Relaxed constraint and functional divergence of the progesterone receptor (PGR) in the human stem-lineage
The steroid hormone progesterone, acting through the progesterone receptor (PR), a ligand-activated DNA-binding transcription factor, plays an essential role in regulating nearly every aspect of female reproductive biology. While many reproductive traits regulated by PR are conserved in mammals, Cat...
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| Veröffentlicht in: | PLoS genetics 2020-04, Vol.16 (4), p.e1008666-e1008666 |
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| description | The steroid hormone progesterone, acting through the progesterone receptor (PR), a ligand-activated DNA-binding transcription factor, plays an essential role in regulating nearly every aspect of female reproductive biology. While many reproductive traits regulated by PR are conserved in mammals, Catarrhine primates evolved several derived traits including spontaneous decidualization, menstruation, and a divergent (and unknown) parturition signal, suggesting that PR may also have evolved divergent functions in Catarrhines. There is conflicting evidence, however, whether the progesterone receptor gene (PGR) was positively selected in the human lineage. Here we show that PGR evolved rapidly in the human stem-lineage (as well as other Catarrhine primates), which likely reflects an episode of relaxed selection intensity rather than positive selection. Coincident with the episode of relaxed selection intensity, ancestral sequence resurrection and functional tests indicate that the major human PR isoforms (PR-A and PR-B) evolved divergent functions in the human stem-lineage. These results suggest that the regulation of progesterone signaling by PR-A and PR-B may also have diverged in the human lineage and that non-human animal models of progesterone signaling may not faithfully recapitulate human biology. |
| doi_str_mv | 10.1371/journal.pgen.1008666 |
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While many reproductive traits regulated by PR are conserved in mammals, Catarrhine primates evolved several derived traits including spontaneous decidualization, menstruation, and a divergent (and unknown) parturition signal, suggesting that PR may also have evolved divergent functions in Catarrhines. There is conflicting evidence, however, whether the progesterone receptor gene (PGR) was positively selected in the human lineage. Here we show that PGR evolved rapidly in the human stem-lineage (as well as other Catarrhine primates), which likely reflects an episode of relaxed selection intensity rather than positive selection. Coincident with the episode of relaxed selection intensity, ancestral sequence resurrection and functional tests indicate that the major human PR isoforms (PR-A and PR-B) evolved divergent functions in the human stem-lineage. These results suggest that the regulation of progesterone signaling by PR-A and PR-B may also have diverged in the human lineage and that non-human animal models of progesterone signaling may not faithfully recapitulate human biology.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1008666</identifier><identifier>PMID: 32302297</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amino acids ; Animal models ; Animals ; Biology and Life Sciences ; Datasets ; Divergence ; Earth Sciences ; Evolution ; Evolution, Molecular ; Gene expression ; Genomes ; Hominids ; Humans ; Isoforms ; Ligands ; Menstruation ; Models, Genetic ; Parturition ; Phylogeny ; Physical Sciences ; Positive selection ; Pregnancy ; Primates - classification ; Primates - genetics ; Progesterone ; Receptors, Progesterone - genetics ; Research and Analysis Methods ; Selection, Genetic ; Social Sciences</subject><ispartof>PLoS genetics, 2020-04, Vol.16 (4), p.e1008666-e1008666</ispartof><rights>2020 Marinić, Lynch. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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While many reproductive traits regulated by PR are conserved in mammals, Catarrhine primates evolved several derived traits including spontaneous decidualization, menstruation, and a divergent (and unknown) parturition signal, suggesting that PR may also have evolved divergent functions in Catarrhines. There is conflicting evidence, however, whether the progesterone receptor gene (PGR) was positively selected in the human lineage. Here we show that PGR evolved rapidly in the human stem-lineage (as well as other Catarrhine primates), which likely reflects an episode of relaxed selection intensity rather than positive selection. Coincident with the episode of relaxed selection intensity, ancestral sequence resurrection and functional tests indicate that the major human PR isoforms (PR-A and PR-B) evolved divergent functions in the human stem-lineage. These results suggest that the regulation of progesterone signaling by PR-A and PR-B may also have diverged in the human lineage and that non-human animal models of progesterone signaling may not faithfully recapitulate human biology.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>32302297</pmid><doi>10.1371/journal.pgen.1008666</doi><orcidid>https://orcid.org/0000-0002-7037-8389</orcidid><orcidid>https://orcid.org/0000-0001-5311-3824</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Amino acids Animal models Animals Biology and Life Sciences Datasets Divergence Earth Sciences Evolution Evolution, Molecular Gene expression Genomes Hominids Humans Isoforms Ligands Menstruation Models, Genetic Parturition Phylogeny Physical Sciences Positive selection Pregnancy Primates - classification Primates - genetics Progesterone Receptors, Progesterone - genetics Research and Analysis Methods Selection, Genetic Social Sciences |
| title | Relaxed constraint and functional divergence of the progesterone receptor (PGR) in the human stem-lineage |
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