1. Extensions of Mendelian Genetics

2. Extensions to Mendelian
Multiple alleles
Modifications of dominance relationships
Gene interactions
Essential genes, lethal genes
Gene expression and environment

3. Incomplete Dominance
Dominance is only partial, one dominant allele is unable to produce the full phenotype seen in homozygous dominant individual.
Example: plumage color in chickens.

4. Fig. 12.3, In complete dominance in chickens

5. Different types (modifications) of dominance relationships:
3. Codominance
Alleles are codominant to one another.
Phenotype of the heterozygote includes the phenotype of both homozygotes.
e.g., ABO blood groups & sickle-cell anemia
Fig. 4.7

6. Multiple alleles Genes have multiple alleles. WHY?
Do different alleles produce different phenotypes?

7. ABO blood groups ABO blood groups; A, B, AB, and O
IA and IB are dominant to i, while IA and IB are codominant.

8. ABO types O i/i none (H) anti-A & B A IA/ IA or IA/i anti-B B
Phenotype
Genotype
RBC-antigen
antibody present in blood O
i/i
none (H)
anti-A & B A
IA/ IA or IA/i
anti-B B
IB /IB or IB /i
anti-A AB
IA/IB
A and B
none

9. ABO inheritance is Mendelian:
Possible parental genotypes for type O offspring:
i/i x i/i
IA/i x i/i
IA/i x IA/i
IB/i x i/i
IB/i x IB/i
IA/i x IB/i

10. Biochemical basis of ABO
ABO locus produces RBC antigens by encoding glycosyltransferases, which add sugars to an existing polysaccharide on membrane glycolipids. These polysaccharides act as the antigen in ABO system.

11. H Antigens
Most people have an H antigen, a glycolipid, on blood cells.
Activity of the IA gene product converts H antigen to the A antigen by adding the sugar alpha-N-acetylgalatosamine to H.
Activity of the IB gene product converts H antigen to the B antigen by adding the galactose to H.
Both enzymes are present in AB individual.
Neither enzyme is present in O individuals.

12. Molecular basis of ABO
blood group O allele differs from the blood group A allele by deletion of guanine-258. The deletion, occurring in the portion of the gene encoding the part near the N terminus of the protein, causes a frameshift and results in translation of an almost entirely different protein. The latter protein is incapable of modifying the H antigen.

13. Molecular basis of ABO
Yamamoto et al. (1990) found 7 nucleotide differences between the alleles that code for the A and B glycosyltransferase enzymes: 4 of the nucleotide differences were accompanied by change in amino acid residue in the transferase. The A gene had A, C, C, G, C, G, and G as nucleotides 294, 523, 654, 700, 793, 800, and 927; the B gene was found to have G, G, T, A, A, C, and A at these positions.

14. Drosophila Eye Color
Drosophila has over 100 mutant alleles at the eye-color locus on X chromosome.
The white eyed variant allele is designated as w.
The wild type allele is w+
A recessive allele, we, produces eosin (reddish-orange) eyes.

15. Eosin x White
P Cross
w (X) Y
we (X)
we/w XX
we/Y XY

16. F1 x Wild type
w+(X) Y
we (X)
we/w+ XX
we/Y XY
w (X)
w/w+
w/Y

17. Number of alleles, number of genotypes
Homozygotes
Heterozygotes 1 2 3 6 4 10 5 15
N(N+1)/2 genotypes; N homozygotes, and N(N-1)/2 heterozygotes

18. Molecular basis of multiple alleles
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

19. ABC transporters
The most intensively studied ABCG gene is the white locus of Drosophila. The white protein, along with brown and scarlet, transports precursors of eye pigments (guanine and tryptophan) in the eye cells of the fly. The mammalian ABCG1 protein is involved in cholesterol transport regulation (18). Other ABCG genes include ABCG2 , a drug-resistance gene; ABCG5 and ABCG8 , coding for transporters of sterols in the intestine and liver.

20. The Drosophila compound eye.
(a) relative positions of cells in an ommatidium of the adult compound eye.
(b) Electron micrograph of a cross-section through an ommatidium. Note the large pigment granules (PG) in pigment cells. Small pigment granules (pg) are located close to the base of the rhabdomeres (Rh), the photosensitive stacks of microvilli in photoreceptor cells.
(c) Light micrograph of a section through a compound eye that is mosaic for deep orange. The approximate boundary between the deep orange (-/-) and wild-type (+/-) tissue is indicated. Note the absence of red pigment granules in the part of the eye that lacks deep orange function (-/-).

21. Different types of dominance
Incomplete dominance
Codominance
Complete dominance

22. Molecular basis of dominance
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.
Completely dominant allele creates full phenotype either by
Producing half the amount of protein found in homozygous dominant individual but that is sufficient to produce the full phenotype (haplo-sufficient alleles).
Expression of the one active allele maybe upregulated, generating protein levels adequate to produce the full phenotype.

23. Molecular Basis of Recessive Mutations
Recessive mutations usually result from partial or complete loss of a wild type function.
Amorphic alleles are those that have completely lost the function. An example would be a mutation in which production of pigment is completely lost in the homozygous state, causing albinism.
Hypomorphic alleles are those in which function is reduced, but not completely lost. An example would be a mutation that causes a partial loss of pigmentation, giving a lighter color when homozygous.

24. Molecular Basis of Dominant Mutations
Are also called gain-of-function alleles.
Hypermorphic alleles are those that cause excess product to be produced.
Antimorphic alleles are those that produce an altered gene product that "poisons" or disrupts the function of the normal gene product.
Neomorphic alleles cause the gene product to be expressed in the wrong types of cells, and can have drastic effects, such as that of the antennapedia gene that coverts the antennae of flies into legs.
Haplo-insufficient alleles. In this case, loss of a gene product causes a recognizably different phenotype in the heterozygote (homozygous can be lethal).

25. 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/BB
2/16 AA/Bb
1/16 AA/bb
2/16 Aa/BB
4/16 Aa/Bb
2/16 Aa/bb
1/16 aa/BB
2/16 aa/Bb
1/16 aa/bb
Deviation from this ratio indicates the interaction of two or more genes producing the phenotype.

26. Two types of interactions
Different genes control the same trait, collectively producing a phenotype.
One gene masks the expression of others (epistasis) and alters the phenotype.

27. Gene Interactions that produce new phenotypes
None allelic genes affect the same characteristic may interact.
Comb shape in chickens, influenced by two gene loci, produce four different comb types.
Rose-comb
Pea-comb
Single-comb
Walnut-comb

28. Fig. 12.6

29. Hypothesize a mechanism for these interactions
Two dominant alleles, two recessive alleles.
Two genes affect comb shape but different aspects of it.
When either gene is not expressed, single shaped; so these genes are only necessary for modifying the shape not for the presence of a comb.
When one of the genes expressed only, a particular phenotype occurs.
When both genes are expressed, a novel modified phenotype occurs.

30. 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.

31. All are modifications of 9:3:3:1
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.
Epistasis may occur in both directions between genes, requiring both A and B to produce a particular phenotype (duplicate recessive epistasis).

32. Recessive Epistasis (9:3:4)
Banding pattern character (A)
Wild mice have individual hairs with an agouti pattern, bands of black (or brown) and yellow pigment. Agouti hairs are produced by a dominant allele, A. Mice with genotype a/a do not produce yellow bands, and have solid-colored hairs.

33. Recessive Epistasis Hair color character (B, and C)
The B allele produces black pigment, while b/b mice produce brown pigment. The allele A is epistatic over B and b, in that it will insert bands of yellow color between either black or brown.
The C allele is responsible for development of any color at all, and so it is epistatic over both the agouti (A) and the pigment (B) gene loci. A mouse with genotype c/c will be albino, regarless of its genotype at the A and B loci.

34. Fig. 12.9,
Recessive epistasis
F2: 9:3:4
(all mice have B)

35. Essential genes, lethal alleles
Some genes are required for life (essential genes), and mutations in them (lethal alleles) may result in death.
Dominant lethal alleles result in death of both homozygotes and heterozygotes.

36. Yellow body color in mice
Wild type agouti mice express the agouti gene only during hair development in the days after birth, and when plucked hair is being regenerated. Gene expression is seen in no other tissues and at no other time.
Heterozygous mice (Ay/A+) express Ay allele at high levels in all tissues during all developmental stages. Tissue specific regulation appears to be lost in the Ay allele.

37. Agouti Gene
The agouti gene has been cloned recently and is thought to encode a signaling molecule that directs follicular melanocytes to switch from the synthesis of black pigment, eumelanin, to yellow pigment, phaeomelanin.

38. Ay allele
Its transcript RNA is 50% longer than that of the wild type A+; because:
The Ay allele results from deletion of an upstream sequence, removing the normal promoter of the agouti gene.
The gene is transcribed from the promoter of an upstream gene called Raly. The beginning of the sequence encoding Raly is fused with the agouti gene, producing a longer transcript.
Embryonic lethality of Ay/Ay mice probably results from lack of Raly gene activity, rather than from the defective agouti gene.

39. Examples of human lethal alleles
Tay-Sachs disease, resulting from an inactive gene for the enzyme hexosaminidase. Homozygous individuals develop neurological symptoms before 1 year of age.
Hemophilia results from and X-linked recessive allele, lethal when untreated.
Dominant lethal allele causes Huntington disease, characterized by progressing central nervous system degenaration.

40. Fig. 12.11, Lethal alleles in mice,
Yellow body color

41. Gene Expression and Environment
Replication of genetic material
Growth
Differentiation of cells into types
Arrangement of cell types into defined tissues and organs

42. Penetrance
How completely the presence of an allele corresponds with the presence of a trait. 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 (100%) penetrant.
If some individuals with the allele don’t show phenotype, penetrance is incomplete (e.g. 80% penetrant).
Brachydactyly (50-80% penetrant).
Many cancer genes have low penetrance.

43. Expressivity
Describes variation in expression of a gene or genotype in individuals.
Two individuals with the same mutation may develop different phenotypes.
Expressivity depends on genotype and environment.

44. Osteogenesis Imperfecta
Osteogenesis imperfecta, inherited as an autosomal dominant with nearly 100% penetrance.
Three traits associated with disease are blueness of sclera, very fragile bones, and deafness.
Shows variable expressivity, an individual may show one or more of the symptoms at a time.

45. Fig. 12.12, Penetrance and expressivity

46. Neurofibromatosis
The allele is an autosomal dominant that shows % penetrance and variable expressivity.
Mildest form is a few pigmented areas on the skin.
Others include, tumors, high blood pressure, speech impediments, heaches, large head, short stature, tumors of eye, brain or spinal cord, curvature of the spine.

47. Effects of the environment
Age of onset (pattern baldness)
Sex (milk production, horn formation)
Temperature (fur color in himalayan rabbits)
Chemicals (phenocopy of a mutation)

48. Male Pattern Baldness
(Fig )
OMIM
Autosomal
Dominant in males
Recessive in females
Also influenced by testosterone

49. Male Pattern Baldness
(Fig )
OMIM
Autosomal
Dominant in males
Recessive in females
Also influenced by testosterone

50. Hair-follicle histology and growth cycle
Hair-follicle histology and growth cycle. (a) The hair cycle, in which phases of growth (anagen) are interspersed with phases of regression (catagen) and rest (telogen). The phases of the cycle affected by null alleles of particular genes are identified. (b) The major histological compartments that make up a pilosebaceous unit, as it would appear in an ideal cross-section through skin tissue. The dashed line depicts the position of the club hair sheath (the fully regressed bulb region) in the telogen stage. Abbreviations: APM, arrector pili muscle; DP, dermal papilla; IRS, inner root sheath; ORS, outer root sheath; SG, sebaceous gland.