CHAPTER 12 Extensions Of Mendelian Genetic Analysis

CHAPTER 12 Extensions Of Mendelian Genetic Analysis
Peter J. Russell CHAPTER 12 Extensions Of Mendelian Genetic Analysis edited by Yue-Wen Wang Ph. D. Dept. of Agronomy, NTU 台大農藝系遺傳學

Multiple Alleles 1. Not all genes have only two forms (alleles); many have multiple alleles. No matter how many alleles for the gene exist in the multiple allelic series, however, a diploid individual will have only two alleles, one on each homologous chromosome. 台大農藝系遺傳學

Fig. 12.1 Allelic forms of a gene
台大農藝系遺傳學 Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

ABO Blood Groups 1. ABO blood groups are important in blood transfusions, and result from a series of three alleles (IA, IB and i) that combine to produce four phenotypes (A, B, AB and O). 2. Both IA and IB are dominant to i, while IA and IB are codominant to each other. The resulting phenotypes are (Table 12.1): a. People with genotype i/i are blood type O. b. People with genotype IA/IA or IA/i are blood type A. c. People with genotype IB/IB or IB/i are blood type B. d. People with genotype IA/IB are blood type AB. 3. ABO inheritance follows Mendelian principles. For example, a type O individual’s genotype is i/i. Possible genotypes of the parents could be: a. i/i and i/i (both blood type O). b. IA/i and i/i (one type A, the other type O). c. IA/i and IA/i (both type A). d. IB/i and i/i (one type B, the other type O). e. IB/i and IB/i (both type B). f. IA/i and IB/i (one type A, the other type B). 4. Blood typing may be used in cases of disputed parentage. Blood typing does not prove the identity of a parent. It can, however, eliminate individuals who are not biological parents of a particular child. Example: a. A child with blood type AB (IA/IB) could not have a parent with type O (i/i). Blood type data are not considered adequate legal proof for parenthood in most states, and DNA fingerprinting is generally used. iActivity: Was She Charlie Chaplin's Child? 台大農藝系遺傳學

Drosophila Eye Color 1. Drosophila has over 100 mutant alleles at the eye-color locus on the X chromosome. Example designations for alleles at this locus: a. The white-eyed variant allele is designated w. b. The wild-type (brick red) allele is w+ . c. A recessive allele, we, produces eosin (reddish-orange) eyes. 2. Soon after Morgan’s discovery of X-linkage, he found new genes for eye shape. and color, including a red one called vermilion (v+). a. He experimentally crossed a white-eyed female with a vermilion eyed male. b. The F1 females were all red-eyed (wild type), rather than either vermilion or white. c. He concluded two different genes were involved in Drosophila eye color (white and vermilion) rather than just alleles of a single locus. d. The original cross was: w v+/ w v+ (white-eyed female) with w+ v/ Y (vermilion-eyed male). e. The F1 females (wild-type red eyes) would be w v+/ w+ v, doubly heterozygous. 3. The eosin allele is recessive to wild-type. Morgan (1912) crossed an eosin-eyed female with a white-eyed male. All F1 females had eosin eyes. 台大農藝系遺傳學

4. Sturtevant (1913) concluded that eosin and white are mutations of a single gene. The relationship between these multiple alleles is: a. The allele red (wild-type) is dominant to eosin and white. b. The eosin allele is recessive to red, but dominant to white. c. For example, in the cross of an eosin-eyed (we/ we) female. with a white-eyed male (w/Y), the Fl females are all we/w. They have eosin eyes, showing that we is dominant over w. d. Next the eosin-eyed Fl females (we/w) are crossed with red-eyed males w+/ Y (Figure ). (1) All female progeny are red-eyed (w+/w or w+/we). (2) Male progeny are 1/2 eosin-eyed (we/Y), and 1/2 white-eyed (w/Y). e. Many alleles of the white-eye gene exist, producing a wide range of colors depending on the deposition of pigment in the eye cells (Table 12.2). 5. The number of possible genotypes in a multiple allelic series depends on how many alleles are involved (Table 12.3). a. The formula n(n + 1)/2 calculates possible genotypes for n alleles. b. Of the genotypes predicted by the formula, n are homozygotes, and n(n - 1)/2 are heterozygotes. 台大農藝系遺傳學

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Fig. 12.2a Results of crosses of Drosophila melanogaster involving two mutant alleles of the same locus 台大農藝系遺傳學 Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

Fig. 12.2b Results of crosses of Drosophila melanogaster involving two mutant alleles of the same locus 台大農藝系遺傳學 Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

Relating Multiple Alleles to Molecular Genetics
1. Genes encode proteins, and changes in amino acids of those proteins may change a phenotype. Multiple alleles exist for many genes, because there are many sites within a gene where introduction of a mutation will alter the protein product. 2. Consequences of multiple alleles in human genetic disorders include: a. Variation in disease symptoms depending on the patient’s allele(s). b. Complications in designing a single DNA-based test to diagnose the disease or detect carriers. 台大農藝系遺傳學

Modifications of Dominance Relationships
1. 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. a. In incomplete dominance, a heterozygote’s phenotype will be intermediate between the two possible homozygous phenotypes. b. In codominance, the heterozygote shows the phenotypes of both homozygotes. c. At the molecular level, these relationships between pairs of alleles depend upon patterns of gene expression. 台大農藝系遺傳學

Incomplete Dominance Animation: Incomplete Dominance and Codominance
1. 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. 2. An example is plumage color in chickens (Figure 12.3): a. Crossing a true-breeding black chicken (CBCB) with a true- breeding white one (CWCW) produces an Andalusian blue F1 (CBCW). b. When the F1 interbreed, the F2 include black (CBCB), Andalusian blue (CBCW) and white (CWCW) birds, in a ratio of 1:2:1. c. At the molecular level, two copies of CB produce black, while 1 copy is sufficient to produce only the gray “Andalusian blue” phenotype. 台大農藝系遺傳學

Fig. 12.3a Incomplete dominance in chickens

Fig. 12.3b Incomplete dominance in chickens

3. Palomino horses (golden-yellow body with nearly white mane and tail) are another example (Figure 12.4). When palominos are interbred, the progeny are: a. 1/4 cremello (cream colored) with genotype Ccr/Ccr. b. 1/2 palomino with genotype C/ Ccr. c. 1/4 light chestnut with genotype C/C. 4. Incomplete dominance often occurs in plants. An example is flower celor in snapdragons involving two alleles, CR and CW. Red- flowered plants (CR/CR) crossed with white-flowered ones (Cw/Cw) produce all pink progeny (CR/Cw ). 台大農藝系遺傳學

Codominance 1. In codominance, the heterozygote’s phenotype includes the phenotypes of both homozygotes. Examples include: a. The ABO blood series, in which a heterozygous IA/IB individual will express both antigens, resulting in blood type AB. b. The human M-N blood group involves red blood cell antigens that are less important in transfusions. There are three types: i. Type M, with genotype LM/LM. ii. Type MN, with genotype LM/LN. iii. Type N, with genotype LN/LN. 台大農藝系遺傳學

Molecular Explanations of Incomplete Dominance and Codominance
1. Current explanations involve levels of gene expression for each allele in the pair. a. In codominance, both alleles make a product, producing a combined phenotype. b. In incomplete dominance, the recessive allele is not expressed, and the dominant allele produces only enough product for an intermediate phenotype. c. By contrast, a completely dominant allele creates the full phenotype by one of two methods: i. 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. ii. Expression of the one active allele may be upregulated, generating protein levels adequate to produce the full phenotype. 台大農藝系遺傳學

Gene Interactions and Modified Mendelian Ratios
1. Phenotypes result from complex interactions of molecules under genetic control. Genetic analysis can often detect the patterns of these reactions. For example: a. In the dihybrid cross A/a B/b X A/a B/b, nine genotypes will result. b. If each allelic pair controls a distinct trait and exhibits complete dominance, a 9:3:3:1 phenotypic ratio results. c. Deviation from this ratio indicates that interaction of two or more genes is involved in producing the phenotype. 2. Two types of interactions occur: a. Different genes control the same general trait, collectively producing a phenotype. b. One gene masks the expression of others (epistasis) and alters the phenotype. 3. Examples here are dihybrid, but in the “real world” larger numbers of genes are often involved in forming traits. 4. The molecular explanations offered here are currently hypothetical models, and await rigorous analysis using the tools of molecular biology. 台大農藝系遺傳學

Gene Interactions That Produce New Phenotypes
1. Nonallelic genes that affect the same characteristic may interact to give novel phenotypes, and often modified phenotypic ratios. Examples include: a. Comb shape in chickens, influenced by two gene loci to produce four different comb types. Each will breed true if parents are homozygous (Figure 12.5). i. In a cross between a homozygous rose-combed (R/R p/p) bird and a single- combed (r/r p/p) bird (Figure 12.6): (1) The F1 (R/r p/p) will all have rose combs. (2) The F2 will be 3 rose (R/– p/p) : 1 single (r/r p/p). ii. Similarly, pea comb (r/r P/P) is dominant over single (r/r p/p), with F1 (r/r P/p) all showing pea combs, and a 3:1 ratio of pea to single in the F2. iii. Crossing true-breeding rose (R/R p/p) and pea (r/r P/P) results in: (1) An F1 with all walnut combs (R/r P/p). (2) An F2 showing a ratio of 9 walnut (R/– P/–) : 3 rose (R/– p/p) : 3 pea (r/r P/–) : 1 single (r/r p/p). iv. These interactions fit the expected ratios for a Mendelian dihybrid cross. The molecular basis for each phenotype is unknown, but it appears that the dominant alleles R and P each produce a factor that modifies comb shape from single to a more complex form. 台大農藝系遺傳學

Fig. 12.6 Complete dominance in chickens

i. Long fruit (a/a b/b) are always true-breeding.
b. Fruit shape in summer squash shows a 9:6:1 ratio. Two genes are involved, each completely dominant. Interaction between the two loci produces a new phenotype (Figure 12.7). i. Long fruit (a/a b/b) are always true-breeding. ii. Sphere-shaped fruit (A/– b/b or a/a B/–) are not always true-breeding, and sometimes produce long (a/a b/b) or disk- shaped (A/– B/–) fruit. iii. A cross between true-breeding spherical strains (A/A b/b 3 a/a B/B) produces a disk-shaped F1. The F2 will be 9⁄16 disk- shaped (A/– B/–), 6⁄16 spherical (A/– b/b or a/a B/–) and 1⁄16 long (a/a b/b). This modification of the Mendelian ratio indicates that two loci are involved. iv. The precise molecular basis of these phenotypes is unknown. 台大農藝系遺傳學

Fig. 12.7 Generation of an F2 9:6:1 ratio for fruit shape in summer squash

Epistasis 1. In epistasis, one gene masks the expression of another, but no new phenotype is produced. a. A gene that masks another is epistatic. b. A gene that gets masked is hypostatic. 2. Several possibilities for interaction exist, all producing modifications in the 9:3:3:1 dihybrid ratio: a. Epistasis may be caused by recessive alleles, so that a/a masks the effect of B (recessive epistasis). b. Epistasis may be caused by a dominant allele, so that A masks the effect of B. c. Epistasis may occur in both directions between genes, requiring both A and B to produce a particular phenotype (duplicate recessive epistasis). 台大農藝系遺傳學

3. Recessive epistasis occurs in coat color determination in rodents, which show a 9:3:4 ratio (Figure 12.9). 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 the yellow bands, and have solid- colored hairs. b. The B allele produces black pigment, while b/b mice produce brown pigment. The A allele is epistatic over B and b, in that it will insert bands of yellow color between either black or brown. c. 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, regardless of its genotype at the A and B loci. d. In the cross A/a C/c X A/a C/c, the offspring will be: i. 9⁄16 agouti (A/– C/–). ii. 3⁄16 solid (a/a C/–). iii. 4⁄16 albino (3/16 A/– c/c + 1/16 a/a c/c). 台大農藝系遺傳學

Fig. 12.9 Recessive epistasis: Generation of an F2 9:3:4 ratio for coat color in rodents

4. Duplicate recessive epistasis (complementary gene action) is seen in flower color determination in sweet peas, which shows a 9:7 ratio (Figure 12.10). a. Purple is dominant for flower color, and when a true-breeding purple plant is crossed with a true-breeding white one, the F2 shows a typical 3:1 ratio. b. White strains usually breed true, but occasionally the cross of two different white strains (p/p C/C X P/P c/c) will produce an F1 that is entirely purple (P/p C/c). i. The F2 of this cross will be 9⁄16 purple (P/– C/–), and 7⁄16 white (3⁄16 P/– c/c + 3⁄16 p/p C/– + 1⁄16 p/p c/c). ii. All of the white F2 plants will breed true, as will 1⁄9 of the purple F2 plants (P/P C/C). c. Two genes appear to be involved. The C/c alleles determine whether the flower can have color, and the P/p alleles determine whether purple is produced. 5. Interactions between genes can produce many types of phenotypes. They are detected by deviations from expected phenotypic ratios. Table shows examples. 6. The complex relationships of epistasis play a role in many human genetic disorders, further complicating their analysis. 台大農藝系遺傳學

Fig Duplicate recessive epistasis: Generation of an F2 9:7 ratio for flower color in sweet peas 台大農藝系遺傳學 Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

Essential Genes and Lethal Alleles
1. 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, while recessive lethal alleles cause death only when homozygous. 2. An example is the yellow body color gene in mice (Cuenot, 1905): a. Yellow crossed with nonyellow results in a ratio of 1 yellow : 1 nonyellow. This suggests yellow is heterozygous. b. Yellow mice never breed true, another indication of heterozygosity. When yellow is bred with yellow, the result is about 2 yellow : 1 nonyellow (instead of the predicted 3:1). c. 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. d. Yellow is an allele of the agouti locus, designated AY. Figure 4.9 shows the yellow 3 yellow cross. i. The cross is AY/A1 X AY/A1, and death of the homozygous yellow animals (AY/AY) results in a 2:1 ratio. ii. When two heterozygotes are crossed and produce a 2:1 ratio of progeny, a recessive lethal allele is suspected. e. Molecular cloning of the agouti locus assists in analysis of these phenotypes: i. 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. ii. Heterozygous mice (AY/A+ ) express the AY allele at high levels in all tissues during all developmental stages. Tissue- specific regulation appears to be lost in the AY allele. iii. The AY allele transcript RNA is 50% longer than that of the wild-type allele (A+). This is because: (1) The AY allele results from deletion of an upstream sequence, removing the normal promoter of the agouti gene. (2) 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. iv. Embryonic lethality of AY/ AY mice probably results from lack of Raly gene activity rather than from the defective agouti gene. 台大農藝系遺傳學

Fig. 12.11 Inheritance of a lethal gene in mice

3. Human examples of recessive lethal alleles include:
a. 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 years of life. b. Hemophilia results from an X-linked recessive allele, and is lethal if untreated. 4. A dominant lethal gene causes Huntington disease, characterized by progressing central nervous system degeneration. The phenotype is not expressed until individuals are in their 30s. Dominant lethals are rare, since death before reproduction would eliminate the gene from the pool. 台大農藝系遺傳學

Gene Expression and the Environment
1. 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: a. Replication of genetic material. b. Growth. c. Differentiation of cells into types. d. Arrangement of cell types into defined tissues and organs. 2. Internal and external environments interact with the genes by controlling their expression and interacting with their products. 台大農藝系遺傳學

Penetrance and Expressivity
1. Penetrance describes 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 (Figure 12.12). a. If all those carrying a dominant mutant allele develop the mutant phenotype, the allele is completely (100%) penetrant. b. 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. c. Human examples include: i. Brachydactyly involves abnormalities of the fingers, and shows 50–80% penetrance. ii. Many cancer genes are thought to have low penetrance, making them harder to identify and characterize. 2. Expressivity describes variation in expression of a gene or genotype in individuals. a. Two individuals with the same mutation may develop different phenotypes, due to variable expressivity of that allele. b. Like penetrance, expressivity depends on both genotype and environment, and may be constant or variable. c. A human example is osteogenesis imperfecta, inherited as an autosomal dominant with nearly 100% penetrance. i. Three traits are associated with the allele: (1) Blueness of the sclerae (whites of eyes). (2) Very fragile bones. (3) Deafness. ii. Osteogenesis imperfecta shows variable expressivity, because an individual with the allele may have 1, 2 or all 3 of the above symptoms, in any combination. Bone fragility is also highly variable. 台大農藝系遺傳學

Fig Illustrations of the concepts of penetrance and expressivity in the phenotypic expression of a genotype 台大農藝系遺傳學 Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

3. Some genes have both incomplete penetrance and variable expressivity. An example is neurofibromatosis (Figure 12.13). a. The allele is an autosomal dominant that shows 50–80% penetrance and variable expressivity. b. Individuals with the allele show a wide range of phenotypes: i. The mildest form of the disease is a few pigmented areas on the skin (café-au-lait spots). ii. More severe cases may include: (1) Neurofibroma tumors of various sizes. (2) High blood pressure. (3) Speech impediments. (4) Headaches. (5) Large head. (6) Short stature. (7) Tumors of eye, brain or spinal cord. (8) Curvature of the spine. 4. Incomplete penetrance and variable expressivity complicate medical genetics and genetic counseling. 台大農藝系遺傳學

Effects of the Environment
1. 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: a. Pattern baldness, appearing in males aged 20–30 years. b. Duchenne muscular dystrophy, appearing in children aged 2–5 years. 2. Sex of the individual affects the expression of some autosomal genes. a. Sex-limited traits appear in one sex but not the other. Examples include: i. Milk production in dairy cattle, where both sexes have milk genes, but only females express them. ii. Horn formation in some sheep species, where only males express the genes used to produce horns. iii. Facial hair distribution in humans. 台大農藝系遺傳學

(1) The genotype b/b produces pattern baldness in both men and women.
b. 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. Human examples include: i. Pattern baldness, controlled by an autosomal gene that is dominant in males and recessive in females. (1) The genotype b/b produces pattern baldness in both men and women. (2) The genotype b1/b1 gives a nonbald phenotype in both sexes. (3) The genotype b1/b will lead to the bald phenotype in men, and the nonbald phenotype in women. ii. Cleft lip and palate (2:1 ratio of males to females). iii. Clubfoot (2:1). iv. Gout (8:1). v. Rheumatoid arthritis (1:3). vi. Osteoporosis (1:3). vii. Systematic lupus erythematosus (1:9). 台大農藝系遺傳學

Fig. 12.14a Sex-influenced inheritance of pattern baldness in humans

Fig. 12.14b Sex-influenced inheritance of pattern baldness in humans

3. Temperature may alter the activity of enzymes so that they function normally at one temperature but are nonfunctional at another. An example is fur color in Himalayan rabbits (Figure 12.15). a. These white rabbits develop darker fur on the cooler parts of their bodies (ears, nose and paws). b. Since all body cells have the same genotype, this fur pattern might result from environmental influences. This was tested by raising Himalayan rabbits under different temperature conditions: i. Rabbits reared above 30°C were entirely white. ii. Rabbits raised at 25°C had the typical Himalayan phenotype. iii. Rabbits raised at 25°C with part of the body experimentally cooled to below 25°C, had a dark spot on the experimentally cooled part. 台大農藝系遺傳學

4. Chemicals can have significant effects. Two examples:
a. Phenylketonuria (PKU) is an autosomal recessive defect in metabolism of the amino acid phenylalanine. If not treated by restricting phenylalanine in the diet, severe mental retardation and other symptoms result. b. A phenocopy is a modification of the phenotype caused by environmental conditions, mimicking a known gene mutation. Phenocopies are not hereditary, and the individual does not carry the allele(s) being mimicked. Examples of phenocopies include: i. Rubella, which produces cataracts, deafness and heart defects in a fetus whose mother is infected during the first 12 weeks of pregnancy, mimics rare recessive alleles. ii. The drug thalidomide, taken on days 35–50 of gestation, mimics the effects of the genetic disorder phocomelia, suppressing development of long bones in the limbs. 台大農藝系遺傳學

Nature versus Nurture 1. Phenotypes seen for many traits are influenced by both genes and environment. Some human examples: a. Human height has both genetic and environmental components. i. Genetically, children tend to have about the same stature as their parents, and several genetic forms of dwarfism are known (achondroplasia is an example). ii. Environmentally, diet and health care are probably responsible for the increase in human height of about 1 inch per generation over the last century. b. Alcoholism is an example of a behavioral trait influenced by both genes and environment. i. A genetic influence is shown in studies of adopted children. Those with alcoholic biological fathers are significantly more likely to become alcoholics than those with non-alcoholic biological fathers. ii. Environment plays a key role also, since alcoholism can only develop if alcohol is available. iii. Genes make individuals more or less susceptible to alcohol abuse, perhaps by affecting metabolism of alcohol or development of personality traits involved in drinking, but the genes alone do not produce the phenotype. c. Human intelligence is an example of a very complex relationship between genes and environment. i. Genetic disorders are known to produce mental retardation. Examples are PKU and Down syndrome. Genes also influence IQ among non-retarded people, with adopted children scoring closer to their biological parents than to their adoptive parents. ii. Environmental influences are seen in studies of identical twins, who frequently differ in IQ scores. iii. Interactions between many genes and all aspects of the environment are involved in forming human intelligence. Genes can’t be changed, but the environment can be altered to affect this very complex phenotype. 台大農藝系遺傳學

CHAPTER 12 Extensions Of Mendelian Genetic Analysis

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