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The cis-regulatory effects of modern human-specific variants

The Neanderthal and Denisovan genomes enabled the discovery of sequences that differ between modern and archaic humans, the majority of which are noncoding. However, our understanding of the regulatory consequences of these differences remains limited, in part due to the decay of regulatory marks in...

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Autores principales: Weiss, Carly V, Harshman, Lana, Inoue, Fumitaka, Fraser, Hunter B, Petrov, Dmitri A, Ahituv, Nadav, Gokhman, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062137/
https://www.ncbi.nlm.nih.gov/pubmed/33885362
http://dx.doi.org/10.7554/eLife.63713
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author Weiss, Carly V
Harshman, Lana
Inoue, Fumitaka
Fraser, Hunter B
Petrov, Dmitri A
Ahituv, Nadav
Gokhman, David
author_facet Weiss, Carly V
Harshman, Lana
Inoue, Fumitaka
Fraser, Hunter B
Petrov, Dmitri A
Ahituv, Nadav
Gokhman, David
author_sort Weiss, Carly V
collection PubMed
description The Neanderthal and Denisovan genomes enabled the discovery of sequences that differ between modern and archaic humans, the majority of which are noncoding. However, our understanding of the regulatory consequences of these differences remains limited, in part due to the decay of regulatory marks in ancient samples. Here, we used a massively parallel reporter assay in embryonic stem cells, neural progenitor cells, and bone osteoblasts to investigate the regulatory effects of the 14,042 single-nucleotide modern human-specific variants. Overall, 1791 (13%) of sequences containing these variants showed active regulatory activity, and 407 (23%) of these drove differential expression between human groups. Differentially active sequences were associated with divergent transcription factor binding motifs, and with genes enriched for vocal tract and brain anatomy and function. This work provides insight into the regulatory function of variants that emerged along the modern human lineage and the recent evolution of human gene expression.
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spelling pubmed-80621372021-04-29 The cis-regulatory effects of modern human-specific variants Weiss, Carly V Harshman, Lana Inoue, Fumitaka Fraser, Hunter B Petrov, Dmitri A Ahituv, Nadav Gokhman, David eLife Evolutionary Biology The Neanderthal and Denisovan genomes enabled the discovery of sequences that differ between modern and archaic humans, the majority of which are noncoding. However, our understanding of the regulatory consequences of these differences remains limited, in part due to the decay of regulatory marks in ancient samples. Here, we used a massively parallel reporter assay in embryonic stem cells, neural progenitor cells, and bone osteoblasts to investigate the regulatory effects of the 14,042 single-nucleotide modern human-specific variants. Overall, 1791 (13%) of sequences containing these variants showed active regulatory activity, and 407 (23%) of these drove differential expression between human groups. Differentially active sequences were associated with divergent transcription factor binding motifs, and with genes enriched for vocal tract and brain anatomy and function. This work provides insight into the regulatory function of variants that emerged along the modern human lineage and the recent evolution of human gene expression. eLife Sciences Publications, Ltd 2021-04-22 /pmc/articles/PMC8062137/ /pubmed/33885362 http://dx.doi.org/10.7554/eLife.63713 Text en © 2021, Weiss et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Evolutionary Biology
Weiss, Carly V
Harshman, Lana
Inoue, Fumitaka
Fraser, Hunter B
Petrov, Dmitri A
Ahituv, Nadav
Gokhman, David
The cis-regulatory effects of modern human-specific variants
title The cis-regulatory effects of modern human-specific variants
title_full The cis-regulatory effects of modern human-specific variants
title_fullStr The cis-regulatory effects of modern human-specific variants
title_full_unstemmed The cis-regulatory effects of modern human-specific variants
title_short The cis-regulatory effects of modern human-specific variants
title_sort cis-regulatory effects of modern human-specific variants
topic Evolutionary Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062137/
https://www.ncbi.nlm.nih.gov/pubmed/33885362
http://dx.doi.org/10.7554/eLife.63713
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