PART A: Human Genome Organization and Function

The objective of this assignment is for you to demonstrate proficiency in navigating and interacting with genome browsers.

Assignment:

I am a poor biologist requiring help and advice from expert bioinformaticians (that's you).

I am studying regulation in Hox gene clusters, with a focal interest in the HoxA cluster. I have been trying to generate humanized mice, but every time I clone in a construct of the region I am met with failure.

Activity A1.

My construct extends from the extremity of the HoxA1 gene (including UTRs) to the extremity of the HoxA13 gene (including UTRs). Could you please confirm the length of the segment I should be considering, and generate a custom track showing the region in blue.

Length of region =

Activity A2.

It seems to be that repeats (as defined by the RepeatMasker track) are less common in the cluster than other parts of the genome. Please help me calculate the repeat content for the HoxA cluster and for the entire chromosome.

Length of cluster =
Repeat content in cluster =
Percentage of cluster occupied by repeats = Length of chromosome =
Repeat content in chromosome =
Percentage of chromosome occupied by repeats =

Activity A3.

Please tell me why you think a decrease in repeat content is biologically important in a Hox cluster?

Activity A4.

Based on decreased repeat content, please tell me whether the HoxA cluster should be extended beyond the extremities of the outermost genes. Prepare a second track (green) showing what you think the entire region should be. I will use it in my next cloning experiment.
New length of region =

Activity 5.

Do you think what we are seeing in HoxA is also observed in other Hox clusters?
Please make tracks (gene extremities in blue, extended region in green) for the other clusters.

PART B: Chromosomes

Instructions:

Deletion and uniparental disomy are two mechanisms that can lead to two very different syndromes that map to the same cytogenetic region of chromosome 15. Prader Willi syndrome occurs in some cases with microscopically visible paternal deletions of the part of the long arm of chromosome 15 or maternal uniparental disomy of 15 (as well as other causes). Angelman syndrome occurs in some cases with maternal deletions of the part of the long arm of chromosome 15 or paternal uniparental disomy of 15 (as well as other causes).

Why do these syndromes have approximately similar proportions of cases which occur by the mechanism of deletion but very dissimilar proportions of cases that occur by uniparental disomy?

Why would one be concerned about a family history of X-linked recessives in the context of an incidental finding of a 45,X karyotype or a de novo apparently balanced X autosome reciprocal translocation in a male and in a female?

PART C: Mendelian and Complex Traits - Dr. Jamie Engert

1 page (single-spaced) = 0.5 page/question. References may be on a separate page.

Prior to undertaking any genetic disease gene identification/cloning projects, researchers usually like to have an assessment of the genetic contribution to the disease. Describe the methods that can be used to achieve such assessments and how the quantitative results can be interpreted.

Dilated cardiomyopathy (DCM) can be an autosomal dominant disease with variable penetrance. Define variable penetrance and explain what are the causes of variable penetrance in general. How would you design a large-scale human study to identify the specific causes of the variable penetrance seen in DCM families?

PART D: Statistics and Applications in Genetics

Instructions:

Questions:

D1. How does the presence of linkage disequilibrium (LD) and haplotype blocks in human populations make whole genome association studies feasible? But conversely, why does LD make it difficult to pinpoint the causative variants?

D2.

What is the meaning of "imputation", as used in the AMD study of the Icelandic population? Give one good reason for using imputation in genetics.

D3.

Exome and Genome sequencing are quickly gaining widespread use in human genetics.

a) How much more sequencing will you have to perform to sequence a genome, as compared to the exome.

b) Suppose you have a SINGLE patient with a very rare DOMINANT disorder. You sequence the patient's exome. Explain why it may be difficult to identify the causative mutation.

c) You decide to collect several additional affected individuals. Briefly describe the pros and cons of collecting patients from the same family as the proband, versus collecting unrelated individuals.

d) Now suppose you have a SINGLE patient with a very rare RECESSIVE disorder. You sequence the patient's exome. Explain why it may be possible and sometimes relatively easy to identify the causative mutation in a single patient.