Extensions of Mendelian Genetics

Extensions to Mendelian

• Multiple alleles

• Modifications of dominance relationships

• Gene interactions

• Essential genes, lethal genes

• Gene expression and environment

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.

Fig. 12.3, In complete 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. 4.7

Multiple alleles

• Genes have multiple alleles.

• WHY?• Do different alleles

produce different phenotypes?

ABO blood groups

• ABO blood groups; A, B, AB, and O

• IA and IB are dominant to i, while IA and IB are codominant.

ABO types

Phenotype Genotype RBC-antigen antibody present in blood

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

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.

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.

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.

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.

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.

Eosin x White

P Cross w (X) Y

we (X) we/wXX

we/YXY

we (X) we/wXX

we/YXY

F1 x Wild type

w+(X) Y

we (X) we/w+

XXwe/YXY

w (X) w/w+

XXw/YXY

Number of alleles, number of genotypes

# alleles # genotypes Homozygotes Heterozygotes

1 1 1 0

2 3 2 1

3 6 3 3

4 10 4 6

5 15 5 10

N(N+1)/2 genotypes; N homozygotes, and N(N-1)/2 heterozygotes

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

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.

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 (-/-).

Different types of dominance

• Incomplete dominance

• Codominance

• Complete dominance

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.

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.

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).

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.

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.

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

Fig. 12.6

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.

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.

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).

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.

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.

Fig. 12.9,Recessive epistasisF2: 9:3:4

(all mice have B)

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.

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.

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.

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.

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.

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

Gene Expression and Environment

• Replication of genetic material

• Growth

• Differentiation of cells into types

• Arrangement of cell types into defined tissues and organs

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.

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.

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.

Fig. 12.12, Penetrance and expressivity

Neurofibromatosis

• The allele is an autosomal dominant that shows 50-80 % 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.

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)

Male Pattern Baldness(Fig. 12.14)

OMIM 109200

•Autosomal

•Dominant in males

•Recessive in females

•Also influenced by testosterone

Male Pattern Baldness(Fig. 12.14)

OMIM 109200

•Autosomal

•Dominant in males

•Recessive in females

•Also influenced by testosterone

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.