 13.5).Born in 1822 to peasant parents, Mendel was educated in amonastery and went on to study science and mathematicsat the University of Vienna, where he failed his examina-tions for a teaching certificate. He returned to themonastery and spent the rest of his life there, eventuallybecoming abbot. In the garden of the monastery, Mendelinitiated a series of experiments on plant hybridization (fig-ure 13.6). The results of these experiments would ulti-mately change our views of heredity irrevocably.

Why Mendel Chose the Garden Pea

For his experiments, Mendel chose the garden pea, thesame plant Knight and many others had studied earlier.The choice was a good one for several reasons. First, manyearlier investigators had produced hybrid peas by crossingdifferent varieties. Mendel knew that he could expect toobserve segregation of traits among the offspring. Second,a large number of true-breeding varieties of peas wereavailable. Mendel initially examined 32. Then, for furtherstudy, he selected lines that differed with respect to seveneasily distinguishable traits, such as round versus wrinkledseeds and purple versus white flowers, a characteristicKnight had studied. Third, pea plants are small and easy togrow, and they have a short generation time. Thus, one canconduct experiments involving numerous plants, grow sev-eral generations in a single year, and obtain results rela-tively quickly.

A fourth advantage of studying peas is that the sexual or-gans of the pea are enclosed within the flower (figure 13.7).The flowers of peas, like those of most flowering plants, con-tain both male and female sex organs. Furthermore, the ga-metes produced by the male and female parts of the sameflower, unlike those of many flowering plants, can fuse toform viable offspring. Fertilization takesplace automatically within an individualflower if it is not disturbed, resulting inoffspring that are the progeny from asingle individual. Therefore, one can ei-ther let individual flowers engage inself-fertilization, or remove the flow-er's male parts before fertilization andintroduce pollen from a strain with al-ternative characteristics, thus perform-ing cross-pollination which results incross-fertilization.

FIGURE 13.6The garden where Mendel carried outhis plant-breeding experiments. GregorMendel did his most important scientificexperiments in this small garden in amonastery.

FIGURE 13.5Gregor Johann Mendel. Cultivating his plants in the garden of amonastery in Brunn, Austria (now Brno, Czech Republic),Mendel studied how differences among varieties of peas wereinherited when the varieties were crossed. Similar experimentshad been done before, but Mendel was the first to appreciate thesignificance of the results.


Mendel's Experimental Design

Mendel was careful to focus on only a few specific differ-ences between the plants he was using and to ignore thecountless other differences he must have seen. He also hadthe insight to realize that the differences he selected to ana-lyze must be comparable. For example, he appreciated thattrying to study the inheritance of round seeds versus tallheight would be useless; the traits, like apples and oranges,are not comparable.

Mendel usually conducted his experiments in three stages:

1. First, he allowed pea plants of a given variety to pro-duce progeny by self-fertilization for several genera-tions. Mendel was thus able to assure himself that theforms of traits he was studying were indeed constant,transmitted unchanged from generation to genera-tion. Pea plants with white flowers, for example,when crossed with each other, produced only off-spring with white flowers, regardless of the numberof generations.

2. Mendel then performed crosses between varietiesexhibiting alternative forms of traits. For example,he removed the male parts fromthe flower of a plant that pro-duced white flowers and fertilizedit with pollen from a purple-flowered plant. He also carriedout the reciprocal cross, usingpollen from a white-flowered in-dividual to fertilize a flower on apea plant that produced purpleflowers (figure 13.8).

3. Finally, Mendel permitted thehybrid offspring produced bythese crosses to self-pollinate forseveral generations. By doing so,he allowed the alternative formsof a trait to segregate among theprogeny. This was the same ex-perimental design that Knightand others had used much earlier.But Mendel went an importantstep farther: he counted the num-bers of offspring of each type ineach succeeding generation. Noone had ever done that before.The quantitative results Mendelobtained proved to be of supremeimportance in revealing theprocess of heredity.

Petals

Anther S

Carpel 9

FIGURE 13.7Structure of the pea flower (longitudinal section). In a peaplant flower, the petals enclose the male anther (containing pollengrains, which give rise to haploid sperm) and the female carpel(containing ovules, which give rise to haploid eggs). This ensuresthat self-fertilization will take place unless the flower is disturbed.

Anthersremoved

Pollen transferred from whiteflower to stigma of purple flower

Mendel's experiments with thegarden pea involved crossesbetween true-breeding varieties,followed by a generation or moreof inbreeding.

FIGURE 13.8How Mendel conducted his experiments. Mendel pushed aside the petals of a whiteflower and cut off the anthers, the source of the pollen. He then placed that pollen onto thestigma (part of the carpel) of a similarly castrated purple flower, causing cross-fertilizationto take place. All the seeds in the pod that resulted from this pollination were hybrids of thewhite-flowered male parent and the purple-flowered female parent. After planting theseseeds, Mendel observed what kinds of plants they produced. All of the progeny of this crosshad purple flowers.


What Mendel FoundThe seven traits Mendel studied in his experiments pos-sessed several variants that differed from one another inways that were easy to recognize and score (figure 13.9).We will examine in detail Mendel's crosses with flowercolor. His experiments with other traits were similar, andthey produced similar results.

The FI Generation

When Mendel crossed two contrasting varieties of peas,such as white-flowered and purple-flowered plants, thehybrid offspring he obtained did not have flowers of

intermediate color, as the theory of blending inheritancewould predict. Instead, in every case the flower color ofthe offspring resembled one of their parents. It is custom-ary to refer to these offspring as the first filial (filius isLatin for "son"), or FI, generation. Thus, in a cross ofwhite-flowered with purple-flowered plants, the FI off-spring all had purple flowers, just as Knight and othershad reported earlier.

Mendel referred to the trait expressed in the FI plantsas dominant and to the alternative form that was not ex-pressed in the FI plants as recessive. For each of theseven pairs of contrasting forms of traits that Mendel ex-amined, one of the pair proved to be dominant and theother recessive.

Trait Dominant vs. recessive F2 generation

Dominant form Recessive form

Ratio

Flowercolor

Purple

705 224 3.15:1

White

Seedcolor

O"

Yellow

6022 2001 3.01:1

Green

Seedshape

Roundx - < • '

Wrinkled5474 1850 2.96:1

Podcolor

X,„=**•'

Green Yellow

428 152 2.82:1

Podshape 882 299 2.95:1</

Round ' "Constricted

Flowerposition

Axial

651 207 3.14:1

Plantheight 787 277 2.84:1

Tall Dwarf

FIGURE 13.9Mendel's experimental results. This table illustrates the seven pairs of contrasting traits Mendel studied in his crosses of the garden peaand presents the data he obtained for these crosses. Each pair of traits appeared in the p2 generation in very close to a 3:1 ratio.


The ¥2 Generation

After allowing individual FI plants to mature and self-pollinate, Mendel collected and planted the seeds fromeach plant to see what the offspring in the second filial, orp2, generation would look like. He found, just as Knighthad earlier, that some p2 plants exhibited white flowers, therecessive form of the trait. Latent in the FI generation, therecessive form reappeared among some ¥2 individuals.

Believing the proportions of the F2 types would providesome clue about the mechanism of heredity, Mendelcounted the numbers of each type among the F2 progeny.In the cross between the purple-flowered FI plants, hecounted a total of 929 F2 individuals (see figure 13.9). Ofthese, 705 (75.9%) had purple flowers and 224 (24.1%) hadwhite flowers. Approximately /4 of the p2 individuals exhib-ited the recessive form of the trait. Mendel obtained thesame numerical result with the other six traits he examined:!/ of the p2 individuals exhibited the dominant form of thetrait, and 14 displayed the recessive form. In other words,the dominant: recessive ratio among the p2 plants was al-ways close to 3:1. Mendel carried out similar experimentswith other traits, such as wrinkled versus round seeds (fig-ure 13.10), and obtained the same result.

FIGURE 13.10Seed shape: a Mendelian trait. One of the differences Mendelstudied affected the shape of pea plant seeds. In some varieties,the seeds were round, while in others, they were wrinkled. As youcan see, the wrinkled seeds look like dried-out versions of theround ones.

у 97 y

FIGURE13.ilA page from Mendel's notebook. In these notes, Mendel istrying various ratios in an unsuccessful attempt to explain asegregation ratio disguised by phenotypes that are so similar hecannot distinguish them from one another.

A Disguised 1:2:1 Ratio

Mendel went on to examine how the F2 plants passed traitson to subsequent generations. He found that the recessiveК were always true-breeding. In the cross of white-floweredwith purple-flowered plants, for example, the white-flowered p2 individuals reliably produced white-floweredoffspring when they were allowed to self-fertilize. By con-trast, only И of the dominant purple-flowered F2 individuals(i4 of all p2 offspring) proved true-breeding, while 2A werenot. This last class of plants produced dominant and reces-sive individuals in the third filial (Рз) generation in a 3:1ratio. This result suggested that, for the entire sample, the3:1 ratio that Mendel observed in the p2 generation wasreally a disguised 1:2:1 ratio: !4 pure-breeding dominantindividuals, 1A not-pure-breeding dominant individuals, and14 pure-breeding recessive individuals (figure 13.11).

When Mendel crossed two contrasting varieties andcounted the offspring in the subsequent generations, hefound all of the offspring in the first generationexhibited one (dominant) trait, and none exhibited theother (recessive) trait. In the following generation, 25%were pure-breeding for the dominant trait, 50% werehybrid for the two traits and appeared dominant, and25% were pure-breeding for the recessive trait.


Mendel's Model of HeredityFrom his experiments, Mendel was able to understand fourthings about the nature of heredity. First, the plants hecrossed did not produce progeny of intermediate appear-ance, as a theory of blending inheritance would have pre-dicted. Instead, different plants inherited each alternativeintact, as a discrete characteristic that either was or was notvisible in a particular generation. Second, Mendel learnedthat for each pair of alternative forms of a trait, one alter-native was not expressed in the FI hybrids, although itreappeared in some ¥2 individuals. The "invisible" traitmust therefore be latent (present but not expressed) in theFI individuals. Third, the pairs of alternative forms of thetraits examined segregated among the progeny of a particu-lar cross, some individuals exhibiting one form of a trait,some the other. Fourth, pairs of alternatives were expressedin the ¥2 generation in the ratio of % dominant to К reces-sive. This characteristic 3:1 segregation is often referred toas the Mendelian ratio.

To explain these results, Mendel proposed a simplemodel. It has become one of the most famous models in thehistory of science, containing simple assumptions and mak-ing clear predictions. The model has five elements:

1. Parents do not transmit physiological traits directly totheir offspring. Rather, they transmit discrete infor-mation about the traits, what Mendel called "factors."These factors later act in the offspring to produce thetrait. In modern terms, we would say that informationabout the alternative forms of traits that an individualexpresses is encoded by the factors that it receives fromits parents.

2. Each individual receives two factors that may code forthe same form or for two alternative forms of the trait.We now know that there are two factors for each traitpresent in each individual because these factors are car-ried on chromosomes, and each adult individual isdiploid. When the individual forms gametes (eggs orsperm), they contain only one of each kind of chromo-some; the gametes are haploid. Therefore, only one fac-tor for each trait of the adult organism is contained inthe gamete. Which of the two factors for each traitends up in a particular gamete is randomly determined.

3. Not all copies of a factor are identical. In modernterms, the alternative forms of a factor, leading to alter-native forms of a trait, are called alleles. When twohaploid gametes containing exactly the same allele of afactor fuse during fertilization to form a zygote, the off-spring that develops from that zygote is said to be ho-mozygous; when the two haploid gametes contain dif-ferent alleles, the individual offspring is heterozygous.

In modern terminology, Mendel's factors are calledgenes. We now know that each gene is composed of aparticular DNA nucleotide sequence (chapter 3). Theparticular location of a gene on a chromosome is re-ferred to as the gene's locus (plural, loci).

FIGURE 13.12A recessive trait. Blue eyes are considered a recessive trait inhumans, although many genes influence eye color.

4. The two alleles, one contributed by the male gameteand one by the female, do not influence each other inany way. In the cells that develop within the new in-dividual, these alleles remain discrete. They neitherblend with nor alter each other. (Mendel referred tothem as "uncontaminated.") Thus, when the individ-ual matures and produces its own gametes, the allelesfor each gene segregate randomly into these gametes,as described in point 2.

5. The presence of a particular allele does not ensure matthe form of the trait encoded by it will be expressed inan individual carrying that allele. In heterozygous indi-viduals, only one allele (the dominant one) is ex-pressed, while the other (recessive) allele is present butunexpressed. To distinguish between the presence ofan allele and its expression, modern geneticists refer tothe totality of alleles that an individual contains as theindividual's genotype and to the physical appearanceof that individual as its phenotype. The phenotype ofan individual is the observable outward manifestationof its genotype, the result of the functioning of the en-zymes and proteins encoded by the genes it carries. Inother words, the genotype is the blueprint, and thephenotype is the visible outcome.

These five elements, taken together, constitute Mendel'smodel of the hereditary process. Many traits in humansalso exhibit dominant or recessive inheritance, similar tothe traits Mendel studied in peas (figure 13.12, table 13.1).

The genes that an individual has are referred to as itsgenotype; the outward appearance of the individual isreferred to as its phenotype.


How Mendel Interpreted His ResultsDoes Mendel's model predict the results he actually ob-tained? To test his model, Mendel first expressed it interms of a simple set of symbols, and then used the symbolsto interpret his results. It is very instructive to do the same.Consider again Mendel's cross of purple-flowered withwhite-flowered plants. We will assign the symbol P to thedominant allele, associated with the production of purpleflowers, and the symbol p to the recessive allele, associatedwith the production of white flowers. By convention, ge-netic traits are usually assigned a letter symbol referring totheir more common forms, in this case "P" for purple

flower color. The dominant allele is written in upper case,as P; the recessive allele (white flower color) is assigned thesame symbol in lower case, p.

In this system, the genotype of an individual that istrue-breeding for the recessive white-flowered traitwould be designated pp. In such an individual, bothcopies of the allele specify the white-flowered phenotype.Similarly, the genotype of a true-breeding purple-floweredindividual would be designated PP, and a heterozygotewould be designated Pp (dominant allele first). Usingthese conventions, and denoting a cross between twostrains with x, we can symbolize Mendel's original crossas pp x PP (figure 13.13).

White(PP) ,

Purple(PP)

Pp Pp

generation

Purple(Pp)

Purple(PP)

PP

Pp

Pp

PPF2 generation

FIGURE 13.13Mendel's cross of pea plants differing in flower color. All of the offspring of the first cross (the FI generation) are Pp heterozygoteswith purple flowers. When two heterozygous FI individuals are crossed, three kinds of ¥2 offspring are possible: PP homozygotes (purpleflowers); Pp heterozygotes (also purple flowers); andpp homozygotes (white flowers). Therefore, in the p2 generation, the ratio ofdominant to recessive type is 3:1.

Recessive Traits

Table Ш

Phenotypes Dominant Traits Phenotypes

Common baldness

Albinism

Alkaptonuria

Red-green colorblindness

Cystic fibrosis

Duchenne musculardystrophy

Hemophilia

Sickle cell anemia

M-shaped hairline receding withage

Lack of melanin pigmentation

Inability to metabolizehomogenistic acid

Inability to distinguish red orgreen wavelengths of light

Abnormal gland secretion,leading to liver degeneration andlung failure

Wasting away of muscles duringchildhood

Inability to form blood clots

Defective hemoglobin thatcauses red blood cells to curveand stick together

Middigital hair

Brachydactyly

Huntington's disease

Phenylthiocarbamide (PTC)sensitivity

Camptodactyly

Hypercholesterolemia (the mostcommon human Mendeliandisorder—1:500)

Polydactyly

Presence of hair on middlesegment of fingers

Short fingers

Degeneration of nervoussystem, starting in middle age

Ability to taste PTC as bitter

Inability to straighten thelittle finger

Elevated levels of bloodcholesterol and risk of heartattack

Extra fingers and toes


The FI Generation

Using these simple symbols, we can now go back and reex-amine the crosses Mendel carried out. Since a white-floweredparent (fp) can produce only p gametes, and a pure purple-flowered (homozygous dominant) parent (PP) can produceonly P gametes, the union of an egg and a sperm fromthese parents can produce only heterozygous Pp offspringin the FI generation (see figure 13.13). Because the P alleleis dominant, all of these FI individuals are expected tohave purple flowers. The p allele is present in these het-erozygous individuals, but it is not phenotypically ex-pressed. This is the basis for the latency Mendel saw in re-cessive traits.

The РЗ Generation

When FI individuals are allowed to self-fertilize, the P andp alleles segregate randomly during gamete formation.Their subsequent union at fertilization to form ¥2 individu-als is also random, not being influenced by which alterna-tive alleles the individual gametes carry. What will the p2individuals look like? The possibilities may be visualized ina simple diagram called a Punnett square, named after itsoriginator, the English geneticist Reginald Crundall Pun-nett (figure 13.14). Mendel's model, analyzed in terms of aPunnett square, clearly predicts that the F2 generationshould consist of % purple-flowered plants and 14 white-flowered plants, a phenotypic ratio of 3:1.

The Laws of Probability CanPredict Mendel's Results

A different way to express Mendel's result is to say thatthere are three chances in four (%) that any particular ¥2 in-dividual will exhibit the dominant trait, and one chance infour (14) that an F2 individual will express the recessive trait.Stating the results in terms of probabilities allows simplepredictions to be made about the outcomes of crosses. Ifboth FI parents are Pp (heterozygotes), the probability thata particular F2 individual will be pp (homozygous recessive)is the probability of receiving a p gamete from the male (A)times the probability of receiving a p gamete from the fe-male (A), or 1A. This is the same operation we perform inthe Punnett square illustrated in figure 13.14. The waysprobability theory can be used to analyze Mendel's resultsis discussed in detail on page 272.

Further Generations

As you can see in figure 13.13, there are really three kindsof F2 individuals: 14 are pure-breeding, white-flowered indi-viduals (pp); Уг are heterozygous, purple-flowered individu-als (Pp); and 14 are pure-breeding, purple-flowered individ-uals (PP). The 3:1 phenotypic ratio is really a disguised1:2:1 genotypic ratio.


(a)

(b)

FIGURE 13.14A Punnett square, (a) To make a Punnett square, place thedifferent possible types of female gametes along one side of asquare and the different possible types of male gametes along theother, (b) Each potential zygote can then be represented as theintersection of a vertical line and a horizontal line.

Mendel's First Law of Heredity: Segregation

Mendel's model thus accounts in a neat and satisfying way forthe segregation ratios he observed. Its central assumption—that alternative alleles of a trait segregate from each other inheterozygous individuals and remain distinct—has sincebeen verified in many other organisms. It is commonly re-ferred to as Mendel's First Law of Heredity, or the Lawof Segregation. As you saw in chapter 12, the segregationalbehavior of alternative alleles has a simple physical basis, thealignment of chromosomes at random on the metaphaseplate. It is a tribute to the intellect of Mendel's analysis thathe arrived at the correct scheme with no knowledge of thecellular mechanisms of inheritance; neither chromosomesnor meiosis had yet been described.

The Testcross

To test his model further, Mendel devised a simple andpowerful procedure called the testcross. Consider a purple-flowered plant. It is impossible to tell whether such a plantis homozygous or heterozygous simply by looking at itsphenotype. To learn its genotype, you must cross it withsome other plant. What kind of cross would provide theanswer? If you cross it with a homozygous dominant indi-vidual, all of the progeny will show the dominant pheno-type whether the test plant is homozygous or heterozygous.It is also difficult (but not impossible) to distinguish be-tween the two possible test plant genotypes by crossingwith a heterozygous individual. However, if you cross thetest plant with a homozygous recessive individual, the twopossible test plant genotypes will give totally different re-sults (figure 13.15):

Alternative 1: unknown individual homozygous (PP).PP x pp: all offspring have purpleflowers (Pp)

Alternative 2: unknown individual heterozygous (Pp).Pp x pp: Уг of offspring have white flow-ers (pp) and И have purple flowers (Pp)

To perform his testcross, Mendel crossed heterozygousFI individuals back to the parent homozygous for the reces-sive trait. He predicted that the dominant and recessivetraits would appear in a 1:1 ratio, and that is what he ob-served.

For each pair of alleles he investigated, Mendel observedphenotypic ¥2 ratios of 3:1 (see figure 13.13) and testcrossratios very close to 1:1, just as his model predicted.

Testcrosses can also be used to determine the genotype ofan individual when two genes are involved. Mendel carried outmany two-gene crosses, some of which we will soon discuss.He often used testcrosses to verify the genotypes of particulardominant-appearing p2 individuals. Thus an ¥2 individualshowing both dominant traits (A_ BJ) might have any of thefollowing genotypes: AABB, AaBB, AABb or AaBb. By crossingdominant-appearing ¥2 individuals with homozygous recessiveindividuals (that is, A_ B_ x aabb), Mendel was able to deter-mine if either or both of the traits bred true among the prog-eny, and so to determine the genotype of the ¥2 parent:

AABB

AaBB

AAbb

AaBb

trait A breeds true trait В breeds true

trait В breeds true

trait A breeds true

00

PP

Homozygousrecessive(white) All offspring are purple;

therefore, unknownflower is homozygous

т Dominant phenotype(unknown genotype)

if Pp

PP

Pp

Pp

PP

PP

Homozygousrecessive(white) Half of offspring are white;

therefore, unknown floweris heterozygous

Alternative 1 Alternative 2

FIGURE 13.15A testcross. To determine whether an individual exhibiting a dominant phenotype, such as purple flowers, is homozygous orheterozygous for the dominant allele, Mendel crossed the individual in question with a plant that he knew to be homozygous recessive, inthis case a plant with white flowers.


Mendel's Second Law of Heredity:Independent Assortment

After Mendel had demonstrated that different alleles of agiven gene segregate independently of each other incrosses, he asked whether different genes also segregate in-dependently. Mendel set out to answer this question in astraightforward way. He first established a series of pure-breeding lines of peas that differed in just two of the sevenpairs of characteristics he had studied. He then crossedcontrasting pairs of the pure-breeding lines to create het-erozygotes. In a cross involving different seed shape alleles(round, R, and wrinkled, r) and different seed color alleles(yellow, Y, and green, y), all the Fj individuals were identi-cal, each one heterozygous for both seed shape (Rr) andseed color (Yy). The FI individuals of such a cross are dihy-brids, individuals heterozygous for each of two genes.

The third step in Mendel's analysis was to allow the di-hybrids to self-fertilize. If the alleles affecting seed shapeand seed color were segregating independently, then theprobability that a particular pair of seed shape alleleswould occur together with a particular pair of seed coloralleles would be simply the product of the individual prob-abilities that each pair would occur separately. Thus, theprobability that an individual with wrinkled green seeds(rryy) would appear in the ¥2 generation would be equal tothe probability of observing an individual with wrinkledseeds (/4) times the probability of observing one with greenseeds (K), or УК,.

Since the genes concerned with seed shape and thoseconcerned with seed color are each represented by a pairof alternative alleles in the dihybrid individuals, four typesof gametes are expected: RY, Ry, rY, and ry. Therefore, inthe F2 generation there are 16 possible combinations ofalleles, each of them equally probable (figure 13.16). Ofthese, 9 possess at least one dominant allele for each gene(signified R Y , where the dash indicates the presenceof either allele) and, thus, should have round, yellowseeds. Of the rest, 3 possess at least one dominant R allelebut are homozygous recessive for color (R_yy); 3 otherspossess at least one dominant Y allele but are homozygousrecessive for shape (rrY ); and 1 combination among the16 is homozygous recessive for both genes (rryy). The hy-pothesis that color and shape genes assort independentlythus predicts that the p2 generation of this dihybrid crosswill display a 9:3:3:1 ratio: nine individuals with round,yellow seeds, three with round, green seeds, three withwrinkled, yellow seeds, and one with wrinkled, greenseeds (see figure 13.16).

What did Mendel actually observe? From a total of 556seeds from dihybrid plants he had allowed to self-fertilize,he observed:

315 round yellow (R_Y_)

108 round green (R yy)

101 wrinkled yellow (rrY, )

32 wrinkled green (rryy)

Round yellowseeds (RRYY)

Wrinkled greenseeds (rryy)

All round yellowseeds (RrYy)

Sperm

(RY к rY ry

Eggs

RRYY J

RRYy

RrYY

RrYy

RRYy

RRyy\

RrYy

Rryy

RrYY

RrYy

rrYY

rrYy

RrYy

^вгRryy

rrYy

rryy

F2 generation

9/16 are round yellow

3/16 are round green

3/16 are wrinkled yellow

1/16 are wrinkled green

FIGURE 13.16Analyzing a dihybrid cross. This Punnett square analyzes theresults of Mendel's dihybrid cross between plants with roundyellow seeds and plants with wrinkled green seeds. The ratio ofthe four possible combinations of phenotypes is predicted to be9:3:3:1, the ratio that Mendel found.

These results are very close to a 9:3:3:1 ratio (whichwould be 313:104:104:35). Consequently, the two genes ap-peared to assort completely independently of each other.Note that this independent assortment of different genes inno way alters the independent segregation of individual pairsof alleles. Round versus wrinkled seeds occur in a ratio of ap-proximately 3:1 (423:133); so do yellow versus green seeds(416:140). Mendel obtained similar results for other pairs.

Mendel's discovery is often referred to as Mendel'sSecond Law of Heredity, or the Law of IndependentAssortment. Genes that assort independently of one an-other, like the seven genes Mendel studied, usually do sobecause they are located on different chromosomes, whichsegregate independently during the meiotic process of ga-mete formation. A modern restatement of Mendel's SecondLaw would be that genes that are located on different chromo-somes assort independently during meiosis.

Mendel summed up his discoveries about heredity intwo laws. Mendel's First Law of Heredity states thatalternative alleles of a trait segregate independently; hisSecond Law of Heredity states that genes located ondifferent chromosomes assort independently.


Mendelian Inheritance Is NotAlways Easy to AnalyzeMendel's original paper describing his experiments, pub-lished in 1866, is charming and interesting to read. His ex-planations are clear, and the logic of his arguments is pre-sented lucidly. Although Mendel's results did not receivemuch notice during his lifetime, three different investiga-tors independently rediscovered his pioneering paper in1900, 16 years after his death. They came across it whilesearching the literature in preparation for publishing theirown findings, which closely resembled those Mendel hadpresented more than three decades earlier.

Modified Mendelian Ratios

In the decades following the rediscovery of Mendel in1900, many investigators set out to test Mendel's ideas. Ini-tial work was carried out primarily in agricultural animalsand plants, since techniques for breeding these organismswere well established. However, scientists attempting toconfirm Mendel's theory often had trouble obtaining thesame simple ratios he had reported. This was particularlytrue for dihybrid crosses. Recall that when individuals het-erozygous for two different genes mate (a dihybrid cross),four different phenotypes are possible among the progeny:offspring may display the dominant phenotype for bothgenes, either one of the genes, or for neither gene. Some-times, however, it is not possible for an investigator toidentify successfully each of the four phenotypic classes, be-cause two or more of the classes look alike. Such situationsproved confusing to investigators following Mendel.

Epistasis

One example of such difficulty in identification is seen inthe analysis of particular varieties of corn, Zevz mays. Somecommercial varieties exhibit a purple pigment called antho-cyanin in their seed coats, while others do not. In 1918,geneticist R. A. Emerson crossed two pure-breeding cornvarieties, neither exhibiting anthocyanin pigment. Surpris-ingly, all of the FI plants produced purple seeds.

When two of these pigment-producing FI plants werecrossed to produce an ¥2 generation, 56% were pigmentproducers and 44% were not. What was happening? Emer-son correctly deduced that two genes were involved in pro-ducing pigment, and that the second cross had thus been adihybrid cross like those performed by Mendel. Mendelhad predicted 16 equally possible ways gametes could com-bine with each other, resulting in genotypes with a pheno-typic ratio of 9:3:3:1 (9 + 3 + 3 + 1 = 16). How many ofthese were in each of the two types Emerson obtained? Hemultiplied the fraction that were pigment producers (0.56)by 16 to obtain 9, and multiplied the fraction that were not(0.44) by 16 to obtain 7. Thus, Emerson had a modifiedratio of 9:7 instead of the usual 9:3:3:1 ratio.

White

AAbb ааВВ

Purple

AII/AaBb

FIGURE 13.17How epistasis affects grain color. The purple pigment foundin some varieties of corn is the product of a two-stepbiochemical pathway. Unless both enzymes are active (the planthas a dominant allele for each of the two genes, A and B), nopigment is expressed.

Why Was Emerson's Ratio Modified? When genes actsequentially, as in a biochemical pathway, an allele ex-pressed as a defective enzyme early in the pathway blocksthe flow of material through the rest of the pathway. Thismakes it impossible to judge whether the later steps of thepathway are functioning properly. Such gene interaction,where one gene can interfere with the expression of an-other gene, is the basis of the phenomenon called epistasis.

The pigment anthocyanin is the product of a two-stepbiochemical pathway:

Enzyme 1 Enzyme 2Starting molecule —> Intermediate —> Anthocyanin

(Colorless) (Colorless) (Purple)

To produce pigment, a plant must possess at least onegood copy of each enzyme gene (figure 13.17). The domi-nant alleles encode functional enzymes, but the recessive al-leles encode nonfunctional enzymes. Of the 16 genotypespredicted by random assortment, 9 contain at least onedominant allele of both genes; they produce purple prog-eny. The remaining 7 genotypes lack dominant alleles at ei-ther or both loci (3 + 3 + 1 = 7) and so are phenotypicallythe same (nonpigmented), giving the phenotypic ratio of 9:7that Emerson observed. The inability to score enzyme2 when enzyme 1 is nonfunctional is an example of epistasis.


Continuous Variation

Few phenotypes are the result of the actionof only one gene. Instead, most traits reflectthe action of polygenes, many genes thatact sequentially or jointly. When multiplegenes act jointly to influence a trait such asheight or weight, the trait often shows arange of small differences. Because all of thegenes that play a role in determining pheno-types such as height or weight segregate in-dependently of one another, one sees a gra-dation in the degree of difference whenmany individuals are examined (figure13.18). We call this graduation continuousvariation. The greater the number of genesthat influence a trait, the more continuousthe expected distribution of the versions ofthat trait.

How can one describe the variation in atrait such as the height of the individuals infigure 13.18я? Individuals range from quiteshort to very tall, with average heightsmore common than either extreme. Whatone often does is to group the variation intocategories—in this case, by measuring theheights of the individuals in inches, round-ing fractions of an inch to the nearest wholenumber. Each height, in inches, is a sepa-rate phenotypic category. Plotting thenumbers in each height category produces ahistogram, such as that in figure 13.18£.The histogram approximates an idealizedbell-shaped curve, and the variation can becharacterized by the mean and spread ofthat curve.

Pleiotropic Effects

Often, an individual allele will have morethan one effect on the phenotype. Such anallele is said to be pleiotropic. When the pioneeringFrench geneticist Lucien Cuenot studied yellow fur inmice, a dominant trait, he was unable to obtain a true-breeding yellow strain by crossing individual yellow micewith each other. Individuals homozygous for the yellow al-lele died, because the yellow allele was pleiotropic: one ef-fect was yellow color, but another was a lethal develop-mental defect. A pleiotropic gene alteration may bedominant with respect to one phenotypic consequence(yellow fur) and recessive with respect to another (lethaldevelopmental defect). In pleiotropy, one gene affectsmany traits, in marked contrast to polygeny, where manygenes affect one trait. Pleiotropic effects are difficult topredict, because the genes that affect a trait often performother functions we may know nothing about.

30-

шя.1 20~Т!С

Num

ber

о

э о 1

1 1 - '

5

•

j

0"

1

/

5

\

У 6 О1

Height

(Ь)

FIGURE 13.18Height is a continuously varying trait, (a) This photograph shows the variation inheight among students of the 1914 class of the Connecticut Agricultural College.Because many genes contribute to height and tend to segregate independently of oneanother, there are many possible combinations of those genes, (b) The cumulativecontribution of different combinations of alleles to height forms a continuous spectrumof possible heights—a random distribution, in which the extremes are much rarerthan the intermediate values.

Pleiotropic effects are characteristic of many inheriteddisorders, such as cystic fibrosis and sickle cell anemia,both discussed later in this chapter. In these disorders,multiple symptoms can be traced back to a single genedefect. In cystic fibrosis, patients exhibit clogged bloodvessels, overly sticky mucus, salty sweat, liver and pancreasfailure, and a battery of other symptoms. All are pleio-tropic effects of a single defect, a mutation in a gene thatencodes a chloride ion transmembrane channel. In sicklecell anemia, a defect in the oxygen-carrying hemoglobinmolecule causes anemia, heart failure, increased suscepti-bility to pneumonia, kidney failure, enlargement of thespleen, and many other symptoms. It is usually difficult todeduce the nature of the primary defect from the range ofits pleiotropic effects.


Lack of Complete Dominance

Not all alternative alleles are fullydominant or fully recessive in het-erozygotes. Some pairs of alleles in-stead produce a heterozygous pheno-type that is either intermediatebetween those of the parents (incom-plete dominance), or representative ofboth parental phenotypes (codomi-nance). For example, in the cross ofred and white flowering Japanese fouro'clocks described in figure 13.19, allthe FI offspring had pink flowers—indicating that neither red nor whiteflower color was dominant. Does thisexample of incomplete dominanceargue that Mendel was wrong? Not atall. When two of the FI pink flowerswere crossed, they produced red-,pink-, and white-flowered plants in a1:2:1 ratio. Heterozygotes are simplyintermediate in color.

Environmental Effects

Sperm

CRCR

•Eggs

T generation

All CRCWCRCV

CWCW

The degree to which an allele isexpressed may depend on the envi-ronment. Some alleles are heat-sensitive, for example. Traits influ-enced by such alleles are more sensi-tive to temperature or light than arethe products of other alleles. Thearctic foxes in figure 13.20, for ex-ample, make fur pigment only whenthe weather is warm. Similarly, thech allele in Himalayan rabbits andSiamese cats encodes a heat-sensitiveversion of tyrosinase, one of the en-zymes mediating the production ofmelanin, a dark pigment. The chversion of the enzyme is inactivatedat temperatures above about 33°C.At the surface of the main body andhead, the temperature is above 33°Cand the tyrosinase enzyme is inactive, while it is moreactive at body extremities such as the tips of the ears andtail, where the temperature is below 33°C. The darkmelanin pigment this enzyme produces causes the ears,snout, feet, and tail of Himalayan rabbits and Siamesecats to be black.

F2 generation

1 : 2 : 1

CRCR:CRCW:CWCW

FIGURE 13.19Incomplete dominance. In a cross between a red-flowered Japanese four o'clock,genotype CRCR, and a white-flowered one (CWCW), neither allele is dominant. Theheterozygous progeny have pink flowers and the genotype CRCW. If two of theseheterozygotes are crossed, the phenotypes of their progeny occur in a ratio of 1:2:1(red:pink:white).

FIGURE 13.20Environmental effects on an allele. An arctic fox in winter has a coat that is almost white,so it is difficult to see the fox against a snowy background. In summer, the same fox's furdarkens to a reddish brown, so that it resembles the color of the surrounding tundra. Heat-sensitive alleles control this color change.

A variety of factors can disguise the Mendeliansegregation of alleles. Among them are geneinteractions that produce epistasis, the continuousvariation that results when many genes contribute to atrait, incomplete dominance that producesheterozygotes unlike either parent, and environmentalinfluences on the expression of phenotypes.


13.2 are on chromes.. • . - . - . -

Chromosomes: The Vehiclesof Mendelian InheritanceChromosomes are not the only kinds of structures that seg-regate regularly when eukaryotic cells divide. Centriolesalso divide and segregate in a regular fashion, as do the mi-tochondria and chloroplasts (when present) in the cyto-plasm. Therefore, in the early twentieth century it was byno means obvious that chromosomes were the vehicles ofhereditary information.

The Chromosomal Theory of Inheritance

A central role for chromosomes in heredity was first sug-gested in 1900 by the German geneticist Karl Correns, inone of the papers announcing the rediscovery of Mendel'swork. Soon after, observations that similar chromosomespaired with one another during meiosis led directly to thechromosomal theory of inheritance, first formulated bythe American Walter Sutton in 1902.

Several pieces of evidence supported Sutton's theory. Onewas that reproduction involves the initial union of only twocells, egg and sperm. If Mendel's model were correct, thenthese two gametes must make equal hereditary contribu-tions. Sperm, however, contain little cytoplasm, suggestingthat the hereditary material must reside within the nuclei ofthe gametes. Furthermore, while diploid individuals havetwo copies of each pair of homologous chromosomes, ga-metes have only one. This observation was consistent withMendel's model, in which diploid individuals have twocopies of each heritable gene and gametes have one. Finally,chromosomes segregate during meiosis, and each pair of ho-mologues orients on the metaphase plate independently ofevery other pair. Segregation and independent assortmentwere two characteristics of the genes in Mendel's model.

A Problem with the Chromosomal Theory

However, investigators soon pointed out one problem withthis theory. If Mendelian traits are determined by genes lo-cated on the chromosomes, and if the independent assort-ment of Mendelian traits reflects the independent assort-ment of chromosomes in meiosis, why does the number oftraits that assort independently in a given kind of organismoften greatly exceed the number of chromosome pairs theorganism possesses? This seemed a fatal objection, and itled many early researchers to have serious reservationsabout Sutton's theory.

Morgan's White-Eyed Fly

The essential correctness of the chromosomal theory ofheredity was demonstrated long before this paradox was

FIGURE 13.21Red-eyed (wild type) and white-eyed (mutant) Drosophila.The white-eyed defect is hereditary, the result of a mutation in agene located on the X chromosome. By studying this mutation,Morgan first demonstrated that genes are on chromosomes.

resolved. A single small fly provided the proof. In 1910Thomas Hunt Morgan, studying the fruit fly Drosophilamelanogaster, detected a mutant male fly, one that differedstrikingly from normal flies of the same species: its eyeswere white instead of red (figure 13.21).

Morgan immediately set out to determine if this newtrait would be inherited in a Mendelian fashion. He firstcrossed the mutant male to a normal female to see if red orwhite eyes were dominant. All of the FI progeny had redeyes, so Morgan concluded that red eye color was domi-nant over white. Following the experimental procedurethat Mendel had established long ago, Morgan thencrossed the red-eyed flies from the FI generation with eachother. Of the 4252 F2 progeny Morgan examined, 782(18%) had white eyes. Although the ratio of red eyes towhite eyes in the ¥2 progeny was greater than 3:1, the re-sults of the cross nevertheless provided clear evidence thateye color segregates. However, there was something aboutthe outcome that was strange and totally unpredicted byMendel's theory—all of the white-eyed p2 flies тоете males!

How could this result be explained? Perhaps it was im-possible for a white-eyed female fly to exist; such individu-als might not be viable for some unknown reason. To testthis idea, Morgan testcrossed the female FI progeny withthe original white-eyed male. He obtained both white-eyedand red-eyed males and females in a 1:1:1:1 ratio, just asMendelian theory predicted. Hence, a female could havewhite eyes. Why, then, were there no white-eyed femalesamong the progeny of the original cross?

256 PartlV Reproduction and Heredity

Y chromosome

Male

X chromosome withwhite-eye gene

Parents

X chromosome withred-eye gene

X

Female

Male

F1 generation

X

Female

F2 generation

FIGURE 13.22Morgan's experiment demonstratingthe chromosomal basis of sex linkagein Drosophila. The white-eyed mutantmale fly was crossed with a normal female.The FI generation flies all exhibited redeyes, as expected for flies heterozygous fora recessive white-eye allele. In the ¥2generation, all of the white-eyed flieswere male.

Sex Linkage

The solution to this puzzle involved sex. In Drosophila, thesex of an individual is determined by the number of copiesof a particular chromosome, the X chromosome, that anindividual possesses. A fly with two X chromosomes is a fe-male, and a fly with only one X chromosome is a male. Inmales, the single X chromosome pairs in meiosis with alarge, dissimilar partner called the Y chromosome. Thefemale thus produces only X gametes, while the male pro-duces both X and Y gametes. When fertilization involvesan X sperm, the result is an XX zygote, which develops intoa female; when fertilization involves a Y sperm, the result isan XY zygote, which develops into a male.

The solution to Morgan's puzzle is that the gene causingthe white-eye trait in Drosophila resides only on the Xchromosome—it is absent from the Y chromosome. (Wenow know that the Y chromosome in flies carries almost nofunctional genes.) A trait determined by a gene on the sex

chromosome is said to be sex-linked. Knowing the white-eye trait is recessive to the red-eye trait, we can now seethat Morgan's result was a natural consequence of theMendelian assortment of chromosomes (figure 13.22).

Morgan's experiment was one of the most important inthe history of genetics because it presented the first clearevidence that the genes determining Mendelian traits doindeed reside on the chromosomes, as Sutton had pro-posed. The segregation of the white-eye trait has a one-to-one correspondence with the segregation of the X chromo-some. In other words, Mendelian traits such as eye color inDrosophila assort independently because chromosomes do.When Mendel observed the segregation of alternative traitsin pea plants, he was observing a reflection of the meioticsegregation of chromosomes.

Mendelian traits assort independently because they aredetermined by genes located on chromosomes thatassort independently in meiosis.


Nocrossingover

carв

•~>f~\

"*•-•s

ou

Genetic RecombinationMorgan's experiments led to the general acceptance ofSutton's chromosomal theory of inheritance. Scientiststhen attempted to resolve the paradox that there are moreindependently assorting Mendelian genes than chromo-somes. In 1903 the Dutch geneticist Hugo de Vries sug-gested that this paradox could be resolved only by assum-ing that homologous chromosomes exchange elementsduring meiosis. In 1909, French cytologist F. A. Janssensprovided evidence to support this suggestion. Investigatingchiasmata produced during amphibian meiosis, Janssensnoticed that of the four chromatidsinvolved in each chiasma, twocrossed each other and two did not.He suggested that this crossing ofchromatids reflected a switch inchromosomal arms between the pa-ternal and maternal homologues, in-volving one chromatid in each ho-mologue. His suggestion was notaccepted widely, primarily becauseit was difficult to see how two chro-matids could break and rejoin at ex-actly the same position.

Crossing Over

Later experiments clearly estab-lished that Janssens was indeed cor-rect. One of these experiments,performed in 1931 by American ge-neticist Curt Stern, is described infigure 13.23. Stern studied two sex-linked eye traits in Drosophila strainswhose X chromosomes were visiblyabnormal at both ends. He first ex-amined many flies and identifiedthose in which an exchange had oc-curred with respect to the two eyetraits. He then studied the chromo-somes of those flies to see if theirX chromosomes had exchangedarms. Stern found that all of the in-dividuals that had exchanged eyetraits also possessed chromosomesthat had exchanged abnormal ends.The conclusion was inescapable:genetic exchanges of traits such aseye color involve the physical ex-change of chromosome arms, a phe-nomenon called crossing over.Crossing over creates new combina-tions of genes, and is thus a form ofgenetic recombination.

The chromosomal exchanges Stern demonstrated pro-vide the solution to the paradox, because crossing overcan occur between homologues anywhere along thelength of the chromosome, in locations that seem to berandomly determined. Thus, if two different genes arelocated relatively far apart on a chromosome, crossingover is more likely to occur somewhere between themthan if they are located close together. Two genes can beon the same chromosome and still show independent as-sortment if they are located so far apart on the chromo-some that crossing over occurs regularly between them(figure 13.24).

F! female

Abnormality at /F]another locus of ' UX chromosome

Abnormality atone locus ofX chromosome

car 1

car+

Fertilizationby spermfrom carnationF-| male

Qi~-~

car4-

p

v>

--X.

8

•

X

J

\

/

"4 car

4.

/ ^car car-IB +

]Carnation,bar

^

^

^I4-

Normal

carr-*.

+

^

~<~*

4~-

1

car4-

Carnation

\L

/

V

T+

rJ

/

чcar

.."-

^

^^

Q

8)+

в

DBar

Parental combinations ofboth genetic traits andchromosome abnormalities

Recombinant combinationsof both genetic traits andchromosome abnormalities

FIGURE 13.23Stern's experiment demonstrating the physical exchange of chromosomal arms duringcrossing over. Stern monitored crossing over between two genes, the recessive carnation eyecolor (car) and the dominant bar-shaped eye (B), on chromosomes with physical peculiaritiesvisible under a microscope. Whenever these genes recombined through crossing over, thechromosomes recombined as well. Therefore, the recombination of genes reflects a physicalexchange of chromosome arms. The "+" notation on the chromosomes refers to the wild-typeallele, the most common allele for a particular gene.


Using Recombination to Make Genetic Maps

Because crossing over is more frequent between two genesthat are relatively far apart than between two that are closetogether, the frequency of crossing over can be used to mapthe relative positions of genes on chromosomes. In a cross,the proportion of progeny exhibiting an exchange betweentwo genes is a measure of the frequency of crossover eventsbetween them, and thus indicates the relative distance sepa-rating them. The results of such crosses can be used to con-struct a genetic map that measures distance between genesin terms of the frequency of recombination. One "mapunit" is defined as the distance within which a crossoverevent is expected to occur in an average of 1% of gametes.A map unit is now called a centimorgan, after ThomasHunt Morgan.

In recent times new technologies have allowed geneti-cists to create gene maps based on the relative positionsof specific gene sequences called restriction sequences be-cause they are recognized by DNA-cleaving enzymescalled restriction endonucleases. Restriction maps, dis-cussed in chapter 18, have largely supplanted genetic re-combination maps for detailed gene analysis because theyare far easier to produce. Recombination maps remainthe method of choice for genes widely separated on achromosome.

The Three-Point Cross. In constructing a genetic map,one simultaneously monitors recombination among threeor more genes located on the same chromosome, referredto as syntenic genes. When genes are close enough to-gether on a chromosome that they do not assort indepen-dently, they are said to be linked to one another. A crossinvolving three linked genes is called a three-point cross.Data obtained by Morgan on traits encoded by genes onthe X chromosome of Drosophila were used by his studentA. H. Sturtevant, to draw the first genetic map (figure13.25). By convention, the most common allele of a gene isoften denoted on a map with the symbol "+" and is desig-nated as wild type. All other alleles are assigned specificsymbols.

Chromosomenumber

Location of genes

©

Flower color Seed color

©

Flower position

Pod color

Pod shape Plantheight

©

Seed shape

FIGURE 13.24The chromosomal locations of the seven genes studied byMendel in the garden pea. The genes for plant height and podshape are very close to each other and rarely recombine. Plantheight and pod shape were not among the pairs of traits Mendelexamined in dihybrid crosses. One wonders what he would havemade of the linkage he surely would have detected had he testedthis pair of traits.

FIGURE 13.25The first genetic map. This map ofthe X chromosome of Drosophila wasprepared in 1913 by A. H. Sturtevant, astudent of Morgan. On it he located therelative positions of five recessive traitsthat exhibited sex linkage by estimatingtheir relative recombination frequenciesin genetic crosses. Sturtevant arbitrarilychose the position of the yellow geneas zero on his map to provide a frameof reference. The higher therecombination frequency, the fartherapart the two genes.

Fivetraits

у Yellow body colorw White eye colorv Vermilion eye colorт Miniature wingr Rudimentary wing

Recombinationfrequencies

у andw 0.010v andm 0.030v andr 0.269v and w 0.300v and/ 0.322w and т 0.327у andm 0.355wandr 0.450

Geneticmap

.58

ол-O't

.31

.010

r~ -

—Г-.с

r

ту

wУ


Analyzing a Three-Point Cross. The first genetic mapwas constructed by A. H. Sturtevant, a student of Morgan'sin 1913. He studied several traits of Drosophila, all of whichexhibited sex linkage and thus were encoded by genes re-siding on the same chromosome (the X chromosome).Here we will describe his study of three traits: y, yellowbody color (the normal body color is grey), w, white eyecolor (the normal eye color is red), and min, miniaturewing (the normal wing is 50% longer).

Sturtevant carried out the mapping cross by crossing afemale fly homozygous for the three recessive alleles with anormal male fly that carried none of them. All of the prog-eny were thus heterozygotes. Such a cross is conventionallyrepresented by a diagram like the one that follows, in whichthe lines represent gene locations and + indicates the nor-mal, or "wild type" allele. Each female fly participating in across possesses two homologous copies of the chromosomebeing mapped, and both chromosomes are represented inthe diagram. Crossing over occurs between these twocopies in meiosis.

P generationу TV mm

у w mm (Y chromosome)

у in mmFI generationfemales + + +

These heterozygous females, the FI generation, are thekey to the mapping procedure. Because they are heterozy-gous, any crossing over that occurs during meiosis will, if itoccurs between where these genes are located, produce ga-metes with different combinations of alleles for thesegenes—in other words, recombinant chromosomes. Thus,a crossover between the homologous X chromosomes ofsuch a female in the interval between the у and w genes willyield recombinant \y +] and [+ TV] chromosomes, which aredifferent combinations than we started with. (In theparental chromosomes, w is always linked with у and+ linked with +.)

Table 13.2 summarizes the results Sturtevant obtained.The parentals are represented by the highest number ofprogeny and the double crossovers by the lowest number.To analyze his data, Sturtevant considered the traits inpairs and determined which involved a crossover event.

1. For the body trait (y) and the eye trait (w), the firsttwo classes, [+ +] and [y w], involve no crossovers(they are parental combinations). In table 13.2, noprogeny numbers are tabulated for these two classeson the "body-eye" column (a dash appears instead).

2. The next two classes have the same body-eye combi-nation as the parents, [+ +] and [y w], so again nonumbers are entered as recombinants under body-eyecrossover type.

3. The next two classes, [+ w] and [y +], do not have thesame body-eye combinations as the parent chromo-somes), so the observed numbers of progeny arerecorded, 16 and 12, respectively.

4. The last two classes also differ from parental chromo-somes in body-eye combination, so again the ob-served numbers of each class are recorded, 1 and 0.

5. The sum of the numbers of observed progeny thatare recombinant for body (y) and eye (TV) is 16 + 12+ 1, or 29. Since the total number of progeny is 2205,this represents 29/2205, or 0.01315. The percentageof recombination between у and w is thus 1.315%, or1.3 centimorgans.

To estimate the percentage of recombination betweeneye (TV) and wing (mm), one proceeds in the same manner,obtaining a value of 32.608%, or 32.6 centimorgans. Simi-larly, body (y) and wing (min) are separated by a recombi-nation distance of 33.832%, or 33.8 centimorgans.

From this, then, we can construct our genetic map. Thebiggest distance, 33.8 centimorgans, separates the two out-side genes, which are evidently у and min. The gene w isbetween them, near j/.

У + 1.3 32.6

—>

In order to see all the recombinant types that mightbe present among the gametes of these heterozygousflies, Sturtevant conducted a testcross. He crossed femaleheterozygous flies to males recessive for all three traitsand examined the progeny. Since males contribute eithera Y chromosome with no genes on it or an X chromo-some with recessive alleles at all three loci, the male con-tribution does not disguise the potentially recombinantfemale chromosomes.

The two distances 1.3 and 32.6 do not add up to 33.8but rather to 33.9. The difference, 0.1, represents chromo-somes in which two crossovers occurred, one between}' andw and another between w and min. These chromosomes donot exhibit recombination between у and min.

Genetic maps such as this are the key tools in geneticanalysis, permitting an investigator reliably to predict howa newly discovered trait, once it has been located on thechromosome map, will recombine with many others.


It ?S Si

Parental

Single crossover

Double crossover

Table 13.2 Яннщякявнининвн

Phenotypes

Body Eye Wing

+ + +

jy TV min

+ + ШВ

+ zy гш'и

^ + ++ ID +

j> + тяги

>turtevant s Results

Number ofProgeny

758

700

401

317

16

12

1

0

Body-Eye

—

- —

16

12

1

0

ИИш " ' • . . 'Crossover Types

Eye- Wing

—

401

317

—

1

0

Body-Wing

- —

401

317

16

12

—

—

TOTAL

Recombination frequency (%)

2205 29

1.315

719

32.608

746

33.832

The Human Genetic Map

Genetic maps of human chromosomes (figure 13.26) are ofgreat importance. Knowing where particular genes are lo-cated on human chromosomes can often be used to tellwhether a fetus at risk of inheriting a genetic disorder actu-ally has the disorder. The genetic-engineering techniquesdescribed in chapter 18 have begun to permit investigatorsto isolate specific genes and determine their nucleotide se-quences. It is hoped that knowledge of differences at thegene level may suggest successful therapies for particulargenetic disorders and that knowledge of a gene's locationon a chromosome will soon permit the substitution of nor-mal genes for dysfunctional ones. Because of the great po-tential of this approach, investigators are working hard toassemble a detailed map of the entire human genome, theso-called human genome project, described in chapter 18.Initially, this map will consist of a "library" of thousands ofsmall fragments of DNA whose relative positions areknown. Investigators wishing to study a particular gene willfirst use techniques described in chapter 18 to screen thislibrary and determine which fragment carries the gene ofinterest. They will then be able to analyze that fragment indetail. In parallel with this mammoth undertaking, the en-tire genomes of other, smaller genomes have already beensequenced, including yeasts and several bacteria. Progresson the human genome is rapid, and the full map is expectedwithin the decade.

Gene maps locate the relative positions of differentgenes on the chromosomes of an organism.Traditionally produced by analyzing the relativeamounts of recombination in genetic crosses, genemaps are increasingly being made by analyzing the sizesof fragments made by restriction enzymes.

I Ichthyosis, X-linkedI Placental steroid sulfatase deficiency,1 Kallmann syndrome

/I Chondrodysplasia punctata,/ I X-linked recessive

/"-•s-Y

Duchenne muscular dystrophy 'Becker muscular dystrophy I

Chronic granulomatous disease 'Retinitis pigmentosa-3 |

Norrie disease 1Retinitis pigrnentosa-2 |

PGK defii

Anhidrotic ectodermal dysplasia |

Agammaglobulinemia IKennedy disease I

Pelizaeus-Merzbacher disease IAlport syndrome

Fabry disease |

Immunodeficiency, X-linked, Iwith hyper IgM

.ymphoprohferative syndrome |

Г

temia'mesmia, X-iinked

1' Adrenal hypoplasia

Glycerol kinase deficiency

Ornithine transcarbamylasedeficiency

I lncontinentia pigmentiWiskott-Aldrich syndromeMenkes syndrome

| Androgen insensitivity

Charcot-lvlarie-Tooth neuropathyChoroideremiaCleft palate, X-linkedSpastic paraplegia, X-linked,

uncomplicatedDeafness with stapes fixation

:

PRPS-related gout

Lowe syndrome

:

Lesch-Nyhan syndromeHPRT-related gout

Hunter syndromeHemophilia В

Hemophilia AG6PD deficiency: favismDrug-sensitive anemiaChronic hemolytic anemiaManic-depressive illness, X-linkedColorblindness, {several forms)Dyskeratosis congenitaTKCR syndromeAdrenoleukodystrophyAdrenomyeloneuropathyErnery-Dreifuss muscular dystrophyDiabetes insipidus, renalMyotubular myopathy, X-linked

FIGURE 13.26The human X chromosome gene map. Over 59 diseases havebeen traced to specific segments of the X chromosome. Many ofthese disorders are also influenced by genes on otherchromosomes.

Lymphopi

Albinism-deafness syndrome \ I

Fragile-X syndrome |


endelian principles.

Multiple Alleles: The ABOBlood GroupsA gene may have more than two alleles in a population, andmost genes possess several different alleles. Often, no singleallele is dominant; instead, each allele has its own effect,and the alleles are considered codominant.

A human gene that exhibits more than one codominantallele is the gene that determines ABO blood type. Thisgene encodes an enzyme that adds sugar molecules to lipidson the surface of red blood cells. These sugars act as recog-nition markers for cells in the immune system and are calledcell surface antigens. The gene that encodes the enzyme, des-ignated 7, has three common alleles: IB, whose product addsthe sugar galactose; IA, whose product adds galactosamine;and /', which codes for a protein that does not add a sugar.

Different combinations of the three / gene alleles occur indifferent individuals because each person possesses two copiesof the chromosome bearing the / gene and may be homozy-gous for any allele or heterozygous for any two. An individualheterozygous for the IA and IB alleles produces both forms ofthe enzyme and adds bom galactose and galactosamine to thesurfaces of red blood cells. Because both alleles are expressedsimultaneously in heterozygotes, the IA and IB alleles arecodominant. Both IA and IB are dominant over the / allele be-cause both IA or IB alleles lead to sugar addition and the / al-lele does not. The different combinations of the three allelesproduce four different phenotypes (figure 13.27):

1. Type A individuals add only galactosamine. They areeither IAIA homozygotes or IAi heterozygotes.

2. Type В individuals add only galactose. They are ei-ther IBIB homozygotes or IBi heterozygotes.

3. Type AB individuals add both sugars and are IAfB

heterozygotes.4. Type О individuals add neither sugar and are

ii homozygotes.

These four different cell surface phenotypes are calledthe ABO blood groups or, less commonly, the Landsteinerblood groups, after the man who first described them. AsLandsteiner noted, a person's immune system can distin-guish between these four phenotypes. If a type A individualreceives a transfusion of type В blood, the recipient's im-mune system recognizes that the type В blood cells possess a"foreign" antigen (galactose) and attacks the donated bloodcells, causing the cells to clump, or agglutinate. This alsohappens if the donated blood is type AB. However, if thedonated blood is type O, no immune attack will occur, asthere are no galactose antigens on the surfaces of blood cellsproduced by the type О donor. In general, any individual'simmune system will tolerate a transfusion of type О blood.Because neither galactose nor galactosamine is foreign totype AB individuals (whose red blood cells have both sug-ars), those individuals may receive any type of blood.


Possible alleles from female

/*") or (f] or

_0)СО

о

ш_ш_ш"со_ф.О

8оCL

ог

/Л/.4

1A1B

JAJB

fli

Blood types

FIGURE 13.27Multiple alleles control the ABO blood groups. Differentcombinations of the three / gene alleles result in four differentblood type phenotypes: type A (either 1A1A homozygotes or lAiheterozygotes), type В (either PIB homozygotes or IBiheterozygotes), type AB (IAIB heterozygotes), and type О(ii homozygotes).

The Rh Blood Group

Another set of cell surface markers on human red bloodcells are the Rh blood group antigens, named for the rhe-sus monkey in which they were first described. About 85%of adult humans have the Rh cell surface marker on theirred blood cells, and are called Rh-positive. Rh-negativepersons lack this cell surface marker because they are ho-mozygous recessive for the gene encoding it.

If an Rh-negative person is exposed to Rh-positiveblood, the Rh surface antigens of that blood are treated likeforeign invaders by the Rh-negative person's immune sys-tem, which proceeds to make antibodies directed againstthe Rh antigens. This most commonly happens when anRh-negative woman gives birth to an Rh-positive child(whose father is Rh-positive). Some fetal red blood cellscross the placental barrier and enter the mother's blood-stream, where they induce the production of "anti-Rh" an-tibodies. In subsequent pregnancies, the mother's antibod-ies can cross back to the new fetus and cause its red bloodcells to clump, leading to a potentially fatal condition callederythroblastosis fetalis.

Many blood group genes possess multiple alleles,several of which may be common within populations.

Human ChromosomesIt wasn't until 1956 that techniques were developed that al-lowed investigators to determine the exact number of chro-mosomes in human cells. We now know that each humansomatic cell normally has 46 chromosomes, which in meio-sis form 23 pairs. By convention, the chromosomes are di-vided into seven groups (designated A through G), eachcharacterized by a different size, shape, and appearance.The differences among the chromosomes are most clearlyvisible when the chromosomes are arranged in order in akaryotype (figure 13.28). Techniques that stain individualsegments of chromosomes with different-colored dyesmake the identification of chromosomes unambiguous.Like a fingerprint, each chromosome always exhibits thesame pattern of colored bands.

Sex Chromosomes

Of the 23 pairs of human chromosomes, 22 are perfectlymatched in both males and females and are called auto-somes. The remaining pair, the sex chromosomes, con-sist of two similar chromosomes in females and two dis-similar chromosomes in males. In humans, as in Drosophila(but by no means in all diploid species), females are desig-nated XX and males XY. One of the pair of sex chromo-somes in the male (the Y chromosome) is highly con-densed and bears few functional genes in most organisms.Because few of the genes on the Y chromosome are ex-pressed, recessive alleles on a male's single X chromosomehave no active counterpart on the Y chromosome. Some ofthe active genes the Y chromosome does possess are re-sponsible for the features associated with "maleness" inhumans. Consequently, any individual with at least oneY chromosome is a male, and any individual without aY chromosome is a female.

FIGURE 13.28A human karyotype. This karyotype shows the colored bandingpatterns, arranged by class A-G.

Barr Bodies

Although males have only one copy of the X chromosomeand females have two, female cells do not produce twiceas much of the proteins encoded by genes on the X chro-mosome. Instead, one of the X chromosomes in females isinactivated early in embryonic development, shortly afterthe embryo's sex is determined. Which X chromosome isinactivated varies randomly from cell to cell. If a woman isheterozygous for a sex-linked trait, some of her cells willexpress one allele and some the other. The inactivatedand highly condensed X chromosome is visible as a deeplystaining Barr body attached to the nuclear membrane(figure 13.29).

One of the 23 pairs of human chromosomes carries thegenes that determine sex. The gene determiningmaleness is located on a version of the sex chromosomecalled Y, which has few other transcribed genes.

/ Randominactivation V

Zygote

Barr body

FIGURE 13.29Barr bodies. In the developing female embryo, one ot theX chromosomes (determined randomly) condenses and becomesinactivated. These condensed X chromosomes, called Barr bodies,then attach to the nuclear membrane.


Human AbnormalitiesDue to Alterations inChromosome NumberOccasionally, homologues or sisterchromatids fail to separate properly inmeiosis, leading to the acquisition orloss of a chromosome in a gamete.This condition, called primary non-disjunction, can result in individualswith severe abnormalities if the af-fected gamete forms a zygote.

Nondisjunction InvolvingAutosomes

6

13

7

it14

8

i15

9 10

-VVJ«

16

11

» *

12

It

18

19 20

*** — A'*"+

21 22 X Y

Almost all humans of the same sexhave the same karyotype, for the samereason that all automobiles have en-gines, transmissions, and wheels: otherarrangements don't work well. Humans who have lost evenone copy of an autosome (called monosomics) do not sur-vive development. In all but a few cases, humans who havegained an extra autosome (called trisomics) also do notsurvive. However, five of the smallest autosomes—thosenumbered 13, 15, 18, 21, and 22—can be present in hu-mans as three copies and still allow the individual to survivefor a time. The presence of an extra chromosome 13, 15, or18 causes severe developmental defects, and infants withsuch a genetic makeup die within a few months. In con-trast, individuals who have an extra copy of chromosome 21or, more rarely, chromosome 22, usually survive to adult-hood. In such individuals, the maturation of the skeletalsystem is delayed, so they generally are short and have poormuscle tone. Their mental development is also affected,and children with trisomy 21 or trisomy 22 are always men-tally retarded.

Down Syndrome. The developmental defect producedby trisomy 21 (figure 13.30) was first described in 1866 byJ. Langdon Down; for this reason, it is called Down syn-drome (formerly "Down's syndrome"). About 1 in every750 children exhibits Down syndrome, and the frequency issimilar in all racial groups. Similar conditions also occur inchimpanzees and other related primates. In humans, thedefect is associated with a particular small portion of chro-mosome 21. When this chromosomal segment is present inthree copies instead of two, Down syndrome results. In97% of the human cases examined, all of chromosome 21 ispresent in three copies. In the other 3%, a small portion ofchromosome 21 containing the critical segment has beenadded to another chromosome by translocation; it existsalong with the normal two copies of chromosome 21. Thiscondition is known as translocation Down syndrome.

FIGURE 13.30Down syndrome. As shown in this male karyotype, Down syndrome is associated withtrisomy of chromosome 21. A child with Down syndrome sitting on his father's knee.

ш

о-о 2с •£>> t±w !й

1.1о =Q оч- ОЪ о

8 sС Ф0) О.тз'о_с

100.0

30.0

20.0

10.0

3.0

2.0

1.0

0.3

I

/*

/•I

Т *

и/*/*

* • * • *• *•• •*•_ 0

1 1 1 1 1 1 115 20 25 30 35 40 45 50

Age of mother

FIGURE 13.31Correlation between maternal age and the incidence ofDown syndrome. As women age, the chances they will bear achild with Down syndrome increase. After a woman reaches 35,the frequency of Down syndrome increases rapidly.

Not much is known about the developmental role of thegenes whose duplication produces Down syndrome, althoughclues are beginning to emerge from current research. Someresearchers suspect that the gene or genes that produce Downsyndrome are similar or identical to some of the genes associ-ated with cancer and with Alzheimer's disease. The reasonfor this suspicion is that one of the human cancer-causinggenes (to be described in chapter 17) and the gene causing


Alzheimer's disease are located on the segment of chromo-some 21 associated with Down syndrome. Moreover, canceris more common in children with Down syndrome. The in-cidence of leukemia, for example, is 11 times higher in chil-dren with Down syndrome than in unaffected children ofthe same age.

How does Down syndrome arise? In humans, it comesabout almost exclusively as a result of primary nondisjunc-tion of chromosome 21 during egg formation. The cause ofthese primary nondisjunctions is not known, but their inci-dence, like that of cancer, increases with age (figure 13.31).In mothers younger than 20 years of age, the risk of givingbirdi to a child with Down syndrome is about 1 in 1700; inmothers 20 to 30 years old, the risk is only about 1 in 1400.In mothers 30 to 35 years old, however, the risk rises to1 in 750, and by age 45, the risk is as high as 1 in 16!

Primary nondisjunctions are far more common inwomen than in men because all of the eggs a woman willever produce have developed to the point of prophase inmeiosis I by the time she is born. By the time she has chil-dren, her eggs are as old as she is. In men, by contrast, newsperm develop daily. Therefore, there is a much greaterchance for problems of various kinds, including those thatcause primary nondisjunction, to accumulate over time inthe gametes of women than in those of men. For this rea-son, the age of the mother is more critical than that of thefather in couples contemplating childbearing.

Nondisjunction Involving the Sex Chromosomes

Individuals that gain or lose a sex chromosome do notgenerally experience the severe developmental abnormali-ties caused by similar changes in autosomes. Such individu-als may reach maturity, but they have somewhat abnormalfeatures.

The X Chromosome. When X chromosomes fail to sep-arate during meiosis, some of the gametes that are producedpossess both X chromosomes and so are XX gametes; theother gametes that result from such an event have no sexchromosome and are designated "O" (figure 13.32).

If an XX gamete combines with an X gamete, the result-ing XXX zygote develops into a female with one functionalX chromosome and two Barr bodies. She is sterile but usu-ally normal in other respects. If an XX gamete insteadcombines with a Y gamete, the effects are more serious.The resulting XXY zygote develops into a sterile male whohas many female body characteristics and, in some cases,diminished mental capacity. This condition, called Klinefel-ter syndrome, occurs in about 1 out of every 500 male births.

If an О gamete fuses with a Y gamete, the resulting OYzygote is nonviable and fails to develop further becausehumans cannot survive when they lack the genes on theX chromosome. If, on the other hand, an О gamete fuses withan X gamete, the XO zygote develops into a sterile female of

Female

FIGURE 13.32How nondisjunction can produce abnormalities in thenumber of sex chromosomes. When nondisjunction occursin the production of female gametes, the gamete with twoX chromosomes (XX) produces Klinefelter males (XXY) andXXX females. The gamete with no X chromosome (O) producesTurner females (XO) and nonviable OY males lacking anyX chromosome.

short stature, with a webbed neck and immature sex organsthat do not undergo changes during puberty. The mentalabilities of an XO individual are in the low-normal range.This condition, called Turner syndrome, occurs roughlyonce in every 5000 female births.

The Y Chromosome. The Y chromosome can also failto separate in meiosis, leading to the formation of YY ga-metes. When these gametes combine with X gametes, theXYY zygotes develop into fertile males of normal appear-ance. The frequency of the XYY genotype is about 1 per1000 newborn males, but it is approximately 20 timeshigher among males in penal and mental institutions. Thisobservation has led to the highly controversial suggestionthat XYY males are inherently antisocial, a suggestion sup-ported by some studies but not by others. In any case, mostXYY males do not develop patterns of antisocial behavior.

Gene dosage plays a crucial role in development, sohumans do not tolerate the loss or addition ofchromosomes well. Autosome loss is always lethal, andan extra autosonie is with few exceptions lethal too.Additional sex chromosomes have less seriousconsequences, although they can lead to sterility.


Human Genetic DisordersIn chapter 17 we will discuss the process of mutation, which pro-duces variant alleles. At this point, we will note only that muta-tion involves random changes in genes, and that such changesrarely improve the functioning of the proteins those genes en-code, just as randomly changing a wire in a computer rarely im-proves the computer's functioning. Therefore, variant allelesarising from mutation are rare in populations of organisms.

Nevertheless, some alternative alleles with detrimentaleffects are present in populations. Usually, they are reces-sive to other alleles. When two seemingly normal individu-als who are heterozygous for such an allele produce off-spring homozygous for the allele, the offspring suffer thedetrimental effects of the mutant allele. When a detrimen-tal allele occurs at a significant frequency in a population,the harmful effect it produces is called a genetic disorder.Table 13.3 lists some of the most prevalent genetic disor-ders in humans. We know a great deal about some of them,and much less about many others. Learning how to preventthem is one of the principal goals of human genetics.

Most Gene Defects Are Rare: Tay-Sachs Disease

Tay-Sachs disease is an incurable hereditary disorder inwhich the brain deteriorates. Affected children appear nor-mal at birth and usually do not develop symptoms untilabout the eighth month, when signs of mental deteriora-tion appear. The children are blind within a year afterbirth, and they rarely live past five years of age.

Tay-Sachs disease is rare in most human populations,occurring in only 1 of 300,000 births in the United States.However, the disease has a high incidence among Jews ofEastern and Central Europe (Ashkenazi), and amongAmerican Jews, 90% of whom trace their ancestry to East-

Per

cent

of n

orm

al e

nzy

me

fun

ctio

n

01

О

о

о

о

-

Tay-Sachs Carrier Normal(homozygous (heterozygous) (homozygous

recessive) dominant)

FIGURE 13.33Tay-Sachs disease. Homozygous individuals (left bar) typically haveless than 10% of die normal level of hexosaminidase k(rightbar), whileheterozygous individuals (middle bar) have about 50% of the normallevel—enough to prevent deterioration of the central nervous system.

ern and Central Europe. In these populations, it is esti-mated that 1 in 28 individuals is a heterozygous carrier ofthe disease, and approximately 1 in 3500 infants has thedisease. Because the disease is caused by a recessive allele,most of the people who carry the defective allele do notthemselves develop symptoms of the disease.

The Tay-Sachs allele produces the disease by encoding anonfunctional form of the enzyme hexosaminidase A. Thisenzyme breaks down gangliosides, a class of lipids occurringwithin the lysosomes of brain cells (figure 13.33). As a re-sult, the lysosomes fill with gangliosides, swell, and eventu-ally burst, releasing oxidative enzymes that kill the cells.There is no known cure for this disorder.

ant Genetic Disorders

Disorder

Cystic fibrosis

Sickle cell anemia

Tay-Sachs disease

Phenylketonuria

Hemophilia

Huntington's disease

Muscular dystrophy(Duchenne)

Hypercholesterolemia

Symptom

Mucus clogs lungs, liver,and pancreas

Poor blood circulation

Deterioration of centralnervous system in infancy

Brain fails to develop ininfancy

Blood fails to clot

Brain tissue graduallydeteriorates in middle age

Muscles waste away

Excessive cholesterol levelsin blood, leading to heartdisease

Defect

Failure of chloride iontransport mechanism

Abnormal hemoglobinmolecules

Defective enzyme(hexosaminidase A)

Defective enzyme(phenylalanine hydroxylase)

Defective blood clotting factorVIII

Production of an inhibitor ofbrain cell metabolism

Degradation of myelin coatingof nerves stimulating muscles

Abnormal form of cholesterolcell surface receptor

Dominant/Recessive

Recessive

Recessive

Recessive

Recessive

Sex-linkedrecessive

Dominant

Sex-linkedrecessive

Dominant

Frequency amongHuman Births

1/2500(Caucasians)

1/625(African Americans)

1/3500(Ashkenazi Jews)

1/12,000

1/10,000(Caucasian males)

1/24,000

1/3700(males)

1/500


Gene Defects Are Inherited in Families:Hemophilia

When a blood vessel ruptures, the blood in the immediatearea of the rapture forms a solid gel called a clot. The clotforms as a result of the polymerization of protein fibers cir-culating in the blood. A dozen proteins are involved in thisprocess, and all must function properly for a blood clot toform. A mutation causing any of these proteins to loosetheir activity leads to a form of hemophilia, a hereditarycondition in which the blood is slow to clot or does not clot

at all.Hemophilias are recessive disorders, expressed only

when an individual does not possess any copy of the normalallele and so cannot produce one of the proteins necessary forclotting. Most of the genes that encode the blood-clottingproteins are on autosomes, but two (designated VIII andIX) are on the X chromosome. These two genes are sex-linked: any male who inherits a mutant allele of either ofthe two genes will develop hemophilia because his othersex chromosome is a Y chromosome that lacks any allelesof those genes.

The most famous instance of hemophilia, often called theRoyal hemophilia, is a sex-linked form that arose in the royalfamily of England. This hemophilia was caused by amutation in gene IX that oc-curred in one of the parents ofQueen Victoria of England(1819-1901; figure 13.34). Inthe five generations sinceQueen Victoria, 10 of her maledescendants have had hemo-philia. The present Britishroyal family has escaped thedisorder because Queen Victo-ria's son, King Edward VII, didnot inherit the defective allele,and all the subsequent rulers ofEngland are his descendants.Three of Victoria's nine chil-dren did receive the defectiveallele, however, and they car-ried it by marriage into manyof the other royal families ofEurope (figure 13.35). It is stillbeing transmitted to futuregenerations through these fam-ily lines—except in Russia,where all of the five children ofAlexandra, Victoria's grand-daughter, were killed soonafter the Russian revolution in1917. (Speculation that onedaughter, Anastasia, mighthave survived ended in 1996when DNA analysis confirmedthe identity of her remains.)

FIGURE 13.34Queen Victoria of England, surrounded by some of herdescendants in 1894. Of Victoria's four daughters who lived tobear children, two, Alice and Beatrice, were carriers of Royalhemophilia. Two of Alice's daughters are standing behind Victoria(wearing feathered boas): Princess Irene of Prussia (right), andAlexandra (left), who would soon become Czarina of Russia. BothIrene and Alexandra were also carriers of hemophilia.

V I I

9Louis IIGrand Duke of Hesse

Frederick VictoriaIII

I No hemophilia |

1 Edward VIIAlice Duke of

HesseAlfred i Helena Arthu

("NO hemophilia ]

German r-4 KingRoyal '-r George VHouse

PrinceHenry

Princess Maurice Leopold QueenEugenie

Alfonso Jamie©

AlfonsoKing of

Spain

JuanGonzalo

ОKing Juan

Carlos

No evidenceof hemophilia

No evidenceof hemophilia

Spanish Royal House

British Royal House

William Henry

FIGURE 13.35The Royal hemophilia pedigree. Queen Victoria's daughter Alice introduced hemophilia into theRussian and Austrian royal houses, and Victoria's daughter Beatrice introduced it into the Spanishroyal house. Victoria's son Leopold, himself a victim, also transmitted the disorder in a third line ofdescent. Half-shaded symbols represent carriers with one normal allele and one defective allele; fullyshaded symbols represent affected individuals.


Gene Defects Often AffectSpecific Proteins: Sickle CellAnemia

Sickle cell anemia is a heritable disor-der first noted in Chicago in 1904. Af-flicted individuals have defective mole-cules of hemoglobin, the protein withinred blood cells that carries oxygen.Consequently, these individuals are un-able to properly transport oxygen totheir tissues. The defective hemoglobinmolecules stick to one another, form-ing stiff, rod-like structures and result-ing in the formation of sickle-shapedred blood cells (figure 13.36). As a re-sult of their stiffness and irregularshape, these cells have difficulty mov-ing through the smallest blood vessels;they tend to accumulate in those vesselsand form clots. People who have largeproportions of sickle-shaped red bloodcells tend to have intermittent illnessand a shortened life span.

The hemoglobin in the defectivered blood cells differs from that innormal red blood cells in only one ofhemoglobin's 574 ammo acid subunits.In the defective hemoglobin, theamino acid valine replaces a glutamicacid at a single position in the protein.Interestingly, the position of thechange is far from the active site of he-moglobin where the iron-bearingheme group binds oxygen. Instead, thechange occurs on the outer edge of theprotein. Why then is the result so cat-astrophic? The sickle cell mutationputs a very nonpolar amino acid on thesurface of the hemoglobin protein,creating a "sticky patch" that sticks toother such patches—nonpolar aminoacids tend to associate with one an-other in polar environments like water.As one hemoglobin adheres to an-other, ever-longer chains of hemoglo-bin molecules form.

Individuals heterozygous for thesickle cell allele are generally indistin-guishable from normal persons. How-ever, some of their red blood cells show the sickling charac-teristic when they are exposed to low levels of oxygen. Theallele responsible for sickle cell anemia is particularly com-mon among people of African descent; about 9% of AfricanAmericans are heterozygous for this allele, and about 0.2%are homozygous and therefore have the disorder. In somegroups of people in Africa, up to 45% of all individuals are

FIGURE 13.36Sickle cell anemia. In individuals homozygous for the sickle cell trait, many of the redblood cells have sickle or irregular shapes, such as the cell on the far right.

Sickle cell \ / Falciparumallele in Africa malaria in Africa

I -5%

Hi 0-20%

FIGURE 13.37The sickle cell allele confers resistance to malaria. The distribution of sickle cellanemia closely matches the occurrence of malaria in central Africa. This is not acoincidence. The sickle cell allele, when heterozygous, confers resistance to malaria, avery serious disease.

heterozygous for this allele, and fully 6% are homozygousand express the disorder. What factors determine the highfrequency of sickle cell anemia in Africa? It turns out thatheterozygosity for the sickle cell anemia allele increases re-sistance to malaria, a common and serious disease in centralAfrica (figure 13.37). We will discuss this situation in moredetail in chapter 19.


Not All Gene Defects Are Recessive:Huntington's Disease

Not all hereditary disorders are recessive. Huntington'sdisease is a hereditary condition caused by a dominant al-lele that causes the progressive deterioration of brain cells(figure 13.38). Perhaps 1 in 24,000 individuals develops thedisorder. Since the allele is dominant, every individual thatcarries the allele expresses the disorder. Nevertheless, thedisorder persists in human populations because its symp-toms usually do not develop until the affected individualsare more than 30 years old, and by that time most of thoseindividuals have already had children. Consequently, theallele is often transmitted before the lethal condition devel-ops. A person who is heterozygous for Huntington's dis-ease has a 50% chance of passing the disease to his or herchildren (even though the other parent does not have thedisorder). In contrast, the carrier of a recessive disordersuch as cystic fibrosis has a 50% chance of passing the alleleto offspring and must mate with another carrier to riskbearing a child with the disease.

Some Gene Defects May Soon Be Curable:Cystic Fibrosis

Some of the most common and serious gene defects resultfrom single recessive mutations, including many of the de-fects listed in table 13.3. Recent developments in genetechnology have raised the hope that this class of disordersmay be curable. Perhaps the best example is cystic fibrosis,the most common fatal genetic disorder among Caucasians(figure 13.39). As we learned in chapter 6, affected individ-uals secrete a thick mucus that clogs their lungs, and thepassages of their pancreas and liver. About 1 in 20 Cau-casians has a copy of the defective gene but shows no symp-toms; homozygous recessive individuals make up about 1 in2500 Caucasian children. These individuals inevitably diefrom complications that result from their disease.

We know that the cause of cystic fibrosis is a defect inthe way certain cells regulate the transport of chlorideions across their membranes. Cystic fibrosis occurs whenan individual is homozygous for an allele that encodes adefective version of the protein that regulates the chlo-ride transport channel. This allele is recessive to the genethat codes for the normal version of the regulatory pro-tein, so the chloride channels of heterozygous individualsfunction normally and the individuals do not develop cys-tic fibrosis.

The gene responsible for cystic fibrosis, dubbed CFTRfor cystic fibrosis transmembrane regulator, was isolated in1989, and attempts are underway to introduce healthycopies of the gene into cystic fibrosis patients. This genetransfer therapy was carried out successfully with mice in1994, but initial attempts to introduce the gene into hu-mans (using cold viruses to carry the gene) have not yetsucceeded. These procedures are discussed in detail inchapter 18.

100

75 -

о 50

CDQ-

25 -

Huntington'sdisease

10 20 30 40 50

Age in years

60 70 80

FIGURE 13.38Huntington's disease is a dominant genetic disorder. It isbecause of the late age of onset of this disease that it persistsdespite the fact that it is dominant and fatal.

FIGURE 13.39A child with cystic fibrosis. In cystic fibrosis patients, the mucusthat normally lines the insides of the lungs thickens, makingbreathing difficult. Affected children are expected to live intotheir late twenties.

Many heritable disorders are the result of recessivemutations in genes encoding critical proteins such asthose that clot blood, carry oxygen, or transportchloride ions into and out of cells. All such disordersare potentially curable if ways can be found tosuccessfully introduce undamaged copies of the genesinto affected individuals.


Amniotic fluidGenetic CounselingAlthough most genetic disorders can-not yet be cured, we are learning agreat deal about them, and progresstoward successful therapy is beingmade in many cases. In the absence ofa cure, however, the only recourse isto try to avoid producing childrenwith these conditions. The process ofidentifying parents at risk of produc-ing children with genetic defects andof assessing the genetic state of earlyembryos is called genetic counseling.

If a genetic defect is caused by a re-cessive allele, how can potential par-ents determine the likelihood that theycarry the allele? One way is throughpedigree analysis, often employed as anaid in genetic counseling. By analyzinga person's pedigree, it is sometimespossible to estimate the likelihood thatthe person is a carrier for certain disor-ders. For example, if one of your rela-tives has been afflicted with a recessivegenetic disorder such as cystic fibrosis,it is possible that you are a heterozy-gous carrier of the recessive allele for that disorder. When acouple is expecting a child, and pedigree analysis indicatesthat both of them have a significant probability of beingheterozygous carriers of a recessive allele responsible for aserious genetic disorder, the pregnancy is said to be a high-risk pregnancy. In such cases, there is a significant proba-bility that the child will exhibit the clinical disorder.

Another class of high-risk pregnancies is that in whichthe mothers are more than 35 years old. As we have seen,the frequency of birth of infants with Down syndrome in-creases dramatically in the pregnancies of older women (seefigure 13. 31).

When a pregnancy is diagnosed as being high-risk, manywomen elect to undergo amniocentesis, a procedure that per-mits the prenatal diagnosis of many genetic disorders (figure1 3 .40). In the fourth month of pregnancy, a sterile hypoder-mic needle is inserted into the expanded uterus of themother, removing a small sample of the amniotic fluidbathing the fetus. Within the fluid are free-floating cells de-rived from the fetus; once removed, these cells can be grownin cultures in the laboratory. During amniocentesis, the po-sition of the needle and that of the fetus are usually observedby means of ultrasound (figure 13.41). The sound waves usedin ultrasound are not harmful to mother or fetus, and theypermit the person withdrawing the amniotic fluid to do sowithout damaging the fetus. In addition, ultrasound can beused to examine the fetus for signs of major abnormalities.

In recent years, physicians have increasingly turned to anew, less invasive procedure for genetic screening calledchorionic villi sampling. In this procedure, the physician

FIGURE 13.40Amniocentesis. A needle is inserted into the amniotic cavity, and a sample of amnioticfluid, containing some free cells derived from the fetus, is withdrawn into a syringe. Thefetal cells are then grown in culture and their karyotype and many of their metabolicfunctions are examined.

FIGURE 13.41An ultrasound view of a fetus. During the fourth month ofpregnancy, when amniocentesis is normally performed, the fetususually moves about actively. The head of the fetus above is to the left.

removes cells from the chorion, a membranous part of theplacenta that nourishes the fetus. This procedure can beused earlier in pregnancy (by the eighth week) and yieldsresults much more rapidly than does amniocentesis.


_GJ(2AJ\T T С

с т ТА A)()Gt

Cut

Z^GA^ATT^CГЖЬ1АА^ Q ZIIIZZZZZ

tCut

G J f J A A T T C

С Т ТА A )(}G

tCut

Short fragment Medium-length fragment

Long

Medium-length fragment— Short fragment

Short(a) No mutation Gel electrophoresis

G A M A T T 3

C T T A A }()( Т А ' А С

tCut

Long-length fragment

iLong-length fragment

Long_^___^J

-*• Short(b) Mutation Gel electrophoresis

tCut

FIGURE 13.42RFLPs. Restriction fragment lengthpolymorphisms (RFLPs) are playingan increasingly important role ingenetic identification. In (a), therestriction endonuclease cuts theDNA molecule in three places,producing two fragments. In (b), themutation of a single nucleotide fromG to A (see top fragment) alters arestriction endonuclease cutting site.Now the enzyme no longer cuts theDNA molecule at that site. As aresult, a single long fragment isobtained, rather than two shorterones. Such a change is easy to detectwhen the fragments are subjected to atechnique called gel electrophoresis.

To test for certain genetic disorders, genetic counselorscan look for three things in the cultures of cells obtainedfrom amniocentesis or chorionic villi sampling. First,analysis of the karyotype can reveal aneuploidy and grosschromosomal alterations. Second, in many cases it is possi-ble to test directly for the proper functioning of enzymes in-volved in genetic disorders. The lack of normal enzymaticactivity signals the presence of the disorder. Thus, the lackof the enzyme responsible for breaking down phenylalaninesignals PKU, the absence of the enzyme responsible for thebreakdown of gangliosides indicates Tay-Sachs disease, andso forth.

Third, genetic counselors can look for an association -withknown genetic markers. For sickle cell anemia, Huntington'sdisease, and one form of muscular dystrophy (a genetic dis-order characterized by weakened muscles), investigatorshave found other mutations on the same chromosomes

that, by chance, occur at about the same place as the muta-tions that cause those disorders. By testing for the presenceof these other mutations, a genetic counselor can identifyindividuals with a high probability of possessing the disorder-causing mutations. Finding such mutations in the first placeis a little like searching for a needle in a haystack, but per-sistent efforts have proved successful in these three disor-ders. The associated mutations are detectable because theyalter the length of the DNA segments that restriction en-zymes produce when they cut strands of DNA at particularplaces (see chapter 18). Therefore, these mutations producewhat are called restriction fragment length polymor-phisms, or RFLPs (figure 13.42).

Many gene defects can be detected early in pregnancy,allowing for appropriate planning by the prospectiveparents.


Probability anaAllele Distribution

Many, although not all, alternative allelesproduce discretely different phenotypes.Mendel's pea plants were tall or dwarf, hadpurple or white flowers, and producedsmooth or shriveled seeds. The eye color ofa fruit fly may be red or white, and the skincolor of a human may be pigmented or al-bino. When only two alternative allelesexist for a given trait, the distribution ofphenotypes among the progeny of a cross isreferred to as a binomial distribution.

As an example, consider the distributionof sexes in humans. Imagine that a couplehas chosen to have three children. Howlikely is it that two of the children will beboys and one will be a girl? The frequencyof any particular possibility is referred to asits probability of occurrence. Letp symbol-ize the probability of having a boy at anygiven birth and q symbolize the probabilityof having a girl. Since any birth is equallylikely to produce a girl or boy:

p - f . M

Table 13.A shows eight possible gendercombinations among the three children.The sum of the probabilities of the eightdifferent ways must equal one. Thus:

/>3 + !>p2q + 3pq2 + q* = I

The probability that the three childrenwill be two boys and one girl is:

3p2g = 3 x (И)2 x (M) = X

To test your understanding, try to esti-mate the probability that two parents het-erozygous for the recessive allele producingalbinism (a) will have one albino child in afamily of three. First, set up a Punnett square:

Mother's AGametes a

Father'sGametesA a

AA AaAa aa

You can see that one-fourth of the chil-dren are expected to be albino {aa). Thus,for any given birth the probability of analbino child is 1A. This probability can besymbolized by q. The probability of anonalbino child is !4, symbolized by p.Therefore, the probability that there willbe one albino child among the three chil-dren is:

Ip2<j = 3 x (X4)2 x (!4) = %, or 42%

This means that the chance of producingone albino child in the three is 42%.

Compositionof Family

3 boys

2 boys and 1 girl

1 boy and 2 girls

3 girls

Orderof Birth

bbbbbgbgbgbb

ggb

gbg

bgg

ggg

Calculation

p xp xp

pxpxq

pxgxp

qxpxp

qxqxp

qxpxq

pxq Xq

qXqXq

Probability

P1

P2q \P2iP2qРЧ2

pq2

pq2 ,

1P24

W

<f

A Vocabularyof Genetics

allele One of two or more alternativeforms of a gene.

diploid Having two sets of chromosomes,which are referred to as homologues. Animalsare diploid as well as plants in the dominantphase of their life cycle as are some protists.

dominant allele An allele that dictatesthe appearance of heterozygotes. One alleleis said to be dominant over another if a het-erozygous individual with one copy of thatallele has the same appearance as a homozy-gous individual with two copies of it.

gene The basic unit of heredity; a se-quence of DNA nucleotides on a chromo-some that encodes a polypeptide or RNAmolecule and so determines the nature ofan individual's inherited traits.

genotype The total set of genes presentin the cells of an organism. This term isoften also used to refer to the set of allelesat a single gene locus.

haploid Having only one set of chromo-somes. Gametes, certain animals, protistsand fungi, and certain stages in the life cycleof plants are haploid.

heterozygote A diploid individual carry-ing two different alleles of a gene on its twohomologous chromosomes. Most humanbeings are heterozygous for many genes.

homozygote A diploid individual whosetwo copies of a gene are the same. An indi-vidual carrying identical alleles of a gene onboth homologous chromosomes is said tobe homozygous for that gene.

locus The location of a gene on achromosome.

phenotype The realized expression ofthe genotype; the observable manifesta-tion of a trait (affecting an individual'sstructure, physiology, or behavior) that re-sults from the biological activity of theDNA molecules.

recessive allele An allele whose pheno-typic effect is masked in heterozygotes bythe presence of a dominant allele.


13.1 Mendel solved the mystery of heredity.

• Koelreuter noted the basic facts of heredity a centurybefore Mendel. He found that alternative traitssegregate in crosses and may mask each other'sappearance. Mendel, however, was the first to quantifyhis data, counting the numbers of each alternative typeamong the progeny of crosses.

• By counting progeny types, Mendel learned that thealternatives that were masked in hybrids (the FIgeneration) appeared only 2 5 % of the time in the p2generation. This finding, which led directly to Mendel'smodel of heredity, is usually referred to as theMendelian ratio of 3:1 dominant-to-recessive traits.

• Mendel deduced from the 3:1 ratio that traits arespecified by discrete "factors" that do not blend. Hededuced that pea plants contain two factors for each traitdiat he studied (we now know this is because the plantsare diploid). When a plant is heterozygous for a trait,the two factors for that trait are not the same, and onefactor, which Mendel described as dominant, determinesthe appearance, or phenotype, of the individual. Wenow refer to Mendel's factors as genes and to alternativeforms of genes as alleles.

• When two heterozygous individuals mate, an individualoffspring has a 50% (that is, random) chance of obtainingme dominant allele from the father and a 50% chanceof obtaining the dominant allele from the mother;dierefore, the probability of being homozygous recessiveis 25%. The progeny thus appear as % dominant and14 recessive, a dominant-to-recessive ratio of 3:1.

• When two genes are located on different chromosomes,the alleles included in an individual gamete aredistributed at random. The allele for one gene includedin the gamete has no influence on which allele of theother gene is included in the gamete. Such genes aresaid to assort independently.

• Because phenotypes are often influenced by more thanone gene, the ratios of alternative phenotypes observedin crosses sometimes deviate from the simple ratios

predicted by Mendel. This is particularly true in epistaticsituations, where the product of one gene masks another.

Genes are on chromosomes.

The first clear evidence that genes reside onchromosomes was provided by Thomas Hunt Morgan,who demonstrated that the segregation of the white-eyetrait in Drosophila is associated with the segregation of meX chromosome, which is involved in sex determination.

The first genetic evidence that crossing over occursbetween chromosomes was provided by Curt Stern, whoshowed that when two Mendelian traits exchange duringa cross, so do visible abnormalities on the ends of thechromosomes bearing those traits.

The frequency of crossing over between genes canbe used to construct genetic maps, which arerepresentations of the physical locations of genes onchromosomes, inferred from the frequency of crossingover between particular pairs of genes.

Human genetics follows Mendelian principles.

Primary nondisjunction results when chromosomes do notseparate during meiosis, leading to gametes with missingor extra chromosomes. In humans, the loss of an autosomeis invariably fatal. Gaining an extra autosome, which leadsto a condition called trisomy, is also fatal, wirn only twoexceptions: trisomy of chromosomes 21 and 22.

Some genetic disorders are relatively common in humanpopulations; others are rare. Many of the most importantgenetic disorders are associated with recessive alleles,which may lead to the production of defective versions ofenzymes that normally perform critical functions.Because such traits are determined by recessive allelesand, therefore, are not expressed in heterozygotes, thealleles are not eliminated from the human population,even though their effects in homozygotes may be lethal.

While there are no cures for any genetic disorder atpresent, many of these conditions can be identifiedthrough genetic therapy.

Homozygous/heterozygous Different versions of thesame gene are called alleles; each diploid offspringreceives one allele from each parent. A diploid individualcontaining two copies of the same allele is homozygous;an individual containing two different alleles isheterozygous.

Dominance In many cases, one (dominant) allele will"mask" the presence of another (recessive) allele in aheterozygous individual, so that the individual shows thedominant trait.

3. The chromosomal theory of inheritance Mendeliantraits are usually the result of the expression of particulargenes located on chromosomes. Each gene is a segmentof DNA encoding a protein.

4. Nondisjunction Errors during meiosis may yieldgametes with either extra or missing chromosomes. In afew instances, these gametes can produce zygotes thatdevelop into individuals with mild to profoundabnormalities.


1. How did Koelreuter's experiments on tobacco plants conflict withthe ideas regarding heredity that were prevalent at that time? Whyweren't the implications of his results recognized for a century?

2. What characteristics of the garden pea made this organism agood choice for Mendel's experiments on heredity?

3. How did Mendel produce self-fertilization in the garden pea?How did he produce cross-fertilization?

4. To determine whether a purple-flowered pea plant of unknowngenotype is homozygous or heterozygous, what type of plantshould it be crossed with? What would the offspring of this crossbe like if the plant with unknown genotype were homozygous?What would the offspring be like if it were heterozygous?

5. In л dihybrid cross, what is the ratio of expected phenotypes?What fraction of the offspring should be homozygous recessivefor both traits? What fraction of the offspring should behomozygous dominant for both traits?

6. What is primary nondisjunction? How is it related to Downsyndrome? hi humans, how are the age and sex of an individual relatedto me likelihood of producing gametes affected by nondisjunction?

7. What is the sex chromosome genotype of an individual withKlinefelter syndrome? Is such an individual genetically male orfemale? Why? Would such an individual usually have male orfemale body characteristics?

8. Is Huntington's disease a dominant or a recessive geneticdisorder? Why is it maintained at its current frequency in humanpopulations?

1. Why did Mendel observe only two alleles of any given trait inthe crosses that he carried out?

2. How might Mendel's results and the model he formulated havebeen different if the traits he chose to study were governed byalleles exhibiting incomplete dominance or codominance?

3. If a heterozygous, Rh-positive woman and a homozygous, Rh-negative man produce an Rh-negative fetus, will the fetus developantibodies against the Rh antigens and kill the mother? Explainyour reasoning.

'

Mendelhttp://ww.stg.brown.edu/MendelWeb/An outstanding site from Brown University for those interested inMendel and his experiments, ivith excellent supplementary materials.

Classic Papers in Mendelian Geneticshttp://www.esp.org/foundations/genetics/classical/A -wonderful collection of original historically-significant papers, includ-ing key papers by Mendel, Eateson, Morgan, and many others.

Virtual Drosophila Crosseshttp://uflylab.calstatela.edu/edesktop/VirtApps/VrflylabIntroVflylab.htmlThe VIRTUAL FLY LAB allows you to learn the principles of geneticinheritance by mating virtual fruit flies and analyzing the offspring.

Online Mendelian Inheritance in Manhttp://www3.ncbi.nlm.nih.gov/omimThe single largest resource on human genetics, this site, maintained bythe National Center of Biotechnology Information of the NIH, providesan extensive data base of genetic disorders and information on individualhuman genes. Over 9,300 genes are included, with roughly 50 newgenes added each month.

Searching For a Curehttp://www.hhmi.org/GeneticTrail/BLAZING A GENETIC TRAIL provides a -wonderful account ofhuman hereditary disorders, their causes, and the on-going search for cures.Prepared by the Howard Hughes Medical Institute. Highly Recommended.

Blixt, S.: "Why Didn't Gregor Mendel Find Linkage?" Nature,vol. 256, 1975, page 206. Modern information on the chromo-somal location of the genes Mendel studied.

Corcos, A., and F. Monaghan: "Mendel's Work and Its Rediscovery: ANew Perspective," Critical Reviews in Plant Sciences, vol. 9, May 1990,pages 197-212. An evaluation of the myths surrounding Mendel's work.

Diamond, J.: "Blood, Genes, and Malaria," Natural History, February1989. An account of the evolutionary history of sickle cell anemia.

Mendel, G.: "Experiments on Plant Hybridization,"(1866), translated and reprinted in The Origins of Genetics: AMendel Source Book, C. Stern and E. Sherwood (eds.), W. H. Free-man, San Francisco, 1966. Mendel's original research, largelyignored for over 30 years.

Morgan, Т. Н.: "Sex-Limited Inheritance in Drosophila," Science,vol. 32, 1910, pages 120-22. Morgan's original account of his fa-mous analysis of the inheritance of the white-eye trait.

Mulligan, R.: "The Basic Science of Gene Therapy," Science,vol. 260, May 14, 1993, pages 926-32. An overview of gene ther-apy, how far we've come, and how it works.

Patterson, D.: "The Causes of Down Syndrome," Scientific Ameri-can, August 1987, pages 52-60. A cluster of genes on chromosome21 associated with Down syndrome are being identified and studied.

Verma, L: "Gene Therapy," Scientific American, November 1990,pages 68-84. Treatment of genetic disorders by introducinghealthy genes into the body of an affected individual is producingexciting results.


Mendelian Genetics Problems1. The illustration describes Mendel's cross of wrinkled

and round seed characters. (Hint: Do you expect allthe seeds in a pod to be the same?) What is wrongwith this diagram?

F1 generation(all round seeds)

Round seeds (3) Wrinkled seeds (1)

The annual plant Haplopappus gradlis has two pairs ofchromosomes 1 and 2. In this species, the probabilitythat two traits a and b selected at random will be onthe same chromosome is equal to the probability thatthey will both be on chromosome 1 (]A x И = У-t, or0.25), plus the probability that they will both be onchromosome 2 (also !4 x И = К, or 0.25), for an overallprobability of И, or 0.5. In general, the probabilitythat two randomly selected traits will be on the samechromosome is equal to % where n is the numberof chromosome pairs. Humans have 23 pairs of chro-mosomes. What is the probability that any twohuman traits selected at random will be on the samechromosome?Among Hereford cattle there is a dominant allelecalled polled; the individuals that have this allelelack horns. Suppose you acquire a herd consistingentirely of polled cattle, and you carefully deter-

mine that no cow in the herd has horns. Some ofthe calves born that year, however, grow horns.You remove them from the herd and make certainthat no horned adult has gotten into your pasture.Despite your efforts, more horned calves are bornthe next year. What is the reason for the appear-ance of the horned calves? If your goal is to main-tain a herd consisting entirely of polled cattle, whatshould you do?

4. An inherited trait among humans in Norway causesaffected individuals to have very wavy hair, not unlikethat of a sheep. The trait, called woolly, is very evidentwhen it occurs in families; no child possesses woollyhair unless at least one parent does. Imagine you are aNorwegian judge, and you have before you a woolly-haired man suing his normal-haired wife for divorcebecause their first child has woolly hair but their sec-ond child has normal hair. The husband claims thisconstitutes evidence of his wife's infidelity. Do youaccept his claim? Justify your decision.

5. In human beings, Down syndrome, a serious develop-mental abnormality, results from the presence ofthree copies of chromosome 21 rather than the usualtwo copies. If a female exhibiting Down syndromemates with a normal male, what proportion of heroffspring would you expect to be affected?

6. Many animals and plants bear recessive alleles for al-binism, a condition in which homozygous individualslack certain pigments. An albino plant, for example,lacks chlorophyll and is white, and an albino humanlacks melanin. If two normally pigmented persons het-erozygous for the same albinism allele marry, what pro-portion of their children would you expect to be albino?

7. You inherit a racehorse and decide to put him out tostud. In looking over the stud book, however, youdiscover that the horse's grandfather exhibited a raredisorder that causes brittle bones. The disorder ishereditary and results from homozygosity for a reces-sive allele. If your horse is heterozygous for the allele,it will not be possible to use him for stud, since thegenetic defect may be passed on. How would you de-termine whether your horse carries this allele?

8. In the fly Drosophila, the allele for dumpy wings (d) isrecessive to the normal long-wing allele (d+), and theallele for white eye (w) is recessive to the normal red-eye allele (w+). In a cross of d+d+w+w x d+divw, whatproportion of the offspring are expected to be "nor-mal" (long wings, red eyes)? What proportion are ex-pected to have dumpy wings and white eyes?

9. Your instructor presents you with a Drosophila withred eyes, as well as a stock of white-eyed flies and an-other stock of flies homozygous for the red-eye allele.You know that the presence of white eyes in Drosophilais caused by homozygosity for a recessive allele. Howwould you determine whether the single red-eyed flywas heterozygous for the white-eye allele?


10. Some children are born with recessive traits (and,therefore, must be homozygous for the recessive al-lele specifying the trait), even though neither of theparents exhibits the trait. What can account for this?

11. You collect two individuals of Drosophila, one a youngmale and the other a young, unmated female. Bothare normal in appearance, with the red eyes typical ofDrosophila. You keep the two flies in the same bottle,where they mate. Two weeks later, the offspring theyhave produced all have red eyes. From among the off-spring, you select 100 individuals, some male andsome female. You cross each individually with a flyyou know to be homozygous for the recessive allelesepia, which produces black eyes when homozygous.Examining the results of your 100 crosses, you ob-serve that in about half of the crosses, only red-eyedflies were produced. In the other half, however, theprogeny of each cross consists of about 50% red-eyedflies and 50% black-eyed flies. What were the geno-types of your original two flies?

12. Hemophilia is a recessive sex-linked human blooddisease that leads to failure of blood to clot normally.One form of hemophilia has been traced to the royalfamily of England, from which it spread throughoutthe royal families of Europe. For the purposes of thisproblem, assume that it originated as a mutation ei-ther in Prince Albert or in his wife, Queen Victoria.a. Prince Albert did not have hemophilia. If the dis-

ease is a sex-linked recessive abnormality, howcould it have originated in Prince Albert, a male,who would have been expected to exhibit sex-linked recessive traits?

b. Alexis, the son of Czar Nicholas II of Russia andEmpress Alexandra (a granddaughter of Victoria),had hemophilia, but their daughter Anastasia didnot. Anastasia died, a victim of the Russian revolu-tion, before she had any children. Can we assumethat Anastasia would have been a carrier of the dis-ease? Would your answer be different if the dis-ease had originated in Nicholas II or in Alexandra?

13. In 1986, National Geographic magazine conducted asurvey of its readers' abilities to detect odors. About7% of Caucasians in the United States could notsmell the odor of musk. If neither parent could smellmusk, none of their children were able to smell it. Onthe other hand, if the two parents could smell musk,their children generally could smell it, too, but a fewof the children in those families were unable to smellit. Assuming that a single pair of alleles governs thistrait, is the ability to smell musk best explained as anexample of dominant or recessive inheritance?

14. A couple with a newborn baby is troubled that thechild does not resemble either of them. Suspecting

that a mix-up occurred at the hospital, they check theblood type of the infant. It is type O. As the father istype A and the mother type B, they conclude a mix-up must have occurred. Are they correct?

15. Mabel's sister died of cystic fibrosis as a child. Mabeldoes not have the disease, and neither do her par-ents. Mabel is pregnant with her first child. If youwere a genetic counselor, what would you tell herabout the probability that her child will have cysticfibrosis?

16. How many chromosomes would you expect to find inthe karyotype of a person with Turner syndrome?

17. A woman is married for the second time. Her firsthusband has blood type A and her child by that mar-riage has type O. Her new husband has type В blood,and when they have a child its blood type is AB.What is the woman's blood genotype and blood type?

18. Two intensely freckled parents have five children.Three eventually become intensely freckled and twodo not. Assuming this trait is governed by a singlepair of alleles, is the expression of intense frecklesbest explained as an example of dominant or recessiveinheritance?

19. Total color blindness is a rare hereditary disorderamong humans. Affected individuals can see no col-ors, only shades of gray. It occurs in individuals ho-mozygous for a recessive allele, and it is not sex-linked. A man whose father is totally color blindintends to marry a woman whose mother is totallycolor blind. What are the chances they will produceoffspring who are totally color blind?

20. A normally pigmented man marries an albino woman.They have three children, one of whom is an albino.What is the genotype of the father?

21. Four babies are born in a hospital, and each has a dif-ferent blood type: A, B, AB, and O. The parents ofthese babies have the following pairs of blood groups:A and В, О and O, AB and O, and В and B. Whichbaby belongs to which parents?

22. A couple both work in an atomic energy plant, andbom are exposed daily to low-level background radiation.After several years, they have a child who hasDuchenne muscular dystrophy, a recessive geneticdefect caused by a mutation on the X chromosome.Neither the parents nor the grandparents have thedisease. The couple sue the plant, claiming thatthe abnormality in their child is the direct result ofradiation-induced mutation of their gametes, and thatthe company should have protected them from thisradiation. Before reaching a decision, the judge hear-ing the case insists on knowing the sex of the child.Which sex would be more likely to result in an awardof damages, and why?


Documents

Patterns of inheritance