{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T02:16:44Z","timestamp":1778638604504,"version":"3.51.4"},"reference-count":33,"publisher":"Proceedings of the National Academy of Sciences","issue":"34","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,8,25]]},"abstract":"<jats:p>\n                    Adaptive modifications of heteromeric proteins may involve genetically based changes in single subunit polypeptides or parallel changes in multiple genes that encode distinct, interacting subunits. Here we investigate these possibilities by conducting a combined evolutionary and functional analysis of duplicated globin genes in natural populations of deer mice (\n                    <jats:italic>Peromyscus maniculatus<\/jats:italic>\n                    ) that are adapted to different elevational zones. A multilocus analysis of nucleotide polymorphism and linkage disequilibrium revealed that high-altitude adaptation of deer mouse hemoglobin involves parallel functional differentiation at multiple unlinked gene duplicates: two \u03b1-globin paralogs on chromosome 8 and two \u03b2-globin paralogs on chromosome 1. Differences in O\n                    <jats:sub>2<\/jats:sub>\n                    -binding affinity of the alternative \u03b2-chain hemoglobin isoforms were entirely attributable to allelic differences in sensitivity to 2,3-diphosphoglycerate (DPG), an allosteric cofactor that stabilizes the low-affinity, deoxygenated conformation of the hemoglobin tetramer. The two-locus \u03b2-globin haplotype that predominates at high altitude is associated with suppressed DPG-sensitivity (and hence, increased hemoglobin-O\n                    <jats:sub>2<\/jats:sub>\n                    affinity), which enhances pulmonary O\n                    <jats:sub>2<\/jats:sub>\n                    loading under hypoxia. The discovery that allelic differences in DPG-sensitivity contribute to adaptive variation in hemoglobin\u2013O\n                    <jats:sub>2<\/jats:sub>\n                    affinity illustrates the value of integrating evolutionary analyses of sequence variation with mechanistic appraisals of protein function. Investigation into the functional significance of the deer mouse \u03b2-globin polymorphism was motivated by the results of population genetic analyses which revealed evidence for a history of divergent selection between elevational zones. The experimental measures of O\n                    <jats:sub>2<\/jats:sub>\n                    -binding properties corroborated the tests of selection by demonstrating a functional difference between the products of alternative alleles.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0905224106","type":"journal-article","created":{"date-parts":[[2009,8,10]],"date-time":"2009-08-10T21:28:49Z","timestamp":1249939729000},"page":"14450-14455","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":192,"title":["Evolutionary and functional insights into the mechanism underlying high-altitude adaptation of deer mouse hemoglobin"],"prefix":"10.1073","volume":"106","author":[{"given":"Jay F.","family":"Storz","sequence":"first","affiliation":[{"name":"School of Biological Sciences, University of Nebraska, Lincoln, NE 68588;"}]},{"given":"Amy M.","family":"Runck","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of Nebraska, Lincoln, NE 68588;"}]},{"given":"Stephen J.","family":"Sabatino","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of Nebraska, Lincoln, NE 68588;"}]},{"given":"John K.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Ecology and Evolutionary Biology, University of Kansas, Lawrence, KS 66045;"}]},{"given":"Nuno","family":"Ferrand","sequence":"additional","affiliation":[{"name":"Centro de Investiga\u00e7\u00e3o em Biodiversidade e Recursos Gen\u00e9ticos, Campus Agr\u00e1rio de Vair\u00e3o, 4485-661 Vair\u00e3o, Portugal;"},{"name":"Departamento de Zoologia e Anthropologia, Faculdade de Ci\u00eancias, Universidade do Porto, 4099-002 Porto, Portugal; and"}]},{"given":"Hideaki","family":"Moriyama","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of Nebraska, Lincoln, NE 68588;"}]},{"given":"Roy E.","family":"Weber","sequence":"additional","affiliation":[{"name":"Zoophysiology, Department of Biological Sciences, Building 1131, University of Aarhus, DK-8000 Aarhus C, Denmark"}]},{"given":"Angela","family":"Fago","sequence":"additional","affiliation":[{"name":"Zoophysiology, Department of Biological Sciences, Building 1131, University of Aarhus, DK-8000 Aarhus C, Denmark"}]}],"member":"341","published-online":{"date-parts":[[2009,8,25]]},"reference":[{"key":"e_1_3_3_1_2","first-page":"139","article-title":"Mechanisms of cooperativity and allosteric regulation in proteins","volume":"22","author":"Perutz MF","year":"1989","unstructured":"MF Perutz, Mechanisms of cooperativity and allosteric regulation in proteins. 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