Exam 8: Identifying Disease Genes and Genetic Susceptibility to Complex Disease

With respect to genomewide association (GWA) studies, which, if any, of the following statements, is false?

What is the basis of HLA associations with autoimmune disorders?

Fill in the blanks Before we had a human genetic map, disease gene identification was difficult. Sometimes, however, knowledge of the gene product provided a path to a gene underlying a Mendelian disorder. For example, haemophilia A was long known to be a deficiency of a specific blood clotting protein, ___1____ ___2___, and using that information it was possible to purify large amounts of ___1____ ___2___ from pig blood and then to design ____3______ oligonucleotides that corresponded to all possible codon interpretations of an optimal part of the amino acid sequence of the pig ___1____ ___2___ protein. The resulting oligonucleotides were then used as ____4_____ probes to screen first a human ____5____ library and then a ____6____ ___ 7____ library to identify the underlying human gene.

Before genomewide association (GWA) studies became successful, association studies used to rely on candidate gene approaches. How successful were the candidate gene approaches?

With respect to genomewide association (GWA) studies, which, if any, of the following statements, is true?

Fill in the blanks While linkage is a ____1_____ phenomenon, association is a _____2_____ property. Linkage is concerned with seeking to identify the map relationship between two or more ___3___, such as disease and marker ___3____, by analysing samples from individuals within ____4____. Association, on the other hand, is a relationship between ____5____and is studied by analysing samples from individuals within ____6____. Linkage works over ____7____ distances whereas, in practice, association works over very ____8_____ distances. If allele A*1 is shown to be positively associated with a complex disease it would be described as a disease ____9____ factor, and if allele A*2 is negatively associated with the disease it would be described as a ____10____ factor

The table below shows the percentage phenotype concordance in monozygotic (MZ) and dizygotic (DZ) twins in four hypothetical genetic diseases A to D. Which disease would you estimate to have the highest heritability and which one has the lowest heritability, and why?

What is a haplotype block, and how are they organized in the human genome?

HLA associations with autoimmune disorders are among the very strongest of associations between genetic variants and disease, but have rarely been mapped to the amino acid level. An exception is the HLA association with rheumatoid arthritis. What is known about this association, and how did detailed knowledge of how HLA proteins function help to identify the amino acids implicated in the association?

Naturally occurring genetic variants are known to act as protective factors to confer reduced risk of infectious disease. List some examples.

To carry out exome sequencing the desired exome is first captured from a sample of genomic DNA. How is that achieved?

In the years when association studies were limited to candidate gene approaches what were the technological drawbacks that prevented genomewide association (GWA) studies and what developments made GWA studies possible?

Regarding two-point linkage analysis, which, if any, of the following statements is true?

List three possible explanations for the general failure of GWA studies to identify genetic factors that collectively might explain the heritability of complex diseases.

List three justifications for the common disease-rare variant hypothesis

Outside of cancers and infectious diseases, various other complex diseases are known to be strongly influenced by environmental factors. Give three examples of environmental factors that are known to increase the risk of specific complex diseases other than cancers and infectious diseases.

Certain common alleles known to be associated with specific complex diseases may have been maintained in the human population because of beneficial advantage in the past. List some examples that might suggest this to be the case.

Fill in the blanks with single words or single letters. Each of us carries our personal ____1____ that shares our body space (but is principally distributed within our ____2____) and that contains ____3____ times more cells than our body. These cells are foreign ____4_____ that are nevertheless tolerated by the body, largely by suppressing ______5______ ____6______ responses, notably those that depend on _____7____ receptors. Our personal _____1_____ is normally beneficial to us because some of the _____4_____ are beneficial to us in different ways. They can help us derived additional energy through the fermentation of undigested _____8______, help us break down _______9_____ , and they synthesize vitamins _____10_____ and _____11_____ for us. In ____12____ ____13____ diseases, however, an abnormal ____6____ response is directed against antigens carried by foreign ____4_____ within our ___2____ and that leads to accumulation of ____14____ blood cells within the linings of the _____15_____ , producing chronic _____16_______.

Fill in the blanks In an autoimmune disorder, cells in the body come under attack from certain antibodies known as ____1_____ , and also from certain types of ____2_____ T cell that may attack specific host cells (such as insulin-producing ____3______ ____4_____ cells in the case of type I diabetes). In ____2_____ T cell responses the host cell peptides serve as ____5_____ and they are presented to T cells after they have been bound by ____6_____ proteins. ____6_____ proteins differ in their ability to bind individual peptide ____5____ and that is the primary basis for ____6____-disease associations.

How successful have genomewide association studies been in identifying genetic susceptibility to complex disease? What has been the main value of these studies?