Medical Genetics
Instructions:
The assignment is to be written up as a single page (approximately 700 words or fewer) with an extra page for figures and references. The student is provided with a family history of an inherited disorder, together with any available detection data, and is required to draw a pedigree and name the pattern of inheritance ( Describe the clinical presentation, and the pattern of inheritance, of common genetic diseases & Effectively use databases and bioinformatic tools to obtain genetic information and design diagnostic probes). S/he should find out and describe concisely the clinical presentation of a chosen genetic disease which will have the same mode of inheritance, and on the basis of independent study, explain the mechanistic basis of the disorder ( Explain mechanistically how genetic diseases can arise from the dysregulation of the genome); both the cytogenetic or molecular abnormality, and the biochemical insufficiency this causes. S/he should use information from the human genome database to show where, within the gene, a diagnostic probe should be designed, and explain how this probe would be used (Effectively use databases and bioinformatic tools to obtain genetic information and design diagnostic probes). Illustrative figures will be credited.
FBMS522 Medical Genetics assignment, December 2012.
GUIDANCE
1. The assignment is worth up to 40% of your marks for the Medical Genetics module. It consists of three structured questions, and a review of a congenital trait. All four questions are compulsory.
2. The task is designed to make you apply genetic concepts, and to make use of appropriate sources. The set texts might be helpful for questions 1-3 (all are in the Library as reference copies). Other useful resources for question 4 are the website Genetics Home Reference, which provides links to Pubmed and OMIM (Online Mendelian Inheritance in Man). GeneCards publishes expression data. Note, however, that some of the assignment requires the use of deduction, and The Answer will not always be found by looking around the web.
3. Please type up your answers in a new document, using complete sentences with explanations where appropriate. Correct English and clarity of expression are important for this assignment. Normal advice about plagiarism applies.
4. You will need to learn the ‘Progeny’ tool for question 1: this is easy to do, and brief instructions may be found in the Formative Task which is still on the module website.
5. You will need to use the ensembl.org database for question 4: see Lecture 6 outline.
6. Question 2 on linakage relies on material from Lecture 7. See supplementary notes in the Study Material tab.
7. Queries about the task should be directed to the Discussion board on the module site. You are encouraged to discuss approaches to the assignment with each other, but there is no point in either giving or accepting ‘the right answer’. How do you know if it’s right ?
8. The assignment must be submitted via the Turnitin tab before 10 am on 4 February 2013. This is essentially a take-home examination paper, and you should dedicate an appropriate amount of time and effort to it. You have almost 7 weeks; you cannot complete it on Sunday after tea the day before the deadline.
Question 1. Inheritance, and mutation mechanisms (21 marks).
This question is based on real data from a large Dutch family. The proband is a 33 year old woman. The geneticists would like to find the genetic basis of the family trait.
1. Draw the pedigree described in the following paragraph, using the ‘Progeny’ tool. Save your pedigree as a JPEG file and embed it in your Word file. Assume that all family members affected with a metabolic disorder express the trait. For this pedigree, number all members of each generation, even if they have married into the family. As a self-check; if you have drawn the pedigree correctly, the proband will appear as II.6 ; her younger sister’s third son will be III.12. Note that inm male-female couples, the male is conventionally placed on the left.
“A family is attending the genetics clinic. Several members suffer from metabolic disorders; Diabetes mellitis (DM) or impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). IFG and IGT are considered as ‘pre-diabetes’ and in ~ 70% of cases lead to the full form. The proband has DM and is married. She has three sons, who all have IGT. The eldest is married with one daughter, who is healthy. The proband has two older siblings (a brother and a sister) and a younger sister, who are all married; the first two have diabetes, the younger sister has IGT. The proband’s brother has a healthy daughter. Her elder sister has two chidren, of either sex, both with IGT. Her younger sister has four sons all with IFG or IGT. They are all married with one healthy daughter each. The proband’s father is healthy, while the proband’s mother had diabetes and is deceased. “
2. What is the apparent inheritance pattern for this trait? Explain your answer, with reference to the transmission between generations, and the variable symptoms.
3. Name one other trait with the same inheritance pattern, and state the name of the gene locus responsible for this trait.
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 ?
5. What is the risk that the proband’s next child will express the trait if it is a boy, or a girl?
6. What is the risk that the next child of II.1 will express the trait, and why ?
7. The daughter of III.12 does not yet show any symptoms. Is this because she is too young?
8. The geneticists extracted leucocyte DNA from cases and controls, and carried out a PCR reaction to amplify regions of several different candidate genes. All the affected family members carried a G->A substitution in the coding region of ND-1, which converted the codon GGG to AGG. Is this a transition or a transversion? Did the amino acid change as a result? Was this substitution conservative or nonconservative?
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).
[A]
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).
[B]
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 [241213] 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 [?]
PEDIGREE 1
PEDIGREE 2
i) From which parent did II.2 inherit alleles [212122] ?
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.
2. Why does a balanced chromosome translocation usually result in no phenotype in the carrier ?
3. What is a Robertsonian translocation, and how does it differ from any other kind of balanced translocation ?
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.
Diagram for question 3
Question 4. Investigation of a named congenital disorder (32 marks)
Your chosen disorder may be inherited or sporadic, mendelian or atypical. Select one for which you can find sufficient information. See the Guidance on p. 1 for advice on sources.
i) Write a concise report no longer than a single page in Arial point 11, to include an html reference to the relevant page of the ensembl.org database.
Ensembl.org database: This is explained in the Lecture Outline for lecture 6. If you are researching a gene mutation you should include an html address for the nucleotide sequence, showing the intron/exon structure. If you are working on a chromosome anomaly, provide the intron/exon reference for a gene plausibly contributing to the phenotype.
ii) In the course of your research for this question, make a record of your sources and list them in Harvard format at the end of the report (references can be on a separate page). See the Guidance on page 1 for a note on sources. Please avoid citing NHS leaflets, patient advocacy organisations, journalistic accounts. These are not suitable material at this level.
An example for the report is given in the Formative Task on the module site, describing the CAH trait. This is not a perfect model, is only half the allowed length, and does not list all the sources, but it shows the range of the question. The ensembl address, which is not given there, would be
http://www.ensembl.org/Homo_sapiens/Transcript/Exons?db=core;g=ENSG00000233151;r=HSCHR6_MHC_COX:31954522-31957894;t=ENST00000452386
Your report might include the following points: name of trait, inheritance pattern, frequency of the trait in populations, gene or chromosome region involved, nature of mutation(s) or anomaly, a plausible mechanism or origin of mutation, most important tissue expression of the wild-type protein(s) encoded by the trait locus, possible effects of mutation on either transcription or protein function, consequence of altered protein in biochemistry or development or physiology, protein structure information where this is informative, brief account of symptoms and treatments.
ORDER THIS ESSAY HERE NOW AND GET ADISCOUNT !!!