0:00
My name's Jonathan Pritchard.
I'm at Stanford University.
Today I'm going to be talking about
genetic variation
in gene regulation.
0:08
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.
1:23
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.
