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Function and Constraint in Enhancer Sequences with Multiple Evolutionary Origins

Thousands of human gene regulatory enhancers are composed of sequences with multiple evolutionary origins. These evolutionarily “complex” enhancers consist of older “core” sequences and younger “derived” sequences. However, the functional relationship between the sequences of different evolutionary...

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Autores principales: Fong, Sarah L, Capra, John A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9673499/
https://www.ncbi.nlm.nih.gov/pubmed/36314566
http://dx.doi.org/10.1093/gbe/evac159
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author Fong, Sarah L
Capra, John A
author_facet Fong, Sarah L
Capra, John A
author_sort Fong, Sarah L
collection PubMed
description Thousands of human gene regulatory enhancers are composed of sequences with multiple evolutionary origins. These evolutionarily “complex” enhancers consist of older “core” sequences and younger “derived” sequences. However, the functional relationship between the sequences of different evolutionary origins within complex enhancers is poorly understood. We evaluated the function, selective pressures, and sequence variation across core and derived components of human complex enhancers. We find that both components are older than expected from the genomic background, and complex enhancers are enriched for core and derived sequences of similar evolutionary ages. Both components show strong evidence of biochemical activity in massively parallel report assays. However, core and derived sequences have distinct transcription factor (TF)-binding preferences that are largely similar across evolutionary origins. As expected, given these signatures of function, both core and derived sequences have substantial evidence of purifying selection. Nonetheless, derived sequences exhibit weaker purifying selection than adjacent cores. Derived sequences also tolerate more common genetic variation and are enriched compared with cores for expression quantitative trait loci associated with gene expression variability in human populations. In conclusion, both core and derived sequences have strong evidence of gene regulatory function, but derived sequences have distinct constraint profiles, TF-binding preferences, and tolerance to variation compared with cores. We propose that the step-wise integration of younger derived with older core sequences has generated regulatory substrates with robust activity and the potential for functional variation. Our analyses demonstrate that synthesizing study of enhancer evolution and function can aid interpretation of regulatory sequence activity and functional variation across human populations.
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spelling pubmed-96734992022-11-21 Function and Constraint in Enhancer Sequences with Multiple Evolutionary Origins Fong, Sarah L Capra, John A Genome Biol Evol Research Article Thousands of human gene regulatory enhancers are composed of sequences with multiple evolutionary origins. These evolutionarily “complex” enhancers consist of older “core” sequences and younger “derived” sequences. However, the functional relationship between the sequences of different evolutionary origins within complex enhancers is poorly understood. We evaluated the function, selective pressures, and sequence variation across core and derived components of human complex enhancers. We find that both components are older than expected from the genomic background, and complex enhancers are enriched for core and derived sequences of similar evolutionary ages. Both components show strong evidence of biochemical activity in massively parallel report assays. However, core and derived sequences have distinct transcription factor (TF)-binding preferences that are largely similar across evolutionary origins. As expected, given these signatures of function, both core and derived sequences have substantial evidence of purifying selection. Nonetheless, derived sequences exhibit weaker purifying selection than adjacent cores. Derived sequences also tolerate more common genetic variation and are enriched compared with cores for expression quantitative trait loci associated with gene expression variability in human populations. In conclusion, both core and derived sequences have strong evidence of gene regulatory function, but derived sequences have distinct constraint profiles, TF-binding preferences, and tolerance to variation compared with cores. We propose that the step-wise integration of younger derived with older core sequences has generated regulatory substrates with robust activity and the potential for functional variation. Our analyses demonstrate that synthesizing study of enhancer evolution and function can aid interpretation of regulatory sequence activity and functional variation across human populations. Oxford University Press 2022-10-31 /pmc/articles/PMC9673499/ /pubmed/36314566 http://dx.doi.org/10.1093/gbe/evac159 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Research Article
Fong, Sarah L
Capra, John A
Function and Constraint in Enhancer Sequences with Multiple Evolutionary Origins
title Function and Constraint in Enhancer Sequences with Multiple Evolutionary Origins
title_full Function and Constraint in Enhancer Sequences with Multiple Evolutionary Origins
title_fullStr Function and Constraint in Enhancer Sequences with Multiple Evolutionary Origins
title_full_unstemmed Function and Constraint in Enhancer Sequences with Multiple Evolutionary Origins
title_short Function and Constraint in Enhancer Sequences with Multiple Evolutionary Origins
title_sort function and constraint in enhancer sequences with multiple evolutionary origins
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9673499/
https://www.ncbi.nlm.nih.gov/pubmed/36314566
http://dx.doi.org/10.1093/gbe/evac159
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