Selection and diversity in human regulatory elements

Vernot, B et al. (2012) "Personal and population genomics of human regulatory variation." Genome Research.

Today I tacke one of the ENCODE papers. The ENCODE project was a large project looking at various aspects of many human genomes, with particular interest in identifying biochemically active parts of the genome.

This particular paper looked at diversity and selection in regions that regulate the expression of genes. They identified these regions in several different cell lines, using DNase I activity. DNase I is an enzyme that is known to cleave parts of the genome that are actively binding transcription factors and other regulatory elements (those proteins that "turn on" genes). They identified the location of these sites that were cleaved by DNase I then looked at variation in a sample of 53 unrelated individuals at and near these sites.

They compared diversity in the peaks of DNase I activity, the "footprint" in the peak (the location where a transcription factor actually bound to DNA), and to the exome (all the DNA that makes proteins). They found many more variant sites in peaks, than in the other categories, and fewest in the exome. They also looked at GERP scores around each variant, this is a measure of how constrained the site is, or how much negative selection is keeping the site from changing. A higher GERP score means that more constraint is acting on the site. Though there were fewer variant sites in the exome, a higher proportion of those sites had a high GREP score, and the peaks had the lowest proportion. They also looked at variation within each individual sample, they found consistently the same patterns described above. They also show, as expected, that the African samples have higher diversity (more variants at DNase I sensitive sites) than non-Africans.

They looked at diversity around specific known regulatory motifs (sequences of DNA where a specific kind of regulation is known to occur). They found that regulatory elements that are used in cell differentiation usually have very low diversity. They also show that regulatory elements with a CpG site (a C followed by a G in the DNA sequence, or vice versa) had higher diversity, probably because these sites have a higher mutation rate.

Finally, they looked at how positive selection had acted in regions around each of their DNase I peaks. They did this by measuring shifts in allele frequencies near the sites of interest. Interestingly, their data shows evidence of an inversion on chromosome 17 that is found in some Europeans (more info on the MAPT inversion region can be found here). They looked at gene pathways that were enriched for sites under positive selection in African, Asian, and European populations. They found many pathways that were under positive selection in all populations, and interesting showed that the pathway involved in skin pigmentation was under positive selection in Europeans, and that pathways involved in susceptibility to diabetes were enriched for selection in Africans.