Decision letter: Genetic interactions affecting human gene expression identified by variance association mapping

Abstract

Every person has two copies of each gene: one is inherited from their mother and the other from their father. These two copies are often not identical because there can be many different variants of the same gene in the human population. Traits (such as height, body mass and risk of disease) vary from one person to the next—and for many traits this variation depends in part on the different gene variants that each person has inherited. Studies seeking to find the differences in DNA that can predict this variation have often assumed that the changes in DNA act on traits independently of the effect of environment and of other genetic variants. In contrast, studies with animals have shown that some genetic variants can interact to produce a bigger (or smaller) effect than would be expected from simply ‘adding together’ their individual effects—a phenomenon called epistasis. But how much does epistasis contribute to variation in human traits, if at all? This question has been much disputed, and is difficult to test, not least because of the sheer number of interactions to assess: tens of millions of changes in DNA have been observed in the human genome, and so there are many more than billions of possible combinations of these changes to investigate. Here, Brown et al. have examined the sequences of all the genes that were expressed in cells taken from a cohort of twins and searched for genetic variants that show these epistatic interactions. By studying gene expression, which can be greatly affected by small changes in the DNA code, Brown et al. were able to identify 508 variants that had a bigger than expected effect on the level of gene expression. This may be a sign that these variants act in combinations: if within one genome a variant increased expression and in another it decreased expression, then this would cause greater variation in gene expression. Further investigation of these 508 variants led to the discovery of 256 examples of epistasis, and 57 of these were replicated in samples from another cohort. Brown et al. calculated that these epistatic interactions explained up to 16% of the variation in gene expression. Furthermore, as well as being involved in epistatic interactions, about 70% of the genetic variants that had an effect on the variation in gene expression were also involved in interactions between genes and the environment. In addition to showing that epistasis contributes to variation in human traits, the work of Brown et al. could help to uncover interactions behind complex traits—beyond the expression level of a gene—that could not previously be investigated.