Resumen
Genes encoding nuclear receptors (NRs) are attractive as candidates for investigating the evolution of gene regulation because they (1) have a direct effect on gene expression and (2) modulate many cellular processes that underlie development. We employed a three-phase investigation linking NR molecular evolution among primates with direct experimental assessment of NR function. Phase 1 was an analysis of NR domain evolution and the results were used to guide the design of phase 2, a codon-model-based survey for alterations of natural selection within the hominids. By using a series of reliability and robustness analyses we selected a single gene, NR2C1, asthebest candidate for experimental assessment. We carried out assays to determine whether changes between the ancestral and extant NR2C1s could have impacted stem cell pluripotency (phase 3). We evaluated human, chimpanzee, and ancestral NR2C1 for transcriptional modulation of Oct4 and Nanog (key regulators of pluripotency and cell lineage commitment), promoter activity for Pepck (a proxy for differentiation in numerous cell types), and average size of embryological stem cell colonies (a proxy for the self-renewal capacity of pluripotent cells). Results supported the signal for alteration of natural selection identified in phase 2. We suggest that adaptive evolution of gene regulation has impacted several aspects of pluripotentiality within primates. Our study illustrates that the combination of targeted evolutionary surveys and experimental analysis is an effective strategy for investigating the evolution of gene regulation with respect to developmental phenotypes.
Idioma original | English |
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Páginas (desde-hasta) | 905-922 |
Número de páginas | 18 |
Publicación | Genetics |
Volumen | 203 |
N.º | 2 |
DOI | |
Estado | Published - jun. 2016 |
Nota bibliográfica
Funding Information:The work described here was supported by a National Science Foundation (NSF) doctoral dissertation research improvement grant (BSC-1455625), a Wenner-Gren Foundation dissertation fieldwork grant (8735), an NSF Integrative Graduate Education and Research traineeship grant (DGE-0801634), an NSF-Human Origins Moving in New Directions (HOMINID) grant (BCS-0827546), a grant from the James S. McDonnell Foundation (220020293), George Washington (GW) Office of the Vice President for Research and the GW School of Medicine for the GW Institute of Neuroscience Biomarker Core Facility, National Institutes of Health grant (DC-001534), Natural Sciences and Engineering Research Council of Canada (DG298394), Centre for Comparative Genomics and Evolutionary Bioinformatics (funded by the Tula Foundation), and Canadian Institutes of Health Research (CMF-108026).
Publisher Copyright:
© 2016 by the Genetics Society of America.
ASJC Scopus Subject Areas
- Genetics
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't
- Research Support, N.I.H., Extramural
- Research Support, U.S. Gov't, Non-P.H.S.