1. Extensions of & Deviations from Mendelian Genetic Principles
Text authored by Dr. Peter J. Russell
Slides authored by Dr. James R. Jabbur
CHAPTER 13
Extensions of & Deviations from Mendelian Genetic Principles

2. Extensions of Mendelian Principles can alter expected Mendelian ratios
Sex Linkage (last chapter; we covered)
Multiple alleles
Codominance
Incomplete dominance
Polygenics
Genetic Interactions
Between non-allelic genes on different loci
Environmental effects
Lethal alleles
Linkage

3. Multiple Alleles
Although a gene only exists in two forms in an individual (alleles), many forms exist in a population (polymorphisms)
The number of possible genotypes in a multiple allelic series depends on how many alleles are involved [n(n-1)/2]

4. ABO Blood Groups
ABO blood groups result from a series of three alleles, IA, IB and i that combine to produce four phenotypes (A, B, AB and O)
Both IA and IB are dominant to i, while IA and IB are codominant to each other
ABO inheritance follows Mendelian principles

5. Biochemistry of ABO Red Blood Cell grouping
The ABO locus produces RBC antigens by encoding
glycosyltransferases, which add sugars to polysaccharides on membrane glycolipid molecules (the H antigen)
Activity of the IA gene product, a-N-acetylgalactosamyl
transferase, converts the H antigen to the A antigen
Activity of the IB gene product, a-D-galactosyltransferase,
converts the H antigen to the B antigen
Neither enzyme is present in an i/i individual, and so the
H antigen remains unmodified
Figure 13.5 Production of the human ABO blood-type antigens. Conversion of the H antigen to the A antigen by the allele product and to the IB antigen by the product.

6. Role of blood antigens and antibodies in blood transfusions
Type AB blood is a universal recipient, but can only donate blood to an AB typed individual
Type O blood is a universal donor, but can only receive blood from type O, due to the presence of anti-A and B antibodies in the serum
Figure 13.4 Antigenic reactions that characterize the human ABO blood types. Blood serum from each of the four blood types was mixed with blood cells from the four types in all possible combinations. In some cases, such as a mix of B serum with A cells, the cells become clumped.

7. The H antigen and the Bombay blood type
Production of the H antigen is controlled by a different genetic locus from the ABO enzymes
Rarely, an individual lacks the dominant allele H needed for H antigen production (h/h genotype)
This genotype results in the Bombay blood type, which is similar to type O except that Bombay blood type individuals produce anti-O antibodies that are not seen in true type O individuals

8. Drosophila Eye Color
Drosophila has over 100 mutant alleles at the eye-color locus on the X chromosome, affecting the spectrum between white and red eye color in the fly
Alfred Sturtevant concluded that eosin (pink) and white eye color results from mutation in a single gene encoding red eye color (dominant)
In the cross to the right, the eosin female and white male produce eosin females. Thus, the eosin allele is dominant to the white allele

9. In the cross to the right, eosin-eyed F1 females (we/w) were crossed with wild-type, red-eyed males (w+/Y)
All female progeny are red-eyed (w+/w or w+/we)
Male progeny are either eosin-eyed (we/Y) or white-eyed (w/Y)
Thus, red-eye color is dominant over eosin-eye color or white-eye color

10. Modifications of Dominance Relationships
Complete dominance and complete recessiveness are two extremes in the range of dominance possible between pairs of alleles
Many allelic pairs are less extreme in their expression, showing incomplete dominance or codominance
In incomplete dominance, a heterozygote’s phenotype will be intermediate between the two possible homozygous phenotypes
In codominance, the heterozygote shows the phenotypes of both homozygotes
At the molecular level, these relationships between pairs of alleles depend upon patterns of gene expression

11. Animation: Incomplete Dominance & Codominance
Incomplete dominance is an allelic relationship where dominance is only partial
In a heterozygote, the recessive allele is not expressed. The one dominant allele is unable to produce the full phenotype seen in a homozygous dominant individual. The result is a new, intermediate phenotype.
Examples include palamino color in horses, flower color in snapdragons, coat color in fowl and sickle-cell anemia in humans
Animation: Incomplete Dominance & Codominance

12. Palomino horses When palominos are interbred, their progeny are:
1⁄4 cremello (cream colored) with the genotype Ccr/Ccr
1⁄2 palomino with genotype C/Ccr
1⁄4 chestnut (full coat color) with genotype C/C
The C allele allows for the full expression of coat color genes, while the Ccr allele dilutes the expression of coat color genes

13. Snapdragon flower color
A cross between a white-flowered plant and a red-flowered plant will produce all pink F1 offspring.
Self-pollination of the F1 offspring produces 25% red, 50% pink and 25% white offspring.
Note: the phenotype ratio is 1:2:1

14. Andalusion Fowl
Figure 13.7 Incomplete dominance in chickens. (a) A cross between a white bird and a black bird produces F1 birds of intermediate grey color, called Andalusian blues. (b) The F2 generation shows the 1:2:1 phenotype ratio characteristic of incomplete dominance.

15. Codominance
In codominance, the heterozygote’s phenotype includes the phenotypes of both homozygotes
Examples of codominance include:
The ABO blood series, in which a heterozygous IA/IB individual will express both antigens, resulting in blood type AB
The human MN blood group, which involves red blood cell antigens that are less important in transfusion. There are three types:
Type M, with genotype LM/LM
Type MN, with genotype LM/LN
Type N, with genotype LN/LN

16. Molecular Explanations of Incomplete Dominance and Codominance
Current explanations involve levels of gene expression for each allele in the pair
In codominance, both alleles make a product, producing a combined phenotype
In incomplete dominance, the recessive allele is not expressed and the dominant allele produces only enough product for an intermediate phenotype
Dominant genetic disorders also exhibit incomplete dominance when involving a gain-of-function phenotype (i.e. heterozygous oncogene)***
By contrast, a completely dominant allele creates the full phenotype by one of two methods:
It produces half the amount of protein found in a homozygous dominant individual, but that is sufficient to produce the full phenotype. These genes are haplosufficient
Expression of the one active allele may be upregulated, generating protein levels adequate to produce the full phenotype

17. Essential Genes and Lethal Alleles
Some genes are required for life (essential genes) and mutations in them may result in death (lethal alleles)
Roughly one-third of all genes are essential
Dominant lethal alleles result in the death of both homozygotes and heterozygotes
Recessive lethal alleles cause death only when homozygous
An example of lethality is the yellow body color gene in mice (yup, body color?!?)

18. Example of a Lethal Gene: Yellow body color gene in mice
Yellow crossed with non-yellow results in a ratio of 1 yellow:1 non-yellow. This suggests yellow is heterozygous…
Yellow mice never breed true, another indication of heterozygosity. But when yellow is bred with yellow, the result is about 2 yellow:1 non-yellow (instead of the predicted 3:1 ratio)
Castle and Little (1910) proposed that yellow homozygotes die in utero and are therefore missing from the progeny. The yellow allele has a dominant effect on coat color but also acts as a recessive lethal allele

19. Yellow is an allele of the agouti locus, designated AY.
When heterozygotes are crossed (AY/A+ X AY/A+), death of the homozygous agouti (AY/AY) results in a 2:1 ratio of progeny (instead of a predicted 3:1 ratio)
Thus, when two agouti heterozygotes are crossed, a recessive embryonic lethal allele is suspected
Agouti embryonic lethality is caused by a lack of Raly activity
The Ay allele results from the deletion of an upstream sequence, removing the normal promoter of the aguoti gene. Thus, the gene is transcribed from the upstream promoter of Raly, producing an abnormal and non-functional transcript for Agouti and Raly

20. examples we have already discussed…
Human examples of recessive lethal alleles are:
Tay-Sachs disease: resulting from an inactive gene for the enzyme hexosaminidase. Homozygous individuals develop neurological symptoms before 1 year of age, and usually die within the first 3–4 years of life.
Hemophilia: results from an X-linked recessive allele, and is lethal if untreated.
A dominant lethal gene causes Huntington disease, characterized by progressive central nervous system degeneration. The phenotype is not expressed until individuals are in their 30’s. Dominant lethals are rare, since death before reproduction would eliminate the gene from the pool

21. Gene Expression and the Environment
Development of a multicellular organism from a zygote is a series of (generally) irreversible phenotypic changes resulting from interaction of the genome and the environment. Four major processes are involved:
Replication of genetic material
Growth
Differentiation of cells into types
Arrangement of cell types into defined tissues and organs
Internal and external environmental factors interact with the genes by controlling their expression and interacting with their products

22. Penetrance and Expressivity
Penetrance describes how completely the presence of an allele corresponds with the presence of a trait (yes or no)
It depends on both the genotype (e.g., epistatic genes) and the environment of the individual
If all those carrying a dominant mutant allele develop the mutant phenotype, the allele is completely (100%) penetrant
If some individuals with the allele do not show the phenotype, penetrance is incomplete. If 80% of individuals with the gene show the trait, the gene has 80% penetrance
Human examples include:
Brachydactyly involves abnormalities of the fingers, and shows 50–80% penetrance
Many cancer genes are thought to have low penetrance, making them harder to identify and characterize

23. Expressivity describes variation in the expression of a gene or genotype in individuals (how much?)
Two individuals with the same mutation may develop different phenotypes, due to variable expressivity of that allele.
Like penetrance, expressivity depends on both genotype and environment, and may be constant or variable
Human example: Osteogenesis imperfecta is inherited as an autosomal dominant with nearly 100% penetrance. However, it has variable expressivity

24. Some genes have both incomplete penetrance and variable expressivity
Neurofibromatosis is an autosomal dominant disorder with 50-80% penetrance and variable expressivity
Individuals with the disease show a wide range of phenotypes
Incomplete penetrance and variable expressivity complicate medical genetics and counseling

25. Effects of the Environment
Age of onset is an effect of the individual’s internal environment. Different genes are expressed at different times during the life cycle, and programmed activation and inactivation of genes influences many traits
Human examples include:
Pattern baldness, appearing in males aged 20–30 years
Duchenne muscular dystrophy, appearing in children aged 2 to 5 years

26. Sex of the individual affects the expression of some autosomal genes
Sex-limited traits can appear in one sex but not the other
Examples include:
Milk production in dairy cattle, where both sexes have milk genes, but only females express them
Facial hair distribution in humans
Sex-influenced traits appear in both sexes, but the sexes show either a difference in frequency of occurrence or an altered relationship between genotype and phenotype
Pattern baldness, controlled by an autosomal gene that is dominant in males and recessive in females
The genotype b/b produces pattern baldness in both men and women
The genotype b+/b+ gives a non-bald phenotype in both sexes
The genotype b+/b will lead to the bald phenotype in men, and the non-bald phenotype in women.
Cleft lip and palate (2:1 ratio of males to females)
Gout, rheumatoid arthritis, osteoporosis, lupus (ratios vary)

28. Anybody see
a mouse?
Temperature may alter the activity of enzymes so that they function normally at one temperature but are nonfunctional at another
The Siamese phenotype occurs in cats homozygous for the recessive allele (cS) of the albino (C) locus, which encodes a tyrosinase
Tyrosinase is required in the melanin synthesis pathway. Activity of the tyrosinase encoded by cS is temperature sensitive
Kittens are uniformly warm, and so stay light colored
As cats grow, extremities become cooler, and tyrosinase becomes active, allowing melanin to be made and fur on the points to become darker

29. Obviously, chemicals can have significant effects on physiology
Phenylketonuria (PKU) is an autosomal recessive defect in the metabolism of the amino acid phenylalanine
If the defect is not treated by restricting phenylalanine in the diet, severe mental retardation and other symptoms result
Cells respond differently to folic acid and retinoic acid*** (next slide)

30. Sidney Farber, M.D.

31. Nature versus Nurture
Phenotypes seen for many traits are influenced by both genes and the environment
Some human examples include:
Human height (diet, health, physical fitness)
Alcoholism (adopted children and foster parent rates)
Intelligence (good schools and nutrition)

32. Animation: Maternal Effect
Some maternally derived phenotypes are produced by the maternal nuclear genome rather than inherited as extranuclear genes (maternal effect v. maternal inheritance)
Proteins/mRNA deposited in the oocyte direct early embryo development by turning on/off nuclear genes
An example is shell coiling in the snail, where the maternal dominant D allele produces a right handed coil (maternal recessive d produces left)
At the molecular level, shell coiling is directed by the orientation of the mitotic spindle in the first mitotic division following fertilization
Animation: Maternal Effect

34. Determining the Number of Genes Involved in a Set of Mutations with the Same Phenotype
The relationship between a phenotype and a gene can be studied through mutants identified by a unique phenotype relative to wild-type
The complementation test (cis-trans test) determines whether independently isolated mutations for the same phenotype are in the same or different genes by crossing two mutants
If mutations are in different genes, the phenotype will be wild-type (complementation)
If mutations are in the same gene, the phenotype will be mutant (no complementation)
Drosophila provides an example…

35. The genes encoding body color are ebony and black.
Wild-type body color is grayish yellow. If two true-breeding mutant, black-bodied strains are crossed, all F1 are wild type due to complementation
Figure 13.1 Complementation test to determine whether two mutations resulting in the same phenotype are in the same or different genes. (a) Complementation occurs when mutations are in different genes. (b) Complementation does not occur when mutations are in the same gene.

36. Gene Interactions & Modified Mendelian Ratios
Phenotypes result from complex interactions of molecules under genetic control
Deviation from expected Mendelian ratios indicates that interaction of two or more genes is involved in producing the phenotype
Two types of interactions occur:
Different genes control the same general trait, collectively producing a phenotype
One gene masks the expression of other(s) and alters the phenotype (epistasis)

37. Gene Interactions That Produce New Phenotypes
Non-allelic genes that affect the same characteristic may interact to give novel phenotypes, and often modified phenotypic ratios (from the usual dihybrid 9:3:3:1 ratio)
An example is eye color in Drosophila, in which 2 loci (bw and st) are involved
At least one wild-type allele for each locus must be present to produce wild-type red eyes
The bw locus encodes a red pigment
The st locus encodes a brown pigment
Flies mutant for both bw and st have white eyes

39. Epistasis
In epistasis, one gene masks the expression of another, but no new phenotype is produced
A gene that masks another is epistatic
A gene that gets masked is hypostatic
Several possibilities for interaction exist, all producing modifications in the 9:3:3:1 dihybrid ratio:
Epistasis may be caused by recessive alleles, so that a/a masks the effect of B (recessive epistasis)
Epistasis may be caused by a dominant allele, so that A masks the effect of B (dominant epistasis)
Epistasis may occur in both directions between genes, requiring both genetic loci to produce a particular phenotype (duplicate epistasis; dominant or recessive types)

40. …summary of epistatic ratios from heterozygote cross

41. An example of recessive epistasis is exhibited in coat color determination in rodents
Wild-type mice have individual hairs with an agouti pattern (bands of black/brown and yellow pigment). Agouti hair is produced by a dominant allele (A)
The B allele encodes a tyrosinase-related protein, which produces black (dominant) or brown (recessive) pigment
The C allele encodes a tyrosinase and is responsible for the development of any color at all, so it is epistatic over A and B
Figure Recessive epistasis: generation of an F2 9 agouti : 3 black : 4 white ratio for coat color in rodents.

42. Another example of recessive epistasis is exhibited in coat color determination in labrador retrievers
The B gene produces black (dominant) or brown (recessive) pigment
E facilitates expression of the aforementioned gene; e does not

43. An example of dominant epistasis is provided by summer squash fruit…
The theoretical biochemical pathway below postulates genetic dominance
Yellow is recessive to White but is dominant to Green

44. An example of duplicate recessive epistasis, or complementary gene action, is flower color determination in sweet peas
The theoretical biochemical pathway above postulates genetic dominance
The c/c alleles determine whether the flower will have color; the P allele determines whether purple is produced

45. Extranuclear Inheritance
Extranuclear DNA is found in mitochondria and chloroplasts
Their genes encode rRNA for ribosomes of the organelles, tRNAs and a few organelle proteins whose functions are related to energy generation and photosynthesis
Extranuclear genes exhibit non-Mendelian inheritance (this genetic material is contributed by the female in the oocyte)
Mutations in mtDNA can produce human genetic disorders. Examples include:
Leber’s hereditary optic neuropathy (LHON). Optic nerve degeneration results in complete or partial blindness in midlife adults.
Kearns-Sayre syndrome produces three types of neuromuscular defects, for example heart disease
In most mtDNA disorders, cells of the affected individuals have a mix of normal and mutant mitochondria (heteroplasmy)