Genetic variation in gene regulation

Published on April 21, 2015   34 min

Other Talks in the Series: Human Population Genetics II

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My name's Jonathan Pritchard. I'm at Stanford University. Today I'm going to be talking about genetic variation in gene regulation.
We now know that a lot of the genetic basis of complex traits is noncoding, and presumably this is because of variants that are affecting gene regulation, as opposed to variants that are affecting protein coding sequences. So just as one example, the figure here shows the results of a genome-wide association study for Crohn's disease. The dots on the figure show the strength of signal for association between individual SNPs and risk of Crohn's disease. Down below, you can see the locations of coding regions in yellow. What you can see is that there's a very significant region of association for Crohn's disease; however, this lies outside any known genes. And in a case like this, presumably what's going on is that there is a SNP in this region that's affecting a regulatory element that drives regulation of one of those genes marked in yellow in such a way that it affects risk for disease. And so it's become clear during the last few years that this is a major mechanism by which genetic variation affects complex traits, and so there's been a great deal of interest in trying to understand how regulatory variants work and how we detect them and understand them.
So what we know now is that only a minority of genome-wide association hits are due to non-synonymous variants. This is a figure here from a paper by Joe Pickrell in 2014 where he estimates the fraction of associated SNPs that are non-synonymous, i.e., that they're changing protein coding sequences. And you can see that all of the traits in this study, approximately between 3% and 20% of the association hits that were discovered, are due to non-synonymous variants, and this suggests that the large majority of genome-wide association hits are due to regulatory variation.