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Human gene regulatory evolution is driven by the divergence of regulatory element function in both cis and trans.

ABSTRACT: Gene regulatory divergence between species can result from cis-acting local changes to regulatory element DNA sequences or global trans-acting changes to the regulatory environment. Understanding how these mechanisms drive regulatory evolution has been limited by challenges in identifying trans-acting changes. We present a comprehensive approach to directly identify cis- and trans-divergent regulatory elements between human and rhesus macaque lymphoblastoid cells using ATAC-STARR-seq. In addition to thousands of cis changes, we discover an unexpected number (~10,000) of trans changes and show that cis and trans elements exhibit distinct patterns of sequence divergence and function. We further identify differentially expressed transcription factors that underlie >50% of trans differences and trace how cis changes can produce cascades of trans changes. Overall, we find that most divergent elements (67%) experienced changes in both cis and trans, revealing a substantial role for trans divergence-alone and together with cis changes-to regulatory differences between species.

SUBMITTER: Hansen T

PROVIDER: S-EPMC9949080 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Human gene regulatory evolution is driven by the divergence of regulatory element function in both cis and trans.

Hansen Tyler T Fong Sarah S Capra John A JA Hodges Emily E

bioRxiv : the preprint server for biology 20230215

Gene regulatory divergence between species can result from cis-acting local changes to regulatory element DNA sequences or global trans-acting changes to the regulatory environment. Understanding how these mechanisms drive regulatory evolution has been limited by challenges in identifying trans-acting changes. We present a comprehensive approach to directly identify cis- and trans-divergent regulatory elements between human and rhesus macaque lymphoblastoid cel ...[more]

PMID: 36824965

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Project description:BackgroundPhenotypic evolution may occur through mutations that affect either the structure or expression of protein-coding genes. Although the evolution of color vision has historically been attributed to structural mutations within the opsin genes, recent research has shown that opsin regulatory mutations can also tune photoreceptor sensitivity and color vision. Visual sensitivity in African cichlid fishes varies as a result of the differential expression of seven opsin genes. We crossed cichlid species that express different opsin gene sets and scanned their genome for expression Quantitative Trait Loci (eQTL) responsible for these differences. Our results shed light on the role that different structural, cis-, and trans-regulatory mutations play in the evolution of color vision.ResultsWe identified 11 eQTL that contribute to the divergent expression of five opsin genes. On three linkage groups, several eQTL formed regulatory "hotspots" associated with the expression of multiple opsins. Importantly, however, the majority of the eQTL we identified (8/11 or 73%) occur on linkage groups located trans to the opsin genes, suggesting that cichlid color vision has evolved primarily via trans-regulatory divergence. By modeling the impact of just two of these trans-regulatory eQTL, we show that opsin regulatory mutations can alter cichlid photoreceptor sensitivity and color vision at least as much as opsin structural mutations can.ConclusionsCombined with previous work, we demonstrate that the evolution of cichlid color vision results from the interplay of structural, cis-, and especially trans-regulatory loci. Although there are numerous examples of structural and cis-regulatory mutations that contribute to phenotypic evolution, our results suggest that trans-regulatory mutations could contribute to phenotypic divergence more commonly than previously expected, especially in systems like color vision, where compensatory changes in the expression of multiple genes are required in order to produce functional phenotypes.

Dataset Information

Human gene regulatory evolution is driven by the divergence of regulatory element function in both cis and trans.

Publications

Human gene regulatory evolution is driven by the divergence of regulatory element function in both <i>cis</i> and <i>trans</i>.

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