NEW YORK (GenomeWeb News) – Epistatic interactions between coding variants and regulatory variants that diminish or enhance their effects have influenced the genetic patterns present in the human genome, according to a study in the most recent issue of the American Journal of Human Genetics.
"[T]he frequency spectrum and impact size distribution of common regulatory polymorphisms [expression quantitative trait loci] appear to be shaped in order to minimize the selective disadvantage of having deleterious coding mutations on the more highly expressed haplotype," senior author Emmanouil Dermitzakis, a medical genetics researcher at the University of Geneva, and co-authors wrote.
The University of Geneva team analyzed gene expression and genetic variation across the genomes of about 120 individuals of European or African ancestry who had been assessed through the 1000 Genomes Project. They found that potentially damaging changes to coding sequences tend to turn up less frequently in conjunction with expression quantitative trait loci that prompt higher expression of the associated gene.
"Analysis of local genomic interactions improves our understanding of how genetic variants give rise to the spectrum of human traits and disease," Dermitzakis said in a statement. "In the future, this will enable us to better predict individual disease risk."
For instance, when they looked at variants previously implicated in common disease risk through genome-wide association studies, the team came across situations in which disease-associated regulatory variants bumped up the expression of genes they regulate — a situation that would be expected to increase the ill effects of any deleterious variations in the genes.
For the study, Dermitzakis and his colleagues focused on potential epistatic interactions involving coding variants and so-called cis-regulatory variants influencing the activity of the same gene. They reasoned that this sort of cis regulation could impact both the prevalence and penetrance of deleterious coding variants.
"[W]hether or not a rare deleterious [coding single nucleotide variation] allele resides on the more highly or less expressed haplotype in a gene with cis-regulatory variation is not fully random: the probability that a new coding mutation lands on a particular haplotype is equal to the haplotype frequency," they explained. "Altogether, these phenomena can shape the patterns of both regulatory and coding variation."
To look for such patterns in the human genome, the researchers brought together array- and RNA sequencing-based gene expression data and low-coverage genome sequence data for 60 individuals of European descent and 58 individuals of African descent who were sequenced through the 1000 Genomes Project pilots 1 and 2.
After they tracked down 433 eQTLs in the European samples and 446 eQTLs in the African samples, the team determined which of the regulatory alleles were associated with higher and lower gene expression before incorporating information on coding variants found in genes regulated by the eQTLs.
As predicted, they found that possibly deleterious coding changes, which should be subject to purifying selection, were less common in genes regulated by versions of eQTLs that ramp up their expression. The extent of the expression differences associated with alternative eQTL alleles also tended to correspond to the types of changes found in the coding sequences.
"[E]pistatic effects appear to shape not only the frequency spectrum of regulatory variants," the study authors noted, "but also the distribution and the magnitude of their effect."
Moreover, when they compared 98 eQTLs implicated in common disease through prior GWAS with more than 900 control eQTLs, the researchers found that the same versions of regulatory variants that were associated with disease also tended to increase gene expression.
"This trend is opposite to that observed for eQTLs overall — suggesting that the variants not following the general pattern putatively optimized by evolution are more likely to contribute to disease," the study authors explained.
For genes containing unfavorable coding variants, such a bump in gene expression could theoretically boost the penetrance of the coding changes, they noted. The team did not see obvious differences in the sorts of coding variants found in the genes regulated by disease-linked eQTLs, but they said additional research may help to further tease apart such relationships.
"Future studies with case-control material will, we hope, clarify whether increased disease risk sometimes arises neither from changed gene expression levels alone nor from an enrichment of rare [coding single nucleotide variants] per se but from their interaction," researchers explained.