Patterns of Inheritance (Classical...

CHAPTER 9

Patterns of Inheritance

(Classical genetics)

New topic •Classical genetics (non-molecular genetics)

Previous two lectures

• Non-sexual reproduction • Sexual reproduction (= cellular foundation of classical genetics)

Today •The laws of Mendel

•The chromosomal basis of inheritance

Next time

•Linkage, crossing over, and mapping •Genetic diseases

•Preimplantation diagnostics and assisted reproduction

THE LAWS OF MENDEL - the foundation of genetics

- and a lesson how to design experiments

• Gregor Mendel – Is the founder of modern genetics: He was the first to

analyze patterns of inheritance. – Deduced the fundamental principles of genetics. – In 1866, Mendel published that parents pass to their

offspring discrete heritable factors that determine inherited traits

– These heritable factors (today called genes) retain their individuality generation after generation.

Gregor Mendel

– As a student, Mendel did not perform well. He failed the exam, the examiner commented that "he lacks insight and the requisite clarity of knowledge".

– Mendel was the first to use mathematical and statistical analysis to interpret biological experiments

– His first published paper is a landmark in clarity and a model experimental report. Many scientists believe that it is perhaps the best scientific paper ever written (1866)

– Mendel’s work was not understood by the leading scientists of his time. He gave up science and became abbot of his monastery. When he died (1884), the new abbot burned Mendel's papers.

– Mendel’s discovery was rediscovered around 1900

– He seems like a twentieth-century biologist displaced into the wrong century.

In an Abbey Garden

Mendel’s garden in Brno (Czech republic)

Mendel worked with the garden pea

• Garden peas were an ideal model to discover the laws of inheritance

– They multiply easily and rapidly and are very fertile

– They occur in easily distinguishable dual varieties

– They can self-fertilize and cross-fertilize.

eggs pollen

– Garden peas can be easily manipulated

– Removal of stamens can prevent self-fertilization

– Covering the flowers and hence carpels can prevent fertilization from other plants

– Transfer of pollen from selected stamens can control breeding

Mendel’s work teaches a key lesson: •Clever selection of the biological model can dramatically facilitate discovery:

• When you have a problem, choose the simplest model for it

•Around the same time as Mendel, others tried to find the laws of inheritance, but using human traits –

• Humans grow slowly • They are not very fertile • They cannot be ordered to mate wrong model

Further prerequisites for Mendel’s success

• He discovered characteristics that occur in two alternative forms

• He created a clean, reproducible starting point: For breeding, he used only plants that by self-fertilization had previously produced offspring all identical to the parent

• Plants that produce identical offspring by self-fertilization are called purebred: 순종

• Plants that result from a breeding of two different purebred plants are called hybrids (잡종)

• P (parent) generation, F1 (first filial) generation, F2 (second filial) generation

- Parent with purple flowers produces offspring with purple flowers

- Parents with white flowers produces offspring with white flowers

- Parents with smooth seeds produces offspring with smooth seeds

- Parents with rough seeds produce offspring with rough seeds

- …..

• Mendel selected 7 characteristics in pea plants and studied their inheritance.

First, Mendel crossed parent plants that differ in only one characteristic (petal color)

-Questions :

•Is the heritable factor for white flowers lost as a result of the cross?

•Do F1 plants carry two factors for the flower-color characteristic?

P Generation (pure-breeding parents)

All purple

Self-Fertilization (F1 × F1)

F2 Generation

3/4 1/4

Purple flowers

White flowers

F1 Generation

705 224 + 929 =

1. There are discrete units of heritable traits (now called genes), which occur in alternative forms [now called alleles (대립유전자) – recall last lecture]

2. For each heritable trait, each organism has two genes, one from each parent. These genes may be the same allele or different alleles:

• Heterozygote: an organism with two different alleles • Homozygote: an organism with two identical alleles

From these findings, Mendel hypothesized:

(in modern language)

3. When two different alleles exist in the same organism, one of them may fully determine the appearance (dominant allele), while the other may show no effect (recessive allele)

• uppercase letter (P) for dominant, lowercase letter (p) for recessive

4. The members of an allele pair segregate (separate) from each other during the production of gametes (sperm and egg); fertilization restores the paired condition

Applied to his purple flower – white flower crosses, these hypotheses mean:

Parent plants

Gametes

PP

p

F1 plants

Gametes All Pp

1/2

pp

P

P 1/2

P

p

PP

Pp Pp F2 plants

p

P

p

pp

Phenotypic ratio 3 purple : 1 white

Genotypic ratio 1 PP : 2 Pp : 1 pp

• P – dominant allele for flower color • p – recessive allele for flower color

(F1 × F1)

What you see = phenotype The underlying genes = genotype

• Phenotype: an organism’s expressed or physical traits (purple or white flowers) - compare word “phenomenon”

• Genotype: its genetic makeup (PP, Pp, pp)

• Recall (previous lecture) that every diploid organism has two sets of homologous chromosomes

Locus (loci): specific location of a gene along the chromosome

The chromosomal basis of Mendel’s principle of segregation

• The two homologous chromosomes are separated from each other during sperm/egg formation in meiosis (recall previous lecture)

After studying individual characteristics, Mendel asked: Are two different characteristics inherited independently of each other? Characteristic 1: Pea shape R – round pea (dominant); r – wrinkled (recessive) Characteristic 2: Pea color Y – yellow pea (dominant); y – green pea (recessive)

•Mendel found that all the 7 characteristics he studied were inherited independently

(modern interpretation: are on different chromosomes)

The probability is low that 7 randomly picked characteristics are on different chromosomes (Garden pea has 2n = 14 chromosomes) Mendel was lucky (some scientists later accused him of cheating) -- or perhaps he disregarded characteristics that did not show independence??

•He was also lucky that the garden pea is diploid (many plants are polyploid; it is hard to get purebred polyploid plants)

Mendel’s discoveries are a model case of how to design experiments …

– Well-defined, well-controlled experimental system: – Reproducible, well defined objects: Use only purebred plants – Smart choice of model: Fertile organism with rapid reproduction cycle – Controlled experiment: Same environment for all offspring – Quantifiable results: Make statistics – Well manipulable: Artificial self-fertilization and cross-fertilization

– Ability to observe and analyze:

– Discovery of pairs of alternative phenotypes – Ability to neglect unimportant details: Neglected genes that are linked? – Understanding of importance of quantification – Intuition …

– And luck:

– Garden pea is diploid – Different phenotypic features were on different chromosomes

Copyright © 2007 Pearson Education Inc., publishing as Pearson Benjamin Cummings

Applications of Mendel’s laws • Mendel’s inheritance laws can be used to determine a genotype: “Testcrosses” Example: Black color allele (B) in dog is dominant over brown color allele (b) How to find out the genotype of a black dog?

Applications of Mendel’s laws • Family pedigrees

• “Dominant” does NOT imply that a dominant phenotype is normal or more common than a recessive phenotype

• Dominance means that a heterozygote (Aa), carrying only a single copy of a dominant allele, displays the dominant phenotype.

• By contrast, the phenotype of the corresponding recessive allele is seen only in a homozygote (aa).

• Recessive traits are often more common in the population than dominant ones.

How do we know how a human trait is inherited? – Try to achieve sample sizes of >100 – Cannot control human mating but can only analyze results of mating use “family trees” ( = pedigrees)

Example: Apply Mendel’s laws to family pedigree from a family that lived on Martha’s Vineyard

can also conclude that healthy brothers and sisters of a deaf child with a deaf parent are Dd

No deafness in the first generation Deafness is recessive

can label all deaf persons as dd

can conclude that healthy parent of deaf person must be Dd

•Most inherited characteristics exist in more than two clear-cut variants - flower color, skin color, height, weight, body build, temperament, facial features, athletic ability, intelligence, hairiness, eye color, …..

In fact, cases where Mendel’s rules can strictly account for the patterns of inheritance are relatively rare

• Types of complications

– Incomplete dominance – Multiple alleles and codominance – Pleiotropy – Polygenic inheritance – Environment (conditional gene expression) – Linkage

BEYOND MENDEL

– Dominant allele: expressed regardless of the other allele

– Recessive allele: suppressed in the heterozygote – Complete dominance phenotype of

heterozygote = phenotype of homozygotes

Incomplete dominance

- F1 hybrids have an appearance in between the phenotypes of the two parents, and are not exactly like either one of them.

Genotype ratio = phenotype ratio

• Example: Flower color

Codominance and multiple alleles

Copyright © 2007 Pearson Education Inc., publishing as Pearson Benjamin Cummings

• Co-dominance • The two alleles are equally

expressed and equally affect the phenotype

• Example: The ABO blood groups in humans

• Multiple alleles – Each individual carries no more than two different alleles of a particular gene,

but a population can contain many alleles of that gene

Pleiotropy • Pleiotropy = the impact of a single gene on more than one characteristic. • Example: Sickle-cell disease

- The most common genetic disease among black Americans: 1/500 have disease, 1/10 is carrier. In some areas in Africa, 40% of people carry the mutation

- Symptoms in homozygotes - Primary defect: amino acid substitution (mutation) in hemoglobin – Abnormal hemoglobins tend to link together and crystallize, especially when the

oxygen content of the blood is low (high altitude, overexertion, respiratory ailments)

(a) Normal red blood cell Normal hemoglobin

1 2 3 4 5

6 7. . . 146

(b) Sickled red blood cell Sickle-cell hemoglobin

2 3 1 4 5

6 7. . . 146

Individual homozygous for sickle-cell allele

Sickle-cell (abnormal) hemoglobin

Abnormal hemoglobin crystallizes, causing red blood cells to become sickle-shaped

Sickled cells

Breakdown of red blood cells

Accumulation of sickled cells in spleen

Physical weakness Anemia Heart

failure Pain and

fever Brain

damage Damage to

other organs

Clumping of cells and clogging of

small blood vessels

Spleen damage

Impaired mental function

Paralysis Pneumonia and other infections

Rheumatism Kidney failure

One molecular change

Many different effects

• Why is sickle cell disease so common? there is a selective advantage

• Normal people are healthy but not protected against malaria • Heterozygotes are healthy AND are protected against malaria

The malaria parasite (Plasmodium) lives in red blood cells triggers sickling of the hemoglobin of heterozygotes red blood cells destroyed together with parasite in spleen

Great animation about malaria (4 min 18 sec) http://www.youtube.com/watch?v=qvlTOhCmxvY

Compare areas that are struck with malaria with geographical distribution of the “sickle cell allele”