From: Suzuki, David T., Anthony J. Griffiths,Jeffrey H. Miller, and Richard C. Lewontin.An Introduction to Genetic Analysis,.3rd Edition.

n Why study genetics? The answers to this question consti-tute the major part of this book, but at the outset a sum-mary answer can be given. Although a relatively youngdiscipline, genetics has assumed a position of central impor-tance in biology. In addition to this powerful unifying role,genetics has gained a position of great importance inhuman affairs. The findings of genetic research have hadconsiderable impact not only in the applied areas of biol-ogy, medicine, and agriculture but also in such areas asphilosophy, law, and religion. It is a rare newspaper, nowa-days, that does not address some aspect of genetics.

The Scope of Genetics

Why has genetics become so important? To answer thisquestion we must first define genetics. Genetics is the studyof genes through their-variation. A gene is the basic functionalunit of heredity, which is composed of a section of a long,threadlike biological molecule called deoxyribose nucleicacid, best known by its abbreviation DNA. In the nuclei ofhigher organisms are found the chromosomes, each a verylong, single, continuous DNA molecule containing thou-sands of unique functional units, the genes, as part of itslength. Each of the trillions of cells in a human being has 46chromosomes, in two equivalent sets of 23. Each of the 23in a set is unique and is matched only by its equivalentpartner in the other set. An average human chromosomecontains about a 50-millimeter length of DNA, and, there-fore, one total chromosome set of 23 is the equivalent ofabout one meter of DNA.

Geneticists study all aspects of genes. The study of themodes of gene transmission from generation to generationis broadly called transmission genetics, the study of genestructure and function is called molecular genetics, andthe study of gene behavior in populations is called popula-tion genetics. These three form the major subdivisions ofthe field of genetics, although, as with all categories in-vented by humans, the subdivision is to a certain extentarbitrary and there is considerable overlap. It is the knowl-edge of how genes act and how they are transmitted downthrough the generations that has unified biology; pre-viously, specific sets of biological phenomena had eachbeen relegated to separate disciplines. An understanding ofhow genes act is now an essential prerequisite for such bio-logical fields of study as development, cytology, physiology,and morphology. An understanding of gene transmission isa fundamental aspect of areas such as ecology, evolution,and taxonomy. Further unification has resulted from thediscovery that the basic chemistry of gene structure and

function is very similar across the entire spectrum of life onthe earth. These points may seem trite to those who havegrown up in the light of current knowledge, but it is impor-tant to realize that our modern view of biology and its inter-related parts is a relatively recent phenomenon. Not so long

2 CHAPTER 1

ago, biology was fragmented into many camps that rarelycommunicated with each other. Today, however, every bi-ologist must be a bit of a geneticist, because the findings andtechniques of genetics are being applied and used in allfields. Genetics, in fact, provides the modern paradigm forall of biology.

Message Genetics has provided a unifying thread for thepreviously disparate fields of biology.

What have been some of the success stories of geneticswithin basic biology? For just about any feature of biologi-cal structure or function—such as size, shape, number ofparts, color, pattern, behavioral pattern, or biochemicalfunction—that has been looked at in experimental orga-nisms, genes have been found to be involved. Determiningthe location of these genes on their respective chromo-somes is relatively easy. It has been found that the majorway in which genes exert their effect is through controllingthe myriad chemical reactions that go on inside cells, andthousands of specific genes have each been associated witha specific chemical reaction. The control of gene action(how genes are "turned on" and "turned off") has beenintensely studied in some organisms, and the mechanism inthese cases is well understood. Many different genes havebeen isolated in the test tube, and their particular chemicalstructures determined. Such studies have provided impor-tant clues about how genes perform their functions. A . genecan be removed from one organism and introduced intoanother, either for the convenience of propagating largeamounts of the gene for later study or to examine its effectsin another biological system. Genes can be modified at willto study the effects of these changes on biological processes;such changes can involve a large part of the genes, or verylocalized regions of interest to the experimenter. Mostgenes have been found to reside rather stably at specificchromosomal locations, but other pieces of DNA have beenfound to be capable of sudden relocation to new areas. Lastbut not least, most of these findings have tremendous rele-vance for evolutionary processes, which of course are con-cerned with changes in the structure and function of theaerie set.

Clearly, the advances in genetics have been truly as-tounding, particularly over the last three decades. Manyrecent accomplishments— such as the isolation and charac-terization of individual genes, which researchers in the1950s believed could never happen in their lifetimes—have already come to be regarded as routine procedures incurrent work in genetics.

This chapter presents an overview of the subject ofgenetics, by way of an orientation to the rest of the book.We shall deal first with generalities about genes, their in-heritance, and the ways in which they interact with theenvironment. Then we shall discover the unique ways in

which geneticists identify specific genes, and examine theuse of these techniques in studying biological phenomena.Finally, we shall consider some of the ways in which ge-netics has interacted with human society.

Gene Transmission

Genetics embraces two contradictory aspects of nature: off-spring resemble their parents, yet they are not identical totheir parents. The offspring of lions are lions and neverlambs, yet no two lions are identical, even if they come fromthe same litter. We have no trouble recognizing the differ-ences between sisters, for example, and even "identical"twins are recognized as distinctive individuals by their par-ents and close friends. But we also can notice subtle similar-ities between parents and children. As we shall see, hered-ity (the similarity of offspring to parents) and variation (thedifference between parents and offspring, and between theoffspring themselves) turn out to be two aspects of the sa efundamental mechanism.

When humans began domesticating plants and ani(around 10,000 years ago), they necessarily became in-volved with both heredity and variation, because they hadto choose the organisms with advantageous characteristicsfrom among those at their disposal and then seek to propa-gate these traits in future generations. References to soundbreeding practices in Egyptian tomb inscriptions and in theBible convince us that conscious concern with genetic phe-nomena is at least as old as civilization. The farmers andshepherds involved with such concerns could quite deserv-edly have claimed .to be called geneticists. But the formalstudy of genetics, as a coherent and unified theory of hered-ity and variation, is little more than a century old.

Modern genetics as a set of principles and analytic rulesbegan with the work of an Augustinian monk, GregorMendel, who worked in a monastery in the middle of thenineteenth century in what is now Brno in Czechoslovakia.Mendel was taken into the monastery by its director, AbbotKnapp, with the express purpose of trying to discover afirm mathematical and physical foundation underlying thepractice of plant breeding. Knapp and others in Brno wereinterested in fruit breeding. They believed that recent ad-vances in mathematics in the physical sciences could be amodel for building a science of variation. Mendel was rec-ommended to Knapp as a good scholar of mathematics andphysics, although a rather mediocre student of biology!

Mendel's methods, which he developed in the monas-tery garden, are the ones still used today (in an extendedform), and the y form an integral part of genetic analysis.(Mendel's work is considered in detail in Chapter 2.) Men-

del realized that both the similarities and the differencesamong parents and their offspring can be explained by amechanical transmission of discrete hereditary units, whichwe now call genes, from parent to offspring. We now know

GENETICS AND THE ORGANISM 3

that in all organisms— whether bacteria, fungi, animals, orplants— there is a regular passage of hereditary informa-tion from parent to offspring by means of the genes. Theregularities we observe in heredity and variation are a con-sequence of the regularities of the mechanical lanes oftransmission and activity of these genes.

Recall that each gene is a portion of a DNA molecule.In more than one sense, then, DNA is truly the thread oflife: not only is a DNA molecule itself a threadlike string ofgenes, but the DNA handed down from parent to offspringrepresents a narrow connecting thread between the gener-ations. When we say that a woman has her mother's hair ora man has his father's nose, what we really mean is that theparent has handed on, in egg or sperm, the instructionsnecessary to direct the synthesis of that specific feature.

Out of these basic considerations emerge two vastlypowerful and unique properties of DNA that make it thefundamental molecule of life. The first of these is its abilityto serve as a model for the production of replicas of itself,termed replication. This property is the key to transmissionand forms the basis of transmission genetics. A parentalorganism transmits a replica of its DNA to the progenitorcell of an individual of the next generation. As this progeni-tor cell goes through its rounds of division to produce amulticellular organism, each division is accompanied by theproduction of identical replicas of the DNA of the progeni-tor cell, which are apportioned into each new cell. Thus,replication is the mechanism through which life persistsacross the generations in a stable fashion.

The second property of DNA that makes it a funda-mental molecule of life is its ability to act as a carrier ofinformation. For example, embodied into the one meter ofDNA that constitutes a human chromosome set is the infor-mation needed to build a specimen of Homo sapiens. Theword information means "that which is necessary to giveform"; this is precisely what the DNA of the genes does.The information is "written" into the sequence of DNA inthe form of a molecular code.

Gene and 01-0-anismt7)

Precisely how does information become form? At the levelof molecules, the answer to this question embraces much ofwhat was defined previously as molecular genetics. Basi-cally, the phenomena and structures of life are produced byan interaction of DNA with the inanimate world, the non-living environment. The universe naturally tends to disar-ray; order tends spontaneously to disorder; complex andorderly objects become piles of dust; the reverse does notoccur unaided. Yet DNA causes an eddy in this river ofchaos; through its interaction with the disorderly compo-nents of the universe, the most orderly system that we knowabout is born: the phenomenon of life. One of the unex-pected discoveries arising from the study of DNA function

Figure 1-1. The genes of a moss direct environmental componentsto be shaped into a moss, whereas the genes of a tree cause a tree tobe constructed from the same components. (From Grant Heilman.)

is that the mechanism of converting information into formis virtually identical across all groups of organisms on thisplanet. We humans share a common genetic chemistry withthe entire variety of life forms on the earth—a staggeringspectrum, including some 286,000 species of floweringplants, 500,000 species of fungi, and 750,000 species ofinsects.

A general view of the interaction of DNA with theenvironment is a necessary prelude to the detailed analysesthat are found in the chapters ahead. We must put the geneand the environment into perspective, in order to provide aframework on which the details of genetic analysis can behung.

It is a characteristic of living organisms that the y mobi-lize the components of the world around themselves andconvert these components into their own living material, orinto artifacts that are extensions of themselves. An acornbecomes an oak tree, using in the process only water. oxy-gen, carbon dioxide, some inorganic materials from thesoil, and light energy.

The seed of an oak tree develops into an oak, while thespore of a moss develops into a moss, although both angrowing side by side in the same forest (Figure 1-1). Thtwo plants that result From these developmental process(

Hemoglobin

Red blood cells distorted to a jagged "sickle" shape

Sickle cell

Rapid destruction

of red blood cells

/Anemia

Physical

weakness

Heartfailure

Circulatory

disturbances

Accumulation of

sickle cells in spleen

Brain

Damage in

Spleen

damage

other organs

damage

Pneumonia Rheumatism

Kidney

failure

4 CHAPTER I

Small molecular change in DNAof the hemoglobin gene

EE Hemoglobin S produced

instead of hemoglobin A

Under low oxygen concentrations

in the tissues of the body (a) (b)

Figure 1-2. The fruits of two different forms of Plectritis congesta,the sea blush. (a) Wingless fruits. (b) Winged fruits. Any one planthas either all wingless or all winged fruits, and only the fruits aredifferent. The striking difference in appearance is determined by asimple genetic difference.

Hemoglobin S aggregates to form

needlelike quasi-crystalline structures

in red blood cells

resemble their parents and differ from each other, eventhough they have access to the same narrow range of inor-ganic materials from the environment. The specificationsfor building living protoplasm from the environmental ma-terials are passed in the form of genes from parent to off-spring through the physical materials of the fertilized egg.As a consequence of the information in the genes, the seedof the oak develops into an oak, and the moss spore be-comes a moss.

What is true for the oak and moss is also true withinspecies. Consider plants of the species Plectritis congesta, thesea blush. Two forms of this species are found wherever theplants grow in nature: one form has winged fruits, and theother has wingless fruits (Figure 1-2). These plants will self-pollinate, and we can observe the offspring that result fromsuch "selfs" when these are grown in a greenhouse underuniform conditions. It is commonly , observed that the prog-eny of a winged-fruited plant are all winged-fruited, andthe progeny from a wingless-fruited plant all have winglessfruits. Since all the progeny were grown in an identicalenvironment, we can safely conclude that the differencebetween the original plants must result from the differentgenes they carry.

The Plectritis example involves inherited forms thatboth can be considered perfectly normal. Yet the deter-minative power of genes is equally well demonstrated whena gene becomes abnormal. The human inherited diseasesickle-cell anemia provides a good example. In this case,careful study has revealed the chain of events whereby thegene has impact upon the organism, from the submicrosco-pic molecular level, through the microscopic level, to themacroscopic anatomical level. The underlying cause of thedisease is a variation in hemoglobin, the oxygen-transport-ing protein molecule found in red blood cells. Normal peo-ple have a type of hemoglobin called hemoglobin A, theinformation for which is encoded in a single unique type ofgene. A minute chemical change at the molecular level inthe DNA of this gene results in the production of a slightlychanged hemoglobin, termed hemoglobin S. In people pos-sessing only hemoglobin S, the ultimate effect of this smallchange is severe ill health and usually death. The geneworks its effect on the organism through a complex ''cas-cade effect," as summarized in Figure 1-3.

Impaired

mentalfunction

Figure 1-3. Chain of events resulting in sickle-cell anemia in humans:

Observations like these lead to a model of the interac-tion of genes and environment like that shown in Figure1-4. In this view, the genes act as a set of instructions forturning more or less undifferentiated environmental mate-rials into a specific organism, much as blueprints specifywhat form of house is to be built from basic materials. Thesame bricks, mortar, wood, and nails can be made into anA-frame or a flat-roofed house, according to differentplans. Such a model implies that the genes are really thedominant elements in the determination of organisms; theenvironment simpl y supplies the undifferentiated raw ma-terials.

But now consider two monozygotic(-identicantwins,

GENETICS AND THE ORGANISM 5

the product of a single fertilized egg that divided and pro-duced two complete individuals with identical genes. Sup-pose that the twins are born in England but separated atbirth and taken to different countries. If one is raised inChina by Chinese-speaking foster parents, she will speakperfect Chinese, while her sister raised in Budapest willspeak fluent Hungarian. Each will absorb the culturalvalues and customs of her environment. Although thetwins begin life with identical genetic properties, the differ-ent cultural environments in which they live produce dif-ferences between the sisters (and differences from theirparents). Obviously, the difference in this case is due to theenvironment, and genetic effects are of little importance.

This example suggests the model of Figure 1-5, whichis the opposite of that shown in Figure 1-4. Here the genesimpinge on the system, giving certain general signals fordevelopment, but the environment determines the actualcourse of change. Imagine a set of specifications for a housethat simply calls for "a floor that will support 30 pounds persquare foot" or "walls with an insulation factor of 15"; theactual appearance and nature of the structure would bedetermined by the available building materials.

Our different types of examples—of purely geneticeffect versus that of the environment— lead to two verydifferent models. Given a pair of seeds and a uniformgrowth environment, we would be unable to predict futuregrowth patterns solely from a knowledge of the environ-ment. In any environment we can imagine, if growth occursat all; the acorn will become an oak and the spore will be-come a moss. On the other hand, considering the twins, noinformation about the set of genes they inherit could possi-bly enable us to predict their ultimate languages and cul-tures. Two individuals that are genetically different may de-velop differently in the same environment, but two geneticallyidentical individuals may develop differently in different en-vironments.

In general, of course, we deal with organisms thatdiffer in both genes and environment. If we wish to under-stand and predict the outcome of the development of a

Genetic"blueprint"

Plan A Organism A

Input IEnvironmental factor 1Environmental Outputfactor 2Environmental factor 3

Organism 8

Figure 1-4. A model of determination that emphasizes the role ofgenes.

living organism, we must first know the genetic constitu-tion that it inherits from its parents. Then we must knowthe historical sequence of environments to which the devel-oping organism is exposed. We emphasize the historicalsequence of environments rather than simply the generalenvironment. Every organism has a developmental historyfrom birth to death. What an organism will become in thenext moment depends critically both on the environment itencounters during that moment and on its present state. Itmakes a difference to an organism not only what environ-ments it encounters but in what sequence it encountersthem. A fruit fly (Drosophila)develops normally at 20°C. Ifthe temperature is briefly raised to 37°C early in the pupalstage of development, the adult fly will be missing part ofthe normal vein pattern on its wings. However, if this "tem-perature shock" is administered just 24 hours later, the flydevelops normally.

Considering the general nature of interactions be-tween gene and environment, we see that there is no reasonto prefer either of the asymmetrical models of Figures 1-4and 1-5. Instead, we can create a more general model (Fig-ure 1-6). Genes and environment are'seen here as symmet-rical factors whose states jointly determine (by some rulesof development) the actual organism.

Message The developmental transformation of an orga-nism from one stage of its life to another is a result of theunique interaction of its genes and its environment at eachmoment of its life history. Organisms are determined nei-ther by their genes nor by their environment; rather, theyare the consequence of the interaction of genes and envi-ronment.

Genotype and Phenotype

In studying the reaction whereby genes and environmentproduce an organism, geneticists have developed some use-ful terms, which are introduced in this section.

A typical organism resembles its parents more than itresembles unrelated individuals. Thus we often speak as ifthe individual characteristics themselves are inherited: "Hegets his brains from his mother," or "She inherited dia-betes from her father." Yetour discussion in the precedingsection shows that such statements are invalid. "His brains"and "her diabetes" develop through long sequences ofevents in the life histories of the affected persons, and bothgenes and environment play roles in those sequences. In thebiological sense, individuals inherit only the molecularstructures of the fertilized eggs from which they develop.Individuals inherit their genes, not the end products of theirindividual developmental histories.

To prevent such confusion between genes (which areinherited) and developmental outcomes (which are not).

6 CHAPTER 1

Environment A

Environment B

t

Environmental factor 1

Environmental factor 2

Environmental factor 3 - - - - -r-

tEnvironmental factor 1 - - - - -r-

Environmental factor 2

Environmental factor 3

General geneticrules

Organism A

--r- Organism B

Figure 1-5. A model of determination thatemphasizes the role of the environment.

geneticists make a fundamental distinction between thegenotype and the phenotype of an organism. Organismsbelong to the same genotype if they have the same set ofgenes. Organisms belong to the same phenotype if theyresemble each other in some manifest way.

Strictly speaking, the genotype describes the completeset of genes inherited by an individual, and the phenotypedescribes all aspects of the individual's morphology, physi-ology, behavior, and ecological relationships. In this sense,no two individuals that have ever lived belong to the samephenotype, because there is always some difference (how-ever slight) between them in morphology or ,physiology.Moreover, except for individuals produced from anotherby asexual reproduction, any two organisms differ at least alittle in genotype. In practice, we use the terms genotypeand phenotype in a more restricted sense. We deal withsome partial phenotype description (say, eye color) andwith some subset of the genotype (say, the genes that influ-ence eye pigmentation).

Message When geneticists use the terms phenotype andgenotype, they generally mean "partial phenotype" and"partial genotype" with respect to some defined set of traitsand genes.

Note one very important difference between genotypeand phenotype: the genotype is essentially a fixed characterof the organism; it remains constant throughout life and isunchanged by environmental effects. Most phenotypeschange continually throughout the life of the individual;the direction of that change is a function of the sequence ofenvironments that the individual experiences. Fixity ofgenotype does not imply fixity of phenotype.

The Norm of Reaction

How can we quantify the relation between the genotype,the environment, and the phenotype? For a particulargenotype, we could prepare a table showing the phenotypethat would result from that genotype for development ineach possible environment. Such a tabulation of environ-ment-phenotype relationships for a given genotype is calledthe norm of reaction of the genotype. In practice, ofcourse, we can make such a tabulation only for a partialgenotype, a partial phenotype, and some particular aspectsof the environment. For example, we might specify the eyesize of a fruit fly that would result from development atvarious constant temperatures for several different partialgenotypes.

Figure 1-7 represents just such norms of reaction forthree partial genotypes in the fruit fly Drosophila melanogas-ter. The graph is a convenient summary of more extensivetabulated data. The size of the fly eye is measured by count-ing its individual facets, or cells. The vertical axis of thegraph shows the number of facets (on a logarithmic scale);the horizontal axis shows the constant temperature atwhich the flies develop.

Three norms of reaction are shown on the graph. Fliesof the wild-type genotype (characteristic of flies in naturalpopulations) show somewhat smaller eyes at higher temper-atures of development. Flies of the abnormal ultra-bargenotype have smaller eyes than wild-type flies at any partic-ular temperature of development. Higher temperaturesalso have a stronger effect upon eye size in the ultra-bar flies(the ultra-bar line slopes more steeply). Any fly of the otherabnormal genotype, infra-bar, also has smaller eyes thanany wild-type fly, but higher temperatures have the oppositeeffect on flies of this genotype.I nfra-bar flies raised at ahigher temperature tend to have. larger eyes than those

Developmentalinteractions

Genes

Environment

Type A Organism A

Type B Organism B I

{

Type I Organism A II

Type II Organism 8 II

Figure 1-6. A more realistic model ofdetermination that emphasizes theinteraction of genes and environment.

50 Medium elevation

Low elevation

4 13 23 24 6 9

Parental plant (source of cuttings)

16

0

GENETICS AND THE ORGANISM 7

High elevation50 50

0

raised at lower temperatures. These norms of reaction in-dicate that the relationship between genotype and pheno-type is complex rather than simple.

Message A single genotype can produce many differentphenotypes, depending on the environment. A single phe-notype may be produced by various different genotypes,depending on the environment.

If we know that a fruit fly has the wild-type genotype, thisinformation alone does not tell us whether its eye has 800or 1000 facets. On the other hand, the knowledge that afruit fly's eye has 170 facets does not tell us whether itsgenotype is ultra-bar or infra-bar. We cannot even make ageneral statement about the effect of temperature on eyesize in Drosophila, because the effect is opposite in two dif-ferent genotypes. We see from Figure 1-7 that some geno-types do differ unambiguously in phenotype, no matterwhat the environment: any wild-type fly has larger eyes thanany ultra-bar or infra-bar fly. But other genotypes overlapin phenotypic expression: the eyes of ultra-bar flies may belarger or smaller than those of infra-bar flies, depending onthe temperatures at which the individuals developed.

To obtain a norm of reaction like those in Figure 1-7,we must allow different individuals of identical genotype to

Figure 1-8. Norms of reaction to elevation for seven differentAchillea plants (seven different genotypes). A cutting from eachplant was grown at low, medium, and high elevations. (CarnegieInstitution of Washington.)

0

50

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EU

Eu

EU

0

1000900800

700

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Infra-bat

100 -90 -8070 Ultra - bar60

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30

Temperature C)

Figure 1-7. Norms of reaction to temperature for three differenteye-size genotypes of Drosophila mela 71 ogaster: wild-type, infra-bar, andultra-bar . Eve size is measured by the number of facets in the eye.The term "bar" comes from the eye shape produced by fewer facets.

0iv

Ez

develop in many different environments. To carry out suchan experiment, we must be able to obtain or produce manyzygotes with identical genotypes. For example, to test ahuman genotype in 10 environments, we would have toobtain identical decuplets and raise each individual in adifferent milieu. Obviously, that is possible neither biologi-cally nor socially. At the present time, we do not know thenorm of reaction of any human genotype for any characterin any set of environments. Nor is it clear how we can everacquire such information without unacceptable manipula-tion of human individuals.

For a few experimental .organisms, special geneticmethods make it possible to replicate genotypes and thusdetermine norms of reaction. Such studies are particularlyeasy in plants that can be propagated vegetatively—that is,by cuttings. The pieces cut from a single plant all have theKline genotype, so all offspring produced in this way haveidentical genotypes. Figure 1-8 shows the results of a studyusing such vegetative offspring of the plant Achillea. Manyplants were collected, and-three cuttings were taken fromeach plant. One cutting was planted at low elevation (30meters above sea level), one at medium elevation (1400meters), arid one at high elevation (3050 meters). Figure1-8 shows the mature individuals that developed front cut-tings of seven collected (parental) plants: the three plants of

400

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Wild-type

_-J3000

8 CHAPTER 1

E

Cat)

identical genotype are aligned vertically in the figure forcomparison.

First, we note an average effect of environment: ingeneral, the plants grew poorly at the medium elevation.This is not true for every genotype, however; the cutting ofplant 24 grew best at the medium elevation. Second, wenote that no genotype is unconditionally superior in growthto all others. Plant 4 showed the best growth at low and highelevations but showed the poorest growth at the mediumelevation. Plant 9 showed the second-worst growth at lowelevation and the second-best at high elevation. Once againwe see the complex relationship between genotype andphenotype. Figure 1-9 graphs the norms of reaction de-rived from the results shown in Figure 1-8. Each genotypehas a different norm of reaction, and the norms cross oneanother so that we cannot identify either a "best" genotypeor a "best" environment for Achillea growth.

We have seen two different patterns of reaction norms.The difference between wild-type and the abnormal eye-sizegenotypes in Drosophila is such that the corresponding phe-notypes show a consistent difference, regardless of the envi-ronment. Any fruit fly of wild-type genotype has larger eyesthan any fruit fly of the abnormal genotypes, so we could(imprecisely) speak of "large-eye" and "small-eye" geno-types. In this case, the differences in phenotype betweengenotypes is much greater than the variation within a geno-type for different environments. In the case of Achillea,however, the variation for a single genotype in differentenvironments is so great that the norms of reaction crossone another and form no consistent pattern. In this case, itmakes no sense to identify a genotype with a particularphenotype except in terms of response to particular envi-ronments.

Developmental Noise

Thus far, we have assumed that the phenotype is uniquelydetermined by the interaction of a specific genotype and aspecific environment_ But a closer look shows some furtherunexplained variation. According to Figure 1-7, a Droso-phila of wild-type genotype raised at 16°C has 1000 facets ineach eye. In fact, this is only an average value; individualflies studied under these conditions commonly have 980 or1020 facets. Perhaps these variations are due to slight fluc-tuations in the local environment or slight differences ingenotypes? However, a typical count may show that a flyhas, say, 1017 facets in the left eye and 982 in the right eye.In another fly, the left eye has slightly fewer facets than theright eye. Yet the left and right eyes of the same fl y are

genetically identical. Furthermore, under typical experi-mental conditions, the fly has developed as a larva a fewmillimeters long burrowing in homogeneous artificial foodin a laboratory bottle, and then completed its developmentas a pupa (also a few millimeters long) glued vertically to theinside of the glass high up off the food surface. Surely, theenvironment has not differed significantly from one side ofthe fly to the other! But if the two eyes have experienced thesame sequence of environments and are identical geneti-cally, then why is there any phenotypic difference betweenleft and right eyes?

Differences in shape and size are partly dependent onthe process of cell division that turns the zygote into themulticellular organism. Cell division, in turn, is sensitive tomolecular events within the cell, and these may have a rela-tively large random component. For example, the vitaminbiotin is essential for growth, but its average concentrationis only one molecule per cell! Obviously, any process thatdepends on the presence of this molecule will necessarily besubject to fluctuations in rate because of random variationsin concentration. But if a cell division is to produce a differ-entiated eye cell, it must occur within a relatively shortdevelopmental period during which the eye is beingformed. Thus we would expect random variation in suchphenotypic characters as the number of eye cells, the num-ber of hairs, the exact shape of small features, and the varia-tion of neurons in a very complex central nervous system— even when the genotype and the,environment are pre-cisely fixed. Even in such structures as the very simple ner-vous system of nematodes, these random variations dooccur.

Figure 1-9. Graphic representation of the complete set of results ofthe type shown in Figure 1-8. Each line represents the norm ofreaction of a separate plant. Notice that the norms of reaction crossone another, so that no sharp distinction is apparent.

103

10 1400

Elevation (m)

/ Type AGenes

Type

Environment

f

Type I

Type II

GENETICS AND THE ORGANISM 9

Message Random events in development lead to an un-controllable variation in phenotype; this variation is calleddevelopmental noise. In some characteristics, such as eyecells in Drosophila, developmental noise is a major source ofthe observed variations in phenotype.

Like noise in a verbal communication, developmentalnoise adds small random variations to the predictable pro-cess of development governed by norms of reaction. Add-ing developmental noise to our model of phenotype devel-opment, we obtain something like Figure 1-10. With agiven genotype and environment, there is a range of possi-ble outcomes of each developmental step. The develop-ment process does contain feedback systems that tend tohold the deviations within certain bounds, so that the rangeof deviation does not increase indefinitely through the

imany steps of development. However, this feedback is notperfect. For any given genotype, developing in any givensequence of environments, there remains some uncertaintyin the exact phenotype that will result.

Techniques of Genetic Analysis

Our discussion thus far has been based on the wisdom ofhindsight. With the wealth of genetic knowledge we nowshare, we can make generalizations about DNA, genes,phenotypes, and genotypes as though these concepts wereself-evident. But obviously this was not always the case; thecurrent wisdom was acquired only after extensive geneticresearch over the years. Mendel, for example, almost cer-tainly was completely without a conceptual basis for hisresearch at the beginning of his work, but he was able to

piece together his genetic principles from the results of hismany experiments. This is true of genetic research in gen-eral: we start in the unknown, and then ideas and factsemerge out of experimentation. But how does everydaygenetics work? We shall explore the answer to this questionin much of the rest of this book, but here let us begin withan overview of the principles of genetic research.

The process of identification of the specific hereditarycomponents of a biological system is called genetic dissec-tion. A geneticist is a type of biologist interested in someaspect of the structure or function of organisms. In thesame way that an anatomist probes biological structure andfunction with a scalpel, the geneticist probes biologicalstructure and function armed with genetic variants, usuallyabnormal. If the geneticist is interested in a biological pro-cess X, he or she embarks upon a search for genetic variantsaffecting X. Each variant identifies a separate component ofX. In much the same way that a novice auto mechanic canlearn a lot about how an internal combustion engine worksby pulling out a spark plug lead, for example, the geneticist"tinkers" with a living system. This approach is tremen-dously effective in charting the unknown—the invisibilityand magnitude of which are often not appreciated by thosewho have not attempted some kind of research—and rep-resents a truly powerful tool.

Message Genetic dissection is a powerful way of discov-ering the components of any biological process.

The use and analysis of hereditary variants embodiesthe primary research tool of the geneticist. This approach isequally powerful from the molecular level, where it can be

Noisydevelopment

Organism 1

Organism 2

-r- Organism 3

Organism 4

1"- Organism 5

7'

_ Organism 9

4- Organism 10

— Organism 11

- r Organism 12

Figure 1-10. A model of phenotypicdetermination that shows how genes.environment, and developmental noiseinteract to produce any given phenotype.

- Organism 6

Organism 7,71

Organism 8

10 CHAPTER I

used to probe cellular and organismal processes, all the wayto the population level, where it can be used to investigateevolutionary processes. The spectrum of variants that hasbeen obtained and studied effectively by geneticists is stag-gering; as we have seen, there are variants affecting shape,number, biochemical function, and so on. In fact, the gen-eral finding has been that variants can be obtained for vir-tually any biological structure or process of interest to theinvestigator.

Recall that a set of variants of any given biological char-acter can fall into either of two broad categories: (1) thosewhose underlying genotypes show nonoverlapping normsof reaction, and (2) those whose underlying genotypes showoverlapping norms of reaction. The techniques of geneticanalysis are different in each case.

The analysis of genotypes with nonoverlapping normsof reaction has produced most of the phenomenal successof genetics in elucidating the cellular and molecular pro-cesses of organisms. The appeal of such systems from theexperimenter's viewpoint is that the environment can vir-tually be ignored, because each genotype produces a dis-crete, identifiable phenotype. In fact, geneticists have de-liberately sought and selected just such variants.Experiments become much easier—in fact, they only be-come possible—when the phenotype observed is an unam-biguous indication of a particular genotype. After all, wecannot observe genotypes; we can visibly distinguish onlyphenotypes.

The availability of such variants made Mendel's exper-iments possible. He used genotypes that were establishedhorticultural varieties. For example, in one set of variants,one genotype always produces tall pea plants, and anotheralways produces dwarf plants. Had Mendel chosen variantswhose genotypes have overlapping norms of reaction, hewould have obtained complex and patternless results likethose in the Achillea experiments. He could never haveidentified the simple relationships that became the founda-tion of genetic understanding. Much of modern moleculargenetics is based on research with variants of bacteria thatsimilarly show distinctive characters whose genotypes havenonoverlapping norms of reaction. For instance, modernDNA manipulation technology relies heavily on selectionsystems based on bacterial genes for drug resistance; theexpression of such genes is very clear-cut and reliable.

In this category, the variants tend to be rather drastic.Many such variants could never survive in nature, simplybecause they are so developmentally extreme. In othercases, such as the winged and wingless fruits of Plectrths, thestrikingly different forms do appear regularly in naturalpopulations.

Reflecting the importance of discrete variants in devel-oping our present understanding of the genetic basis of life,most of the rest of this book is devoted to analysis of thiskind of variation. The story begins with Mendel's researchand theories, proceeds through classical genetics, and ends

with the startling discoveries Of molecular biology. It mustbe emphasized that the entire development of this knowl-edge critically depended on the availability of phenotypeshaving simple relationships to genotypes. Because ourstudy of genetic analysis necessarily puts so much emphasison such simple trait differences, you may get the impressionthat they represent the most common relationship betweengene and trait. They do not. Geneticists have to pick andchoose among cases of genetic variation to find those with asimple correspondence between genotype and phenotype.For example, among the hundreds of classical mutants ofDrosophila that have been well enough characterized toplace them on specific chromosomes, about half are toovariable in their phenotypic expression to be used in fur-ther genetic analysis (so-called Rank 4 and Rank 5 mu-tants). Only a quarter ("Rank 1" mutants) are ideally suitedfor the purposes of careful genetic analysis. And this countexcludes the large number of mutants that were so unreli-able that they could not be put on genetic maps in the firstplace. Even among the most useful mutants, environmentand developmental age can be quite important to their ex-pression. The widely used mutation purple produces an eyecolor like the normal ruby color in very young flies, whichdarkens to a distinguishable difference only with age. Themutation Curly, one of the most important tools in geneticanalysis in Drosophila, results in curled wings at 25°C, butnot at 19°C, where the flies have normally straight wings.

Whereas simple one-to-one relationships betweengenotype and phenotype dominate the world of experi-mental genetics, in the natural world such relationships arequite rare. When norms of reaction for size, shape, color,metabolic rate, reproductive rate, and behavior have beenobtained for organisms taken from natural populations,they almost always turn out to be like those of Achillea. Therelationships of genotype to phenotype in nature are almostalways one-to-many rather than one-to-one. This is the un-derlying cause of the rarity of discrete phenotypic classes innatural populations.

Obviousl y , the analysis of these one-to-many relation-ships is far more complex. The researcher is confrontedwith a bewildering range of phenotypes. Special statisticaltechniques must be used to disentangle the genetic, envi-ronmental, and noise components. Chapter 22 deals withsuch techniques.

There is another problem that is distinct from thepurely anal y tical difficulties. The major. .discoveries of ge-netics were founded on work with discrete norms of reac-tion. Although these discoveries have revolutionized pureand applied biology, great care must be taken in extrapolat-ing such ideas to systems that are based on complex interac-tion of gene and environment. especially those found innature. For example, the difference between yellow-bod-ied and gra y-bodied Drosophila in laboratory stocks can beshown to be a simple genetic difference, but it does notfollow that skin color in humans obeys similar genetic laws.

GENETICS AND THE ORGANISM 11

In fact, even in Drosophila, the various intensities of blackpigment in flies from natural populations turn out to be aconsequence of the interaction of temperature with a com-plex genetic system.

Message In general, the relationship between genotypeand phenotype cannot be extrapolated from one species toanother or even between phenotypic traits that seem super-ficially similar within a species. A genetic analysis must becarried out for each particular case.

Our overview of the scope of genetics would not becomplete without a discussion of some of the ways in whichgenetics affects our everyday lives.

Genetics and Human Affairs

Knowledge about hereditary phenomena has been impor-tant to humans for a very long time. Civilization itself be-came possible when nomadic tribes learned to domesticateplants and animals. Long before biology existed as a scien-tific discipline, people selected grains with higher yieldsand greater vigor and animals with better fur or meat.They also puzzled about the inheritance of desirable andundesirable traits in the human population. Despite thislong-standing concern with heredity and the practice ofselective breeding, it was not until the discovery of Men-del's laws that we were able to elucidate the actual basis forinheritance.

As in many areas of science, this new knowledge hasproduced new challenges as well as solutions to somehuman problems. For example, early in this century a newwheat strain called Marquis was developed in Canada. This

high-quality strain is resistant to disease; furthermore, itmatures two weeks earlier than other commercially usedstrains—a very important factor where the growing seasonis short. At the time of its introduction, the use of Marquiswheat opened up millions of square miles of fertile soil tocultivation in such northern countries as Canada, Sweden,and the U.S.S.R. Table 1-I shows how geneticists havebred a wide range of desirable characteristics into anothercommercial crop, rice. In addition to improving crop varie-ties, geneticists have learned to alter the genetic systems ofinsects to reduce their fertility. This technique is providingan important new weapon in the age-old struggle to keepinsects out of human crops and habitations.

Such successes in recent years led to the concept of the"Green Revolution" as the scientific answer to the problemof human hunger. Using sophisticated breeding techniquesbased on new knowledge about genes, geneticists createdhigh-yield varieties of dwarf wheat (Figure 1-11) and rice(Figure 1-12). Extensive planting of these crops around theworld did provide new food supplies, but new problemsquickly became apparent. These specialized crops requireextensive cultivation and costly fertilizers. Figure 1-12 is anorm-of-reaction , curve, a classic example of the variableinteraction of genotype with environment. The use of thenew high-yield varieties produced a wide range of socialand economic problems in the impoverished countrieswhere they were most needed. Furthermore, the spread ofmonoculture (the extensive reliance on a single plant vari-ety) left vast areas at the mercy of some newly introduced ornewly evolved form of pathogen —say, a plant disease oran insect pest. With the huge population of humans onearth, our dependence on high-yield varieties of cropplants and domestic animals is becoming increasingly obvi-ous. In a very real sense, the stability of human societydepends on the ability of geneticists to juggle the inheritedtraits that shape life forms, keeping the crops a jump ahead

n TABLE 1-1. Development of pest-resistant strains of rice

StrainYear

developed

Diseases Insects

Blastfungus

Bacterialblight

Leaf-strea kvirus

Grassystuntvirus

Tungrovirus

GreenJeaf-hopper

Brownhopper

Stemborer

IR 8 1966 MR S S S S R S MS

IR 5 1967 S S MS S S R .5 5

IR 20 1969 MR R MR S R R S MS

IR 99 1969 S R MS S S S S S

IR 24 1971 S S • MR S MR R S S

IR 26 1973 MR R MR MR - R R R MR

N OTE: The entries describe each strain's susceptibility or resistance to each pest as follows: S = susceptible: MS = moderatel y susceptible: MR = moderatek

resistant; R = resistant. (From Research Highlights, I.R.R.1, 1973, p. 11.)

12 CHAPTER

Figure 1-11. A specially bred strain ofdwarf wheat (right) resists crop damagefar better than the normal strain (left).(Courtesy of The RockefellerFoundation.)

of the destructive parasites and predators (Figure 1-13).In recent years, advances in biotechnology have led to

the creation of special genetically engineered strains of bac-teria and fungi that carry specific genes from unrelatedorganisms such as humans. The microbes produce suchuseful compounds as insulin, human growth hormone, andthe antiviral (and possibly anticancer) agent interferon.

But the most exciting and frightening application ofgenetic knowledge is to the human species itself. Geneticdiscoveries have had major effects on medicine.- We cannow diagnose hereditary disease before or soon after birth,and in some cases we can provide secondary treatments.Using family pedigrees, a genetic counselor can give pro-spective parents the information they need to make intelli-gent decisions about the risks of genetic disease in theiroffspring. Such refined techniques as amniocentesis andfetoscopy provide information about possible genetic dis-ease at early stages of pregnancy. A battery of postnatalchemical tests can detect problems in the newborn infant,so that some corrective techniques can be applied immedi-ately to alleviate the effects of many genetic diseases.

Our new ability to recognize genetic disease poses animportant moral dilemma. An estimated 5 percent of ourpopulation survives with severe physical or mental geneticdefects. This percentage probably will increase with ex-tended exposure to various environmental factors — and,paradoxically, with improved medical technology. As ge-neticist Theodosius Dobzhansky has remarked,

If - we enable the weak and the deformed to live and propagatetheir kind, we face the prospect of a genetic twilight. But if we letthem die or suffer when we can save or help them, we face thecertainty of a moral twilight.

Of those patients admitted to pediatric hospitals in NorthAmerica, 30 percent are estimated to have diseases that can

be traced to genetic causes. The financial burden to societyis already significant. Are we prepared to shoulder this ge-netic burden? How much money are we willing to spend tokeep the genetically handicapped alive and to enable themto lead as normal a life as possible?

Many other significant issues are raised by the potentialapplications of genetic knowledge to human beings. Ob-viously, the human brain is subject to the same rules ofgenetic determination as the rest of the body. Does this

10–

IR 8

–

6–

PETA

a-

2 r-

0 20 40 60 80 100 120

Nitrogen applied (kilograms per hectare)

Figure 1-12. The specially bred strain of dwarf rice called IR 8owes part of its success to its remarkable response to the applicationof fertilizer. The strain PET:). is an older. nondwarf strain showinga more typical response. (Front Peter R. Jennings. "TheAmplification of Agricultural Production. - Copyright © 1976 byScientific American, Inc. All rights reserved.)

GENETICS AND THE ORGANISM 13

Figure 1-13. The findings of genetics have powerful impacts onmany interacting areas of human endeavor.

mean that our thoughts and behavior are extensively deter-mined by inherited predispositions? Or can we view themind as a clean slate at birth, written upon only by individ-ual experience? The nature of inborn constraints onthought and personality—the implications for present so-ciological problems—have fascinated many geneticists andother scientists. Such books as African Genesis, The Territo-rial Imperative, On Aggression, and other popular titles onsociobiology have stimulated widespread public interest. Abitter debate has raged about the differences in intelligenceamong various racial and social groups. Of course, thistopic is not new. It was debated by Lycurgus in Spartaagainst Plato in Athens, and dreams of producing a purerace of superior humans have motivated many importantfigures in history. As the problem of human overpopula-tion becomes obvious to almost everyone, there is increasedtalk of legislated sterilization and the planned selection ofhuman offspring. There is very serious talk, even amonggeneticists, about the ability of the human race to take con-trol of its own evolution. Others are frightened by the possi-bilities for disastrous error or unpleasant sociological con-sequences.

The sophisticated technology of molecular geneticshas given us a wide range of new techniques for shaping ourgenetic makeup. Even more bizarre procedures loom in thenear future. We have moved beyond conventional breed-ing techniques to the ability to make chemical and molecu-lar modifications in the genetic apparatus. While some sci-entists emphasize the promised benefits of such research,

others raise disturbing questions about possible dangers.Could there be an accidental release from some laboratoryof an artificial pathogen that has never existed on thisplanet before? Such worries have led to calls for a completemoratorium on such research—or at least for legislationthat requires ruthlessly efficient containment facilities. Anumber of popular books warn us of a Genetic Fix, a Biologi-cal Time Bomb, the Genetic Revolution, a Fabricated Man, andthe Biocrats. Knowledge of genetic mechanisms has made usaware of other new dangers as well. Some geneticists fearthat increased exposure to chemical food additives and tothe vast array of chemicals in other commercial productsmay be changing the human genetic makeup in a very un-desirable and haphazard way. This type of random geneticchange can also be caused by such environmental agents asfallout from nuclear weapons, radioactive contaminationfrom nuclear reactors, and radiation from various X-raymachines. These agents may be contributing to inheriteddisease, but they almost certainly are contributing to theincidence of cancer, a genetic disease of the somatic("body") cells.

The study of genetics is relevant not only to the biolo-gist but to any thinking member of today's complex techno-logical society. A working knowledge of the principles ofgenetics is essential for making informed decisions on manyscientific, political, and personal levels. Such a workingknowledge can come only through an understanding of theway that genetic inferences are made—that is, from anunderstanding of genetic analysis, the subject of this book.