Number of Pages: 4 (Double Spaced) Category: Medicine and Health VIP Support: N/A
Language Style: English (U.K.)
3 parts questions of medical Genetics as bolow:
4. Assume that the locus responsible for the ‘glucose metaboloism’ character in this pedigree can be occupied by two alternate alleles. Assign symbols to these alleles. Give the genotypes of the proband and her husband. If the pedigree was different, and II.2 expressed the trait and was heterozygous, what would be the phenotype of III.1, and why ?
9. Deamination is a spontaneous mechanism that could have given rise to the mutation described in 8 above. Explain this briefly, and the substitution that would occur in the next round of DNA synthesis. What DNA repair mechanism would need to have failed for this to occur ? A tautomeric mutation mechanism is also possible, as discussed in lecture 3; suggest how this mechanism would produce the G-> A substitution in the next round of DNA synthesis, and why DNA repair would not be engaged in this case.
10. If the mutation had been a gene deletion instead of a point mutation, could this have arisen during meiosis in the mother? Explain your answer.
Question 2 . Linkage and positional cloning (32 marks).
Pedigree 1 below shows a real family in which several members suffer from degrees of hearing impairment from mild loss in one ear to complete deafness.
1) From the pedigree alone, what is the apparent inheritance pattern for this form of hearing impairment?
2) What is the genotype of the gametes produced by II.1 and II.2 ?
3) What frequency of heterozygotes and homozygotes would you expect to see among the children of II.2 ?
4) If II.3 had been unaffected by the trait, how could the genotypes of his children be explained, assuming no other changes in the pedigree?
4) Does the trait appear to be typically mendelian ? Explain your answer (you may argue for and against the proposition if you wish).
This section is about genetic linkage in the same family, shown in pedigree 2.
In lecture 7, you saw an example of linkage to a trait for two polymorphic markers. The geneticists are tracking the inheritance of six polymorphic markers on chromosome 3 within this family. As shown in pedigree 2, the names of these markers are: D3S-1558, -1303, -1292, -3554, -1569, and -1744. Up to five alleles of each marker occur in this pedigree. Members of the family carry different alleles of these markers. The set of alleles for any single family member is their haplotype. For example, the haplotype for II.2 is [2 1 2 1 2 2] on one chromosome, and  on the other. We can write this as [212122:241213]. As shown in pedigree 2 below, her mother and father had these haplotypes: Mother [212122 : 224???], Father [241213: 23????]. Some markers were not evaluated, as denoted by [?]
i) From which parent did II.2 inherit alleles  ?
ii) From which parent did II.2 inherit the deafness trait?
iii) What do you deduce from i) and ii) above about the linkage of these alleles to the trait?
iv) Considering II.3, and his children, which markers seem to segregate most closely with the trait?
v) Refine your answer to iv), taking into account the phenotype of III.5 and III.9 [Hint: from which parent did III.5 inherit allele 4 of D3S-1744 ?]
vi) Looking at the haplotype of II.2, in how many of her children has recombination occurred between the trait locus and the alleles of D3S -3554 and -1569 ? (Ignore III.2)
vii) Assuming complete linkage of the three loci in vi) above, ie =0, what is the probability of observing the children of II.2 with the observed genotypes ? (Ignore III.2)
viii) Assuming independence of the three loci in vi) above, what is the probability of observing the children of II.2 with the observed genotype? (Ignore III.2). You should first consider how many gametes can result if there are three independent loci; note that for two independent loci, there are 4 possible outcomes.
ix) Using your answers to vii and viii, what is the LOD score for linkage of the trait with these polymorphic markers ? Comment on the strength of the score.
x) The authors of this study calculated the LOD for two-point linkage (ie between the trait and one marker only), and compiled this table. Based on these data, what is the ‘map distance’ in Mb between the best-linked marker and the trait locus?
xi) Given the average gene length and the average inter-gene distance, how many genes would you expect to reside in this interval ?
xii) Twenty-three known coding genes reside in this interval according to the Human Genome Database. Because procollagen and sulfation of lipids are important for inner ear tissue development, the authors sequenced PCOLCE2 and CHST2 genes in the hearing-impaired family members, but found no mutations. They did not sequence the closely linked genes SLC9A9, a Na+ transporter which has been implicated in autism; PAQR9, which is involved in cilia formation; or U2-SURP which appears to be a transcript splicing factor in blood and other tissues. Which one of these might have been a good candidate (any biologically plausible reason will be accepted)? Note, positional cloning of this trait locus (which has been named OTSC5, or otosclerosis 5) has still not been accomplished.
xiii) Suggest a recently developed, more rapid alternative to linkage analysis for identifying candidate genes from a small number of subjects in a single family.
xiv) Explain why the haplotype of family member III.2 is problematic, and what is meant by the term ‘phenocopy.’
xv) The allele 2 of marker D3S-1569 occurs in the general population at a frequency of 16%. In families with this form of deafness, it has a frequency of 67%, and is often linked with the trait locus. What is the name of this phenomenon ? Does this mean that the marker allele might contribute to the trait?
Question 3. Chromosome abnormalities. (15 marks).
1. Suggest two (or more) features of meiosis that favour the formation of de novo translocations.4. 70% of Robertsonian translocations involve chromosomes 13 and 14 and may be defined as t(13;14). This is illustrated in the following diagram, showing a primary spermatocyte that has completed meiosis I (the other cell that resulted from this cell division is not shown) . Three alternate meioses generate six gametes (note, any single meiosis will produce only one of the gamete pairs shown). Two products of meiosis II are already indicated. After fertilisation, the karyotype of the first two embryos would be written as 46 XY and 45 XY t(13;14) respectively, assuming that the sperm supplies a Y chromosome. /46 XY means simply that the embryo has the complete set of chromosomes, with both sex chromosomes present/ Work out and write down the karyotype of all the six embryos. Explain which ones are genotypically normal, balanced carriers, or monosomic/trisomic. State whether the embryos are likely to reach full term of the pregnancy. Which one of the embryos is likely to suffer from a recognised syndrome ?
5. ‘For any single meiosis II, both gametes of each pair shown in the diagram will be present in sperm.’ Why is this statement NOT true for oocytes ?
6. One of the children will likely be affected by persistence of foetal haemoglobin (a switch to infant haemoglobin normally occurs in the first few months after birth). A 2011 article in the journal PNAS, vol. 108 (4) , presented evidence for involvement of two genes in this condition. Find the abstract of this article via the library search tool and summarise the authors’ findings in a few sentences (do not quote directly).
7. Suggest two cytological detection methods that would show the presence of the chromosome translocation t(13;14) in prenatal diagnosis. Name a suitable source of the genetic material.
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