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LSM 1102 [Molecular Genetics] Continual Assessment, Semester 2 2005-6 Open book and open discussion exam, dated:

23 March 2006

(1) Physical Basis of Inheritance: The horse (Equus caballus) has a diploid complement of 64 chromosomes including 36 acrocentric autosomes while the ass (Equus asinus) has 62 chromosomes including 22 acrocentric autosomes. (a) What is an acrocentric autosome? (2 marks) Acrocentric autosomes are chromosomes that have arms that are of distinctly unequal size. (2 marks) (note only: the short arm is called p arm and the long arm is called q arm) (note only: autosomes with median centromeres i.e., centromeres at the middle or have equal arms are called metacetric chromosomes) (note only: acrocentric chromosomes are also sometimes called submetacentric chromosomes) (b) Predict the number of chromosomes to be found in the hybrid offspring (mule) produced by mating a male ass (jack) to a female horse (mare). (do not just give me the number of chromosomes in the hybrid, the mule, but explain why in at most two or three sentences only) (4 marks) The sperm (gamete) of the jack (ass) carries the haploid number of chromosomes for its species (62/2=31 chromosomes). (1 mark) The egg (gamete) of the mare (horse) carries the haploid number of the chromosome for its species (64/2=32 chromosomes). (1 mark) The hybrid (mule) formed by the union of these gametes would have a diploid number of 31+32=63 chromosomes. (2 marks) (c) Why are mules usually sterile (incapable of producing viable gametes)? (explain in at most two or three sentences only) (2 marks) The haploid set of chromosomes of the horse, which includes 18 acrocentric autosomes, is so dissimilar to that of the ass, which includes only 11 acrocentric autosomes, that meiosis in the mule germ line cannot proceed beyond the first prophase where synapsis of homologues occurs. (2 marks)

(Total = 8 marks)

(2) Biochemical Basis of Inheritance:

A COOH B

*
D

NH2 C

Given the hypothetical enzyme above with regions A, B, C, and D (* = disulfide bond; shaded area = active site), explain the effect of each of the following mutations in terms of the biological activity of the mutant enzyme: (a) nonsense in DNA coding for region A; Effect: The mutant enzyme should still function normally despite the fact that the protein may be slightly shorter than normal (due to the nonsense mutation at A). (2 marks) Explanation: Since region A does not seem to interact with other portions of the polypeptide chain (barring unpredictable interaction of the side chain with other parts of the molecule), the enzyme should still function properly as the enzymes active site does not seem affected. (2 marks) (note only: if a nonsense mutation occurred in region D however, a very short chain of polypeptide would have been produced that would have be devoid of the catalytic site. Proteins are synthesized beginning at the NH2 end) (b) silent in region D; Effect: The mutant enzyme should function normally and similarly as the original (wild-type). (2 marks)

Explanation: Silent mutation does not change the amino acid that is coded and thus does not change the polypeptide product that is produced. (2 marks) (c) deletion of one complete codon in region C; Effect: The mutant enzyme may still function normally despite the fact that the protein may be one amino acid shorter. (2 marks) Explanation: The polypeptide would be one amino acid shorter than the original (wild-type) but because region C does not seem to be critical to the tertiary structure of the molecule (unlike the regions where disulfide bonds are formed or where internal structure integrity is maintained), there should be no or little adverse effect on the enzymes function. (2 marks) (d) missense in region B; Effect: The mutant enzyme may still function normally despite the fact that the protein may be represented by a different amino acid at region B. (2 marks) Explanation: The polypeptide would be represented by a different amino acid at region B compared to the original (wild-type) but because region B does not seem to be critical to the tertiary structure of the molecule (unlike the regions where disulfide bonds are formed or where internal structure integrity is maintained), there should be no or little adverse effect on the enzymes function. (2 marks) (e) nucleotide addition in region C. Effect: The mutant enzyme would be catalytically inactive (no function). (2 marks) Explanation: The addition of a nucleotide in region C would result in a frameshift in the reading of the sequence. This would result in probably many missense codons (or even nonsense codon) from that point on through to the carboxyl terminal (or even resulting in a shorter amino acid in the case of nonsense codon), which includes the active site. Such drastic changes would result in the loss of function. (2 marks) (please give the effect and explain the reason for that answer in at most two to three sentences each only) (4 marks each, two marks for the effect and two marks for the explanation) (Total = 20 marks)

(3) Biochemical Basis of Inheritance: A number of nutritional mutant strains were isolated from wild-type Neurospora that responded to the addition of certain supplements in the culture medium by growth (+) or no growth (0). Given in the table below are the responses for single-gene mutants. (a) Draw a metabolic pathway that could exist in the wild-type strain consistent with the data in the table. (10 marks) Glutamic Acid Glutamic Semialdehyde Ornithine Citrulline Arginine

(10 marks for putting the pathway with all components in the correct order.) (b) Indicate which part of the pathway is blocked in each of the mutant strains. (8 marks) Glutamic Acid 2 Glutamic Semialdehyde 3 Ornithine 1 Citrulline 4 Arginine

(8 marks in total; 2 marks for each correct blocked path identified for each strain.)

Strain 1 2 3 4 (Total = 18 marks)

Mutant supplements added to minimal culture medium Citrulline Glutamic Arginine Ornithine Semialdehyde + 0 + 0 + + + + + 0 + + 0 0 + 0

Glutamic Acid 0 0 0 0

(4) Patterns of Inheritance: Red colour in wheat kernels is produced by the genotype R-B-, white by the double recessive (rrbb). The genotype Rbb and rrB- produce brown kernels. A homozygous red variety is crossed to a white variety. (a) What phenotypic results are expected in the F1 and F2 generations? (give the genotypes, phenotypes and proportions of each phenotype at each of these generations) (8 marks) P: RRBB red x rrbb white

F1: F2: RB Rb rB rb RB RRBB red RRBb red RrBB red RrBb red

RrBb (1 mark) red (or all red, 1 mark) Rb RRBb red RRbb brown RrBb red Rrbb brown rB RrBB red RrBb red rrBB brown rrBb brown rb RrBb red Rrbb brown rrBb brown rrbb white

(note: drawing the punnett square alone without summarizing the data as shown below will result in no marks) (note: deriving the answers below, however, without showing the punnett square will result only in half of the marks given for each phenotype, i.e., 1 mark instead of 2 marks each) 9/16 R-B- = 9/16 red (2 marks) 3/16 R-bb + 3/16 rrB- = 6/16 brown (2 marks) 1/16 rrbb = 1/16 white (2 marks) (b) If the brown F2 is artificially crossed amongst brown F2 progenies at random (note that wheat is normally selffertilized), what phenotypic and genotypic proportions are expected in the offsprings? (Dont just give me the final answers but show me how you worked out and derived at the final answers. If I do not understand your working, even if you have the correct final answer, there will be no marks) (26 marks) Based on the punett square above, the brown F2 progenies are made up of the following genotypes: RRbb Rrbb rrBB rrBb Rrbb rrBb i.e., among the brown F2 progenies: 1/6 RRbb, 2/6 Rrbb, 2/6 rrBb, and 1/6 rrBB (8 marks in total, one mark each for the correct frequency and one mark each for the correct genotype)

Using a punett square again, the relative frequencies of the different crosses can be calculated: 1/6 RRbb 2/6 Rrbb 2/6 rrBb 1/6 rrBB 1/6 RRbb 1/36 2/36 2/36 1/36 RRbb x RRbb RRbb x Rrbb RRbb x rrBb RRbb x rrBB (1) (2) (3) (4) 2/6 Rrbb 2/36 Rrbb x RRbb (5) 2/36 rrBb x RRbb (9) 1/36 rrBB x RRbb (13) 4/36 Rrbb x Rrbb (6) 4/36 rrBb x Rrbb (10) 2/36 rrBB x Rrbb (14) 4/36 Rrbb x rrBb (7) 4/36 rrBb x rrBb (11) 2/36 rrBB x rrBb (15) 2/36 Rrbb x rrBB (8) 2/36 rrBb x rrBB (12) 1/36 rrBB x rrBB (16)

2/6 rrBb

1/6 rrBB

Cross (1) RRbb x RRbb (2) RRbb x Rrbb (3) RRbb x rrBb (4) RRbb x rrBB (5) Rrbb x RRbb (6) Rrbb x Rrbb

Progeny RRbb RRbb Rrbb RrBb Rrbb RrBb RRbb Rrbb RRbb Rrbb rrbb RrBb rrBb Rrbb rrbb RrBb rrBb RrBb Rrbb RrBb rrBb Rrbb rrbb rrBB rrBb rrbb rrBB rrBb RrBb RrBb rrBb rrBB rrBb rrBB

(7) Rrbb x rrBb

(8) Rrbb x rrBB (9) rrBb x RRbb (10) rrBb x Rrbb

(11) rrBb x rrBb

(12) rrBb x rrBB (13) rrBB x RRbb (14) rrBB x Rrbb (15) rrBB x rrBb (16) rrBB x rrBB

Progeny proportion within cross (a) 100% 1/2 1/2 1/2 1/2 100% 1/2 1/2 1/4 1/2 1/4 1/4 1/4 1/4 1/4 1/2 1/2 1/2 1/2 1/4 1/4 1/4 1/4 1/4 1/2 1/4 1/2 1/2 100% 1/2 1/2 1/2 1/2 100%

Cross frequency (b) 1/36 2/36 2/36 1/36 2/36 4/36

4/36

2/36 2/36 4/36

4/36

2/36 1/36 2/36 2/36 1/36

Progeny proportion (a x b) 1/36 x 1 = 1/36 2/36 x 1/2 = 2/72 2/36 x 1/2 = 2/72 2/36 x 1/2 = 2/72 2/36 x 1/2 = 2/72 1/36 x 1 = 1/36 2/36 x 1/2 = 2/72 2/36 x 1/2 = 2/72 4/36 x 1/4 = 4/144 4/36 x 1/2 = 4/72 4/36 x 1/4 = 4/144 4/36 x 1/4 = 4/144 4/36 x 1/4 = 4/144 4/36 x 1/4 = 4/144 4/36 x 1/4 = 4/144 2/36 x 1/2 = 2/72 2/36 x 1/2 = 2/72 2/36 x 1/2 = 2/72 2/36 x 1/2 = 2/72 4/36 x 1/4 = 4/144 4/36 x 1/4 = 4/144 4/36 x 1/4 = 4/144 4/36 x 1/4 = 4/144 4/36 x 1/4 = 4/144 4/36 x 1/2 = 4/72 4/36 x 1/4 = 4/144 2/36 x 1/2 = 2/72 2/36 x 1/2 = 2/72 1/36 x 1 = 1/36 2/36 x 1/2 = 2/72 2/36 x 1/2 = 2/72 2/36 x 1/2 = 2/72 2/36 x 1/2 = 2/72 1/36 x 1 = 1/36

Summary of the proportion of all progeny genotypes: RRbb = 1/36 + 2/72 + 2/72 + 4/144 = 4/144 + 4/144 + 4/144 + 4/144 = 16/144 = 1/9 Rrbb = 2/72 + 2/72 + 2/72 + 4/72 + 4/144 + 2/72 + 4/144 = 32/144 = 2/9 RrBb = 2/72 + 1/36 + 4/144 + 2/72 + 2/72 + 4/144 + 1/36 + 2/72 = 2/9 rrBB = 4/144 + 2/72 + 2/72 + 1/36 = 1/9 rrBb = 4/144 + 2/72 + 4/144 + 4/72 + 2/72 + 2/72 +2/72 = 2/9 rrbb = 4/144 + 4/144 + 4/144 + 4/144 = 1/9 (12 marks in total, two marks each for correct proportion of each genotype) (note: drawing the punnett square alone without summarizing the data as shown above will result in no marks) (note: deriving the answers above, however, without showing the punnett square [or the possible cross combinations] will result only in half of the marks given for each genotype and phenotype, i.e., 1 mark instead of 2 marks each) Summary of the proportion of all progeny phenotypes: RRbb = 1/9 (brown) Rrbb = 2/9 (brown) RrBb = 2/9 (red) rrBB = 1/9 (brown) rrBb = 2/9 (brown) rrbb = 1/9 (white) Thus, the proportion of red, brown and white progenies are 2/9, (1/9+2/9+1/9+2/9=6/9=2/3) and 1/9 respectively. (6 marks in total, two marks each for correct proportion of each phenotype)

(c) Propose a molecular or biochemical mechanism for this form of gene interaction illustrated in this example. (bonus question, 10 marks) i. This effect is seen in duplicate genes with cumulative effect (4 marks). ii. This happens when the dominant condition (either homozygous or heterozygous) at either locus (but not both at the same time) produces the same phenotype (2 marks). iii. However, when both loci show dominant conditions (either homozygous or heterozygous), the effect is cumulative (2 marks). iv. This form of epistatic genes produce a F2 ratio of 9:6:1 (2 marks) (instead of 9:3:3:1 when no gene interaction occurs, i.e., collapse of the intermediate phenotypes into one group since the two genes produce the same phenotype individually). (Explanation note: In this example, the epistatic genes produce are involved in producing various amounts of a substance such as pigment, the dominant genotypes of each locus may be considered to produce one unit of pigment independently. Thus genotype A-bb and aaB- produce one unit of pigment each and therefore have the same phenotype (brown). The genotype aabb produces no pigment and would thus be white, while in the genotype A-B-, the effect is cumulative and two units of the pigment are produced (thus more intense colour = red). (Total = 34 marks + 10 bonus question marks)

(5) Patterns of Inheritance: A recessive sex-linked gene h prolongs the blood-clotting time, resulting in what is commonly called bleeders disease (hemophilia). Based on the pedigree below, answer the following:

I 1 2

II 1 2 3 4

(a) If II2 marries a normal man, what is the chance of her first child being a hemophilic boy? (4 marks) Hemophilia is a X-linked recessive condition (carried on the X-chromosome). II2 has a brother who is hemophilic (II4), as such her mother (I1) would likely be a carrier. II2 does not present with the disease, as such, she could either be a homozygous normal or a heterozygous carrier, i.e., 50% probability of being a carrier. If she marries a normal man (who must thus carry a normal X-chromosome), the probability of her first child being a hemophilic boy is: 1/2 x 1/2 x 1/2 = 1/8 (workings and answer: 2 marks) (50% chance that the child is a boy, multiply by 50% chance that II2 is a carrier, multiply by 50% chance that II2 passes down the affected X-chromosome) (explanation: 2 marks) (b) Suppose the first child of II2 (from the marriage above) is actually hemophilic. What is the probability that her second child will be a hemophilic boy? (4 marks) If the first child of II2 is actually hemophilic, then it is confirmed that II2 is a carrier. The probability of the second child being a hemophilic boy is: 1/2 x 1/2 = 1/4 (workings and answer: 2 marks) (50% chance that the child is a boy, multiply by 50% chance that II2 passes down the affected X-chromosome) (explanation: 2 marks) (c) If II3 marries a hemophilic man, what is the probability that her first child would be normal? (4 marks) As with section (a), II3 has a brother who is hemophilic (II4), as such her mother (I1) would likely be a carrier. Similarly, II3 does not present with the disease, as such, she could either be a homozygous normal or a heterozygous carrier, i.e., 50% probability of being a carrier. If she is a carrier and marries a hemophilic man, her first child will have 50% chance of being hemophilic (irregardless of whether the first child is a boy or a girl) Thus, if she marries a hemophilic man (who must thus carry an affected X-chromosome), the probability of her first child being hemophilic is: 1/2 x 1/2 = 1/4. Thus, the probability of her first child being normal would be 1 1/4 = 3/4 (workings and answer: 2 marks) (50% chance her first child will be hemophilic, multiply 50% chance she is a carrier). (explanation: 2 marks)

(Note: must show working and explanation. Giving the answers alone without working will result in only half the marks awarded. Giving the workings without an understandable explanation will also result in only half the marks awarded) (Total = 12 marks)

(6) Patterns of Inheritance: Hustad et al., 1995, (Genetics 104: 255-265) studied six different recessive alleles at the agouti (A) locus in mice. All of these alleles when homozygous caused a darker coat color than the wild-type allele. (a) How is it possible to study six different alleles when a diploid cell can have only two alleles at a single locus? (4 marks) Any one diploid individual can carry only two alleles for a particular locus. However the number of alleles that are possible in a single locus in a population of many individuals may be many (but each carrying only a max of two of these alleles). Researchers can thus study many different alleles by studying different individuals that carries these alleles. (4 marks) (b) None of these alleles studied were lethal. With your understanding of the molecular basis of lethal alleles, propose an explanation as to why all these alleles in this example do not cause lethality when homozygous. (4 marks) A lethal allele causes lethality when homozygous because the mutation that created the allele deleted a gene close to the locus that is essential for survival (important physiologically). Homozygous individuals would thus lack that gene and cannot survive. Most mutations above are not lethal and thus suggest that the mutations that generated these alleles are not large enough to affect the adjacent gene (critical for survival) and are instead restricted to the particular gene locus only. The product of this particular locus is not critical for survival and so, mutant alleles should not cause lethality when homozygous. (4 marks)

(Total = 8 marks)

(Grand total = 100 marks + 10 bonus question marks)