Enhancer Runaway and the Evolution of Diploid Gene Expression

Abstract

Evidence is mounting that the evolution of gene expression plays a major role in adaptation and speciation. Understanding the evolution of gene regulatory regions is indeed an essential step in linking genotypes and phenotypes and in understanding the molecular mechanisms underlying evolutionary change. The common view is that expression traits (protein folding, expression timing, tissue localization and concentration) are under natural selection at the individual level. Here, we use a theoretical approach to show that, in addition, in diploid organisms, enhancer strength (i.e., the ability of enhancers to activate transcription) may increase in a runaway process due to competition for expression between homologous enhancer alleles. These alleles may be viewed as self-promoting genetic elements, as they spread without conferring a benefit at the individual level. They gain a selective advantage by getting associated to better genetic backgrounds: deleterious mutations are more efficiently purged when linked to stronger enhancers. This process, which has been entirely overlooked so far, may help understand the observed overrepresentation of cis-acting regulatory changes in between-species phenotypic differences, and sheds a new light on investigating the contribution of gene expression evolution to adaptation.

Cis-regulator runaway and divergence in asexuals

“…Mutations change additively the log 10 of enhancer strength, which ensures that the mutational effect size remains constant irrespectively of arbitrarily chosen absolute values of enhancer strength (see Fyon et al. for details). Mutation effects are drawn from a Normal distribution of mean zero and standard deviation σ E .…”

“…To summarize Fyon et al. (), this runaway occurs when enhancers compete for expression with different “strength.” Differences in strength of the cis ‐regulatory region can arise because the “fit” of binding sequences toward transcription factor(s) differ or because the number of binding sequence (to transcription factor) differ, or because chromatin state differ etc. Stronger enhancers (i.e.…”

“…Enhancer Runaway may also have contributed to shape many features of expression control and regulatory networks (see discussion in Fyon et al. ). For example, some of the complexity of regulatory architecture might stem from the accumulation of cis ‐regulatory elements driven by this process.…”

“…We know already that moderate rates of self‐fertilization slows Enhancer Runaway (Fyon et al. ). To obtain a more comprehensive view of the dependence of Enhancer Runaway process on the reproductive mode, we investigate in this article how this process varies in a wide variety of such systems, considering in particular the major forms of automixis and apomixis found in parthenogenetic species (see Asher ; Suomalainen et al.…”

Evolutionary mysteries in meiosis

“…Another possibility might be that the cooccurrence of both COs and gene-conversion events (i.e. where resolution of DSBs without CO is achieved by exchanging small segments of DNA) specifically in regulatory regions could repress enhancer runaway, a mechanism that can lead to suboptimal expression levels [190]. The evolutionary significance of the second kind of hotspot is similarly elusive.…”