Chapter 5

Modifications to Mendelian Patterns of Inheritance

Variations on Dominance
Mendelian genetics : dominant allele requires only 1 copy to determine a phenotype ; masks expression of recessive allele recessive allele requires 2 copies to determine a phenotype ; expression masked by dominant allele crossing 2 monohybrid heterozygotes when dominance is complete gives a 3:1 phenotypic ratio sometimes this simple dominant-recessive relationship does not hold, and a heterozygous genotype does not always express a dominant phenotype

Incomplete Dominance in Fouroclock Plants (Mirabilis jalapa)

Neither allele is dominant to the other : use R1,R2 instead of R, r

F2 Phenotypic ratio

Incomplete dominance : heterozygotes exhibit a phenotype intermediate to the phenotypes expressed by the two homozygotes

Incomplete Dominance

R1 : specifies red pigment R2 : specifies no color R1, R2 heterozygotes : lighter red because they have only 1 allele that produces color

Mendelian patterns of inheritance are still followed (1:2:1 ratio in F2), but phenotypes do not follow patterns of strict dominance

Codominance The ABO Blood Classification

Erythrocytes expressing one (or both) of the ABO antigens have an antibody against the other antigens in their serum

Codominance : the heterozygote expresses phenotypes of both homozygotes simultaneously

Codominance The ABO Blood Classification

(type A)

(type B)

IA IA

x
(type AB)

IB IB
Phenotype includes both A and B simultaneously : codominance

F1 :
F2 :

100% IAIB
?

Pedigree Analysis of the Inheritance of Tay-Sachs Disease

this disease causes severe neurodegeneration before age 3 homozygous normal and heterozygotes do not have any symptoms

Analysis of the pedigree indicates that Tay-Sachs is inherited as an autosomal recessive trait
at the level of viability, shows Mendelian genetics of complete dominance (only homozygous recessive is not viable)

Hexosaminidase-A in normal and Tay-Sachs individuals at the level of enzyme activity

Figure 5.2b

The heterozygote individuals possess less activity than the homozygote dominant individual. The homozygous recessive individual exhibits no activity. at the level of enzyme activity, shows incomplete dominance

Hexosaminidase-A in normal and Tay-Sachs individuals at the level of protein structure

One variant in Tay-Sachs disease produces a protein smaller than the wild-type protein. Afflicted individuals (aa) produce only the smaller protein

Heterozygote individuals (Aa) produce both proteins

Homozygous normal (AA) produce the larger protein at the level of protein structure, shows codominance

Multiple Alleles
we have considered genes that have only 2 alleles a gene can have more than 2 alleles - diploid organism can have only 2 alleles, but many different alleles of any given gene can exist in a population polymorphic alleles

- in fact, multiple alleles are the rule rather than the exception

The ABO Blood Classification

3 alleles : IA, IB, and i IA, IB : glocosyltransferase enzymes that make A and B structures on a sugar molecule (H structure) on RBCs i : nonfunctional enzyme (recessive to IA and IB)

The ABO Blood Classification

Complete dominance (Mendelian) : i is recessive to IA and IB - IA and/or IB will modify the H product and mask the fact that the i allele is present

Codominance : IA and IB can be expressed simultaneously

Fur Color in the Mouse : Controlled by Several Genes Including Agouti

over 25 different agouti alleles have been identified these alleles either exhibit a unique phenotype or have different genetic interactions with other agouti alleles Consider 4 of these alleles : A, Aw, at, and a
(Wild type) (white-bellied allele ; dominant) (black&tan allele) (recessive)

Heterozygous mice reveal that the Aw allele is dominant to the other three agouti alleles

Phenotypes of the Different Allelic Combinations of Mouse Agouti Gene

Wild-type agouti allele (A) -Dark gray fur color -Deposition of yellow and black pigments White-bellied agouti allele (Aw) -Dark gray fur on the back, white or cream on the belly dominant Nonagouti allele, a, is recessive to other alleles

Phenotypes of the Different Allelic Combinations of Mouse Agouti Gene

These alleles show a hierarchy of dominance : Aw is dominant to A Aw and A are dominant to a . . . and complex patterns of dominance :

A is dominant to at on the back

at is dominant to A on the belly

Testing Allelism
* There may be many different variations of the 2 alleles that code for a gene (such as with the gene for mouse fur color) * Also, mutations in different genes may cause similar or identical phenotypes To study how phenotypes are inherited, need to know which mutations are different versions of the same gene (alleles) and which are in completely different genes

Partial map of Drosophila chromosomes

ruby and scarlet are 2 different mutations of 2 different genes on different chromosomes, but they both produce a similar eye color

Complementation test in flies: determine whether 2 recessive mutations are alleles

wingless wingless

: mutation
wild-type

mutant gene 1, wt gene 2 wt gene 1, mutant gene 2

Cross flies with homozygous recessive mutations, examine progeny : 1) wild-type phenotype : mutations complement each other mutations are in different genes arrangement of the two recessive mutations on different chromosomes is called the trans configuration (each homolog contains 1 mutation)

Noncomplementation (1)
wingless wingless

wingless

mutant gene 1, wt gene 2 mutant gene 1, wt gene 2

2) none of the F1 progeny exhibit the wild-type phenotype: mutations do not complement each other mutations are in different alleles of the same gene

Noncomplementation (2)
wingless Small, wrinkled wings

Very Small, wrinkled wings

mutant gene 1, wt gene 2 mutant gene 1, wt gene 2

Cross flies with nonidentical recessive mutations, examine progeny - F1 progeny : small, crinkled wings (not wild-type trait) these mutations do not complement each other and must be alleles

The Cis-Trans Test

examine a large # of mutants and place them in complementation groups
** identifies : 1) mutations in separate genes and 2) independent alleles of a single gene

Parents :

i) ii)

both mutants on same chromosome wild-type

i) 1 mutant on 1 chromosome ii) other mutant on other chromosome

(cis configuration is a control for test to make sure a wt can be produced)

(trans configuration determines if mutations are allelic or not)

The Cis-Trans Test

can use this test to determine how many genes control a biochemical pathway - try to mutate every gene in a pathway, then use cis-trans test to determine how many distinct genes code for proteins that affect the same mutant phenotype helps to treat genetic diseases

Lethal Alleles
cause a deviation from expected 3:1 phenoptypic ratio in a monohybrid cross caused by certain genotypes that result in death and are not seen in the progeny these alleles can still follow standard Mendelian dominant-recessive relationships but will skew Mendelian phenotypic ratios

Relationship of yellow (AY) allele to the wild-type agouti (A) allele

2 important crosses :
(1)
?
we already know agouti mice are genotypically AA

Homozygous agouti X yellow : always produces yellow and agouti mice (expected 1:1 ratio for a monohybrid test cross) because the agouti mice are known to be homozygous, yellow mice must be heterozygous with yellow dominant to agouti

Relationship of yellow (AY) allele to the wild-type agouti (A) allele

(2)

Yellow X yellow

2/3 yellow, 1/3 agouti

Expected results phenotypic ratio 3:1 yellow to agouti (monohybrid cross of heterozygotes) Possible explanations?

Relationship of yellow (AY) allele to the wild-type agouti (A) allele

Examination of pregnant mice revealed 25% of the developing embryos were dead

Homozygous yellow allele is lethal: AyAy

2/3 of the surviving mice will be yellow (heterozygous)

1/3 will be agouti (homozygous)

Relationship of yellow (AY) allele to the wild-type agouti (A) allele

AY allele is dominant for coat color, recessive for lethality

Pleitropy : when a single mutation causes multiple phenotypes

Other Lethal Mutations

Dominant lethal mutations Can only exist if :

i. Lethality is only expressed after sexual maturity

- example : Huntington disease (onset : after age 40) ii. Incomplete penetrance : a phenotype is not expressed for a certain genotype Deleterious mutations - reduce viability without always causing death ; depends on environment - example : temperature sensitive mutations in flies

What about when a specific genotype does not express the expected phenotype ?

3 possibilities :
i. incomplete penetrance ii. variable expressivity iii. 1 gene affects the expression of another gene

Incomplete Penetrance: A Percentage of individuals with a genotype do not express the expected phenotype

(all are homozygous recessive genotype)

Only 60% of the individuals are expressing the expected phenotype ; it is 60% penetrant
Most genotypes are 100% penetrant

Variable Expressivity : the range of phenotypes associated with a specific genotype is increased

(all are homozygous recessive genotype)

All express a mutant phenotype, but there is a range of these phenotypes (light red to complete white) - these phenotypes are associated with a single mutant allele (caused by different expression levels?)

Incomplete Penetrance and Variable Expressivity : Polydactyly

Autosomal dominant trait Extreme manifestations characterized by an extra digit on each hand and one or two extra toes on each foot Variable expressivity: Extra toes or extra fingers Portion of an extra digit thumb Partial extra little toe
incomplete penetrance and variable expressivity : affected by genetics and environmental factors

Genotypic Interactions
Mendelian Inheritance : Cross between 2 independent traits should always produce 9:3:3:1 phenotypic ratio - 9/16 have both dominant phenotypes - 1/16 has both recessive phenotypes

Variations in phenotypes or in ratios indicates that 2 genes may be interacting

2 Genes Contribute to a Single Phenotype:

1) mixed phenotypes : genetic interactions in the combs of chickens
Cross Rose-combed chicken X peacombed chicken (or vice versa) F1 offspring are walnut-combed Cross F1 Heterozygous walnutcombed chickens F2 progeny 9:3:3:1 indicates 2 genes are involved 9/16 walnut-combed fowl 3/16 rose-combed fowl 3/16 pea-combed fowl 1/16 single-combed fowl prediction of genotypes ?

2 Genes Contribute to a Single Phenotype:

1) mixed phenotypes : genetic interactions in the combs of chickens
Interpretation:
Dominant alleles for each gene: (R-) (P-) : walnut-combed Dominant rose allele (R-) and homozygous pea (pp) rose-combed

Dominant pea allele (P-) and homozygous rose (rr) pea-combed

Homozygous recessive (pprr) for both alleles single-combed fowl 2 genes affect 1 phenotype

2 Genes Contribute to a Single Phenotype:

2) complementary gene action : genetic interactions in the color of corn kernels
Crossing 2 white corn varieties yields all purple kernels in F1 F1 cross yields 9/16 purple 7/16 white ???

-Must be dealing with 2 traits, each with 2 alleles because ratios are in sixteenths -9:7 is variation of 9:3:3:1 ratio -genotypic possibilities in Punnet square : purple color appears when at least one dominant allele for both genes is present white color appears when one or both genes only have recessive alleles

2 Genes Contribute to a Single Phenotype:

2) complementary gene action : genetic interactions in the color of corn kernels

a dominant allele for 2 different genes must be present to produce a phenotype (purple)
without this allele at either or both genes, white color results

can order these genes in a biochemical pathway

Colorless precursor

colorless intermediate

Gene B catalyzes

purple product

Gene A catalyzes

2 Genes Contribute to a Single Phenotype:

3) duplicate gene action : 2 genes produce a phenotype ; both genes appear equivalent
Shepherds purse plant (Capsella bursa-pastoris)

Indicates heart-shaped is dominant to narrow; should be a simple monohybrid cross

???
- expect 3:1, 1:2:1, or 2:1 for monohybrid F2 ratio

Ratio is modification of 9:3:3:1 2 genes are involved

2 Genes Contribute to a Single Phenotype:

3) duplicate gene action : 2 genes produce a phenotype ; both genes appear equivalent
15:1 ratio indicates that the dominant allele (for either the A or B gene) is sufficient to produce the heart-shaped phenotype. the enzymes encoded by the A and B alleles are equivalent in the biochemical pathway :

2 different genes encode identical enzymes one of these enzymes can have a slightly different function ; creates gene families with similar function (as with -globin family composed of 5 genes, each expressed at different times in development)

2 Genes Contribute to a Single Phenotype:

4) epistasis : phenotype produced by 1 gene (epistatic gene) masks the phenotype produced by 2nd gene (hypostatic gene)
* * Indicated by modified 9:3:3:1 ratio with only 3 phenotypes

Coat Color in Mice: Black, Albino, or Agouti

Crossing a pure-breeding black mouse with a pure-breeding albino mouse produce 100% agouti mice The albino phenotype results from the absence of pigment in the hair

2 Genes Contribute to a Single Phenotype:

4) epistasis : phenotype produced by 1 gene masks the phenotype produced by 2nd gene
F2 progeny:
9/16 agouti A-C3/16 black aaC-

4/16 albino
(3/16 A-cc and 1/16 aacc)

F2 9:3:4 ratio is a modification of 9:3:3:1 recessive epistasis any genotype with cc is albino and masks phenotype of the A gene (agouti or black) ; without this, the A gene expresses (A>a)

2 Genes Contribute to a Single Phenotype:

4) epistasis : phenotype produced by 1 gene masks the phenotype produced by 2nd gene
Color of Summer Squash Can Be White, Yellow, or Green

P1: pure-breeding white X pure-breeding green F1 progeny : all white squash F1 is self-crossed

2 Genes Contribute to a Single Phenotype:

4) epistasis : phenotype produced by 1 gene masks the phenotype produced by 2nd gene

F2 12:3:1 ratio is a modification of 9:3:3:1 dominant epistasis

dominant A allele masks phenotype of B gene

Mechanism of Epistasis

Defects in the Biochemical Pathway Producing Melanin Results in Albino Mice

Mouse coat color : Both the agouti and black phenotypes need melanin in order to be expressed Albinism is caused by defects pathway for melanin production :

The Epistatic Gene Functions Early in the Pathway Resulting in the Albino Phenotype for cc Mice

The recessive c allele is responsible for the albino pigment by blocking the pathway ; its product is required by next gene (A) in making the yellow coat color

In biochemical pathways involving epistasis :

epistatic gene functions earlier than hypostatic gene

genetic analysis complements a biochemical analysis

2 Genes Contribute to a Single Phenotype:

5) suppression : one gene pushes the mutant phenotype of a 2nd gene towards wild-type phenotype
Suppression of the Vestigial (vg) Wing Phenotype in Drosophila : In this case the su(vg) recessive mutation pushes the vestigial phenotype toward the wild-type recessive suppressor
classes: + + + - - - - - - + -

Suppressors :
1) May have no other phenotype than to suppress another genes mutant phenotype dihybrids produce only 2 phenotypes 2) Only make the second genes mutant phenotype more like wild-type (no effect on wild-type allele) 3) Can be either dominant or recessive, may suppress a dominant or recessive allele 4) May have both dominant or recessive phenotypes

Possible Mechanisms of Suppression:

A suppressor gene may encode a protein that specifically interacts with another protein :
Two genes (m and su) encode different proteins that interact to convert a substrate to a product and produce the wildtype phenotype
* finding these suppressor mutations is a powerful way to identify which gene product forms a protein complex with another gene product

Possible Mechanisms of Suppression: Other mechanisms (nonspecific; can act on several other genes): 1) increase or decrease expression level of gene 2) affect translation of an mRNA - prevent a stop in translation induced by nonsense mutation

Modified 9:3:3:1 ratio in F2 generation 2 genes are interacting in the phenotype

epistasis : often only 3 phenotypes 9:3:4 12:3:1

suppression : often only 2 phenotypes 13:3

Epigenetics
heritable modification of gene function without a change in DNA sequence

Example of epigenetics : mosaicism in human females

Random inactivation of X chromosome during embryonic development in female mammals
-some cells (and developing tissues) have paternal X chromosome inactivated, others have maternal X chromosome inactivated

If the female is heterozygous for a sex-linked gene, she is mosaic (composed of two or more genetically distinct tissues or cell types) - some tissues express dominant allele, other tissues express recessive allele

Epigenetics

Barr bodies

http://www.mun.ca/biology/scarr/Barr_Bodies.html

Epigenetics

histone modifications

DNA methylation
methyl group

adapted from http://www.landesbioscience.com/curie/chapter/4639/

Effects of diet and behavior on epigenetics and gene expression : http://video.pbs.org/video/1525107473/