Chapter 13: Extensions of Mendelian Principles:

Multiple alleles

Modifications of dominance relationships

Gene interactions

Essential genes and lethal alleles

Gene expression and the environment

Epigenetics

Multiple alleles:

Not all genes have two forms (alleles), many have multiple alleles.

Diploid individuals have only two alleles, one on each chromosome.

Examples:

ABO blood groups

Drosophila eye color

Fig. 13.3

Human ABO blood groups:

1. 4 blood phenotypes: O, A, B, & AB

2. 3 alleles: IA, IB, I

1. IA and IB are dominant to i.

2. IA and IB are codominant to each other.

Phenotype Genotype RBC-antigen Blood-antibody

O i/i none (H) anti-A & B

A IA/ IA or IA/i A anti-B

B IB /IB or IB /i B anti-A

AB IA/IB A and B none

ABO inheritance is Mendelian:

Possible parental genotypes for type O offspring:

1. i/i x i/i

2. IA/i x i/i

3. IA/i x IA/i

4. IB/i x i/i

5. IB/i x IB/i

6. IA/i x IB/i

Drosophila eye color:

> 100 mutant alleles for the eye color locus on the X chromosome.

w+ wild type, redw mutant, white-eyewe mutant, eosin (reddish-orange)

1912, Thomas H. Morgan

Crossed eosin-eyed female with a white-eyed male:

All F1 had eosin eyes.

P Cross w (X) Y

we (X) we/wXX

we/YXY

we (X) we/wXX

we/YXY

Drosophila eye color:

Alfred H. Sturtevant (1913) observed:

1. Red (w+) is dominant to white (w) and eosin (we).2. Eosin (we) is recessive to red (w+), but dominant to white (w).3. Concluded eosin (we) and white (w) are multiple alleles of the

same gene.

1. Confirmed by crossing F1 female with wild type red-eyed male:

w+(X) Y

we (X) we/w+

XXwe/YXY

w (X) w/w+

XXw/YXY

Molecular basis of multiple alleles and dominance relationships:

Genes encode proteins and regulatory factors, substitutions result in different alleles.

Different alleles of the same gene reflect activity and expression of the gene product.

Drosophila homozygote Phenotype Relative eye pigment

w+ wild type 1.0000

w white 0.0044

wt tinged 0.0062

wa apricot 0.0197

wbl blood 0.0310

we eosin 0.0324

wch cherry 0.0410

wa3 apricot-3 0.0632

ww wine 0.0650

wco coral 0.0798

wsat satsuma 0.1404

wcol colored 0.1636

Number of alleles (n) and number of genotypes (Table 12.3):

# genotypes = n(n + 1)/2

Homozygotes = nHeterozygotes = n(n - 1)/2

# alleles # genotypes Homozygotes Heterozygotes

1 1 1 0

2 3 2 1

3 6 3 3

4 10 4 6

5 15 5 10

Different types (modifications) of dominance relationships:(depend upon molecular patterns of gene expression)

1. Complete dominance

2. Incomplete dominance

3. Codominance

Different types (modifications) of dominance relationships:

1. Complete dominance (complete recessiveness)

1. One allele is completely dominant to another.

2. Phenotype of the heterozygote is the same as homozygous dominant.

3. Recessive phenotype is expressed only when the organism is homozygous recessive.

4. e.g., Mendel’s pea traits (Fig. 11.5)

Different types (modifications) of dominance relationships:

2. Incomplete (partial) dominance

1. One allele is not completely dominant to another.

2. Phenotype of the heterozygote is intermediate between the phenotypes of homozygotes for each allele.

3. e.g., plumage color in chickens and palomino horses

Fig. 13.7, Incomplete dominance in chickens

Different types (modifications) of dominance relationships:

3. Codominance

1. Alleles are codominant to one another.

2. Phenotype of the heterozygote includes the phenotype of both homozygotes.

3. e.g., ABO blood groups & sickle-cell anemia

Fig. 4.9

Molecular explanations for dominance relationships:

Complete dominance

Dominant allele creates full phenotype by one of two methods:

1. Half the amount of gene product produced by homozygote is sufficient (haplosufficient), OR…

2. Expression of dominant allele in heterozygote is up-regulated to match the homozygote.

Incomplete dominance

Recessive allele is not expressed in heterozygote:

1. Homozygote: 2 doses of a gene product

2. Heterozygote: 1 dose of a gene product

Codominance

Both alleles are expressed equally resulting in a combined phenotype.

Gene interactions and modified Mendelian ratios:

Phenotypes result from complex interactions of genes (molecules).

e.g., dihybrid cross of two independently sorting gene pairs, each with two alleles (A, a & B, b).

9 genotypes (w/9:3:3:1 phenotypes):

1/16 AA/BB2/16 AA/Bb1/16 AA/bb2/16 Aa/BB4/16 Aa/Bb2/16 Aa/bb1/16 aa/BB2/16 aa/Bb1/16 aa/bb

Deviation from this ratio indicates the interaction of two or more genes producing the phenotype.

Two types of gene interactions:

1. Multiple genes control the same trait and by their interactions produce a new phenotype.

2. Epistasis - one or more genes mask the expression of other genes and alter the phenotype.

1. Different genes control the same trait and collectively produce a new phenotype, e.g., comb shape in chickens.

4 phenotypes resulting from dominant and recessive alleles at 2 loci:

Rose-comb R-/ppPea-comb rr/P-Walnut-comb R-/P-Single-comb rr/pp

• Cross true-breeding rose-combed (RR/pp) and pea-combed (rr/PP) chickens.

1. Interaction of two dominant alleles (R & P), produces a third phenotype (walnut), all F1 are walnut-combed (Rr/Pp).

2. Fourth phenotype (single-comb, rr/pp) appears in the F2.

3. F2 is 9:3:3:1 (walnut:rose:pea:single) and fits Mendelian ratios.

4. Multiple genes involved, and interaction of two dominant alleles (R & P) produce factors that modify comb shape from a simple (rose/pea) to more complex form (walnut).

http://www.bio.miami.edu/dana/250/25008_11.html

Fig. 13.9

2. Epistasis

No new phenotype is produced, but one gene (epistatic) masks the phenotypic expression of another gene (hypostatic) .

Recessive epistasis, caused by recessive alleles, aa masks the effect of B at another locus.

Can occur in both directions, requiring A and B to produce a phenotype (duplicate recessive epistasis).

Dominant epistasis, A masks the effect of B.

Recessive epistasis, coat color determination in rodents:

Three loci involved (agouti = color banded hairs, ~grey):

1. C allele determines pigment (C- = pigment, cc = albino)2. A allele determines agouti factor (A- = banded, aa = solid)3. B allele determines color (B- = black, bb = brown)

4. A allele is epistatic over B locus, inserts bands of color between black and brown (appears grey).

5. C allele is epistatic over A and B loci, as cc is albino regardless of its genotype at the A and B loci.

----cc A---C- aaB-C-

Recessive epistasis, coat color determination in rodents (cont.):

1. Assume for this cross that all mice have one B allele (B- = black) and there are no brown mice (bb).

2. Cross true-breeding black-agouti (AA/CC) with albino (aa/cc).

3. All F1 are agouti Aa/Cc.

4. In the F2, A-/cc and aa/cc individuals show the same albino phenotype.

5. F2 phenotypic ratio is 9:3:4 instead of 9:3:3:1.

Fig. 13.11,Recessive epistasisF2: 9:3:4

Essential genes and lethal alleles:

Essential gene = may result in a lethal phenotype when mutated.

Lethal allele = mutation that results in death.(can be dominant or recessive)

Dominant lethal allele Aa and AA dieRecessive lethal allele aa dies

Yellow body color, an example of a lethal allele in mice:

Yellow mice never breed true.

Cross yellow x non-yellow, F1 is 1:1 yellow and non-yellow (all yellow mice are heterozygotes, AY/A).

Cross yellow x yellow (AY/A x AY/A), F2 is 2:1 yellow:non-yellow instead of the predicted 3:1 ratio.

Homozygotes (AY/ AY) are aborted in utero.

Yellow is dominant with respect to coat color, but acts as a recessive lethal allele.

Studies indicate that the AY allele has a large deletion and is fused to the promoter of a nearby (Raly) gene (Raly is inactivated).

Fig. 13.17, Lethal alleles in mice,Yellow body color

Why do lethal alleles persist in the population?

Recessive lethal alleles are not eliminated; rare alleles occur in the heterozygote (protected polymorphism).

Allele frequency q = 0.01Expected frequency of double recessive homozygotes, q2 = 0.0001Expected frequency of heterozygotes, 2pq = 0.0198

For complete recessive allele at equilibrium ( = mutation rate and s = selection coefficient):q = √ (/s)

If homozygote is lethal (s = 1) then q = √

Influence of the environment on gene expression:

4 major steps to development:

1. DNA replication2. Chromatin synthesis3. Growth4. Cell differentiation5. Arrangement of cells into tissue and organs

Internal and external environments interact with genes and gene products to control their expression at each stage of development.

Some basic terminology:

Penetrance describes how completely an allele corresponds with a trait in the population (0-100%) ~ Frequency (+/-)

Expressivity describes variation in expression of a gene or genotype (can be constant or variable) ~ Variability

Fig. 13.18, Penetrance and expressivity

Some effects of the environment:

Age of onset (male pattern baldness)

Sex (male pattern baldness)

Temperature (influences enzymes, coloration in Siamese cats, sex determination in reptiles)

Chemicals (phenocopy, chemicals mimic phenotype produced by rare recessive alleles)

Measles during the first 12 weeks of pregnancy produces fetal cataracts, deafness, and heart defects.

Thalidomide (1959-1961), prescribed as a sedative for expectant mothers suppressed limb-bone development.

Male Pattern Baldness(Fig. 13.20)

OMIM 109200

•Autosomal

•Dominant in males

•Recessive in females

•Influenced by testosterone

Male Pattern Baldness(Fig. 13.20)

OMIM 109200

•Autosomal

•Dominant in males

•Recessive in females

•Influenced by testosterone

Epigenetics:

Study of heritable changes caused by mechanisms other than changes in the underlying DNA.

Examples include changes in gene expression caused by DNA methylation and chromatin/histone modification.

Persist through cell divisions and multiple generations.

http://learn.genetics.utah.edu/content/epigenetics/

Examples of epigenetic inheritance:

Waterfleas (Daphnia) grow protective helmets in the presence of predators, stimulated by chemicals produced by the predators in the environment. The helmets are passed to the offspring and the next generation. The grandkids have smaller helmets.

A common fungicide (vinclozolin) used on grape plants causes low sperm count, prostate, and kidney disease in laboratory rats. The great grandsons of the rats also have lower sperm count after the pesticides is removed from the environment three generations prior.

The incidence of heart disease and diabetes may be regulated by epigenetic factors. The amount of food your grandfather ate when he was 9-12 may influence your susceptibility to these diseases. Age 9-12 is when the cells are grown that give rise to sperm.

Epigenetics:

While epigenetic changes by definition must persist through multiple generations, their effects gradually wash out.

How many generations is a current question of interest.

Provides a buffer to changing environmental conditions.

To demonstrate that the change is epigenetic, the trait must be stable and persist in the F2 generation (to distinguish from maternal effect – subject of next lecture).