title: Population genetic analysis of the uncoupling proteins supports a role for UCP3 in human cold resistance.
abstract: Production of heat via nonshivering thermogenesis (NST) is critical for temperature homeostasis in mammals. Uncoupling protein UCP1 plays a central role in NST by uncoupling the proton gradients produced in the inner membranes of mitochondria to produce heat; however, the extent to which UCP1 homologues, UCP2 and UCP3, are involved in NST is the subject of an ongoing debate. We used an evolutionary approach to test the hypotheses that variants that are associated with increased expression of these genes (UCP1 -3826A, UCP2 -866A, and UCP3 -55T) show evidence of adaptation with winter climate. To that end, we calculated correlations between allele frequencies and winter climate variables for these single-nucleotide polymorphisms (SNPs), which we genotyped in a panel of 52 worldwide populations. We found significant correlations with winter climate for UCP1 -3826G/A and UCP3 -55C/T. Further, by analyzing previously published genotype data for these SNPs, we found that the peak of the correlation for the UCP1 region occurred at the disease-associated -3826A/G variant and that the UCP3 region has a striking signal overall, with several individual SNPs showing interesting patterns, including the -55C/T variant. Resequencing of the regions in a set of three diverse population samples helped to clarify the signals that we found with the genotype data. At UCP1, the resequencing data revealed modest evidence that the haplotype carrying the -3826A variant was driven to high frequency by selection. In the UCP3 region, combining results from the climate analysis and resequencing survey suggest a more complex model in which variants on multiple haplotypes may independently be correlated with temperature. This is further supported by an excess of intermediate frequency variants in the UCP3 region in the Han Chinese population. Taken together, our results suggest that adaptation to climate influenced the global distribution of allele frequencies in UCP1 and UCP3 and provide an independent source of evidence for a role in cold resistance for UCP3.
authors.affiliation: Department of Human Genetics, University of Chicago, USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Hancock
authors.forename: Vanessa J
authors.initials: VJ
authors.lastname: Clark
authors.forename: Yudong
authors.initials: Y
authors.lastname: Qian
authors.forename: Anna
authors.initials: A
authors.lastname: Di Rienzo
mesh_terms: D000064:Acclimatization / Q000235:genetics*; D001833:Body Temperature Regulation / Q000235:genetics*; D003081:Cold Climate; D005006:Ethnicity / Q000235:genetics; D005787:Gene Frequency; D005828:Genetics, Population; D005838:Genotype; D006706:Homeostasis; D006801:Humans; D007473:Ion Channels / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604371:UCP1 protein, human; C000604389:UCP2 protein, human; C000604392:UCP3 protein, human; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
references.citation: J Clin Invest. 2009 Jan;119(1):70-9
references.pmid: 19075393
references.citation: J Comp Physiol B. 2008 Mar;178(3):269-77
references.pmid: 17987299
references.citation: Br Med J. 1954 Feb 6;1(4857):290-4
references.pmid: 13115700
references.citation: Mol Biol Evol. 2006 May;23(5):1076-84
references.pmid: 16520336
references.citation: Diabetes. 2009 Jul;58(7):1526-31
references.pmid: 19401428
references.citation: Int J Obes Relat Metab Disord. 1999 Dec;23(12):1242-5
references.pmid: 10643679
references.citation: Obes Res. 1997 Jan;5(1):1-8
references.pmid: 9061709
references.citation: Mol Biol Evol. 1992 Jan;9(1):138-51
references.pmid: 1552836
references.citation: Theor Popul Biol. 1975 Apr;7(2):256-76
references.pmid: 1145509
references.citation: PLoS Genet. 2008 Feb;4(2):e32
references.pmid: 18282109
references.citation: Nat Med. 2000 Oct;6(10):1115-20
references.pmid: 11017142
references.citation: J Clin Endocrinol Metab. 2009 Jul;94(7):2537-43
references.pmid: 19351729
references.citation: Nat Rev Mol Cell Biol. 2005 Mar;6(3):248-61
references.pmid: 15738989
references.citation: Genetics. 1994 Apr;136(4):1329-40
references.pmid: 8013910
references.citation: Diabetes. 1999 Sep;48(9):1890-5
references.pmid: 10480626
references.citation: Am J Hum Biol. 2007 Mar-Apr;19(2):165-80
references.pmid: 17286259
references.citation: Exp Biol Med (Maywood). 2001 Feb;226(2):78-84
references.pmid: 11446442
references.citation: FEBS Lett. 1999 Feb 12;444(2-3):250-4
references.pmid: 10050769
references.citation: Maturitas. 2003 May 30;45(1):39-45
references.pmid: 12753942
references.citation: J Biol Chem. 1997 Sep 26;272(39):24129-32
references.pmid: 9305858
references.citation: Aging Cell. 2005 Jun;4(3):147-55
references.pmid: 15924571
references.citation: Metabolism. 2008 Mar;57(3):410-5
references.pmid: 18249216
references.citation: J Biol Chem. 2001 Jun 8;276(23):20240-4
references.pmid: 11274222
references.citation: Genetics. 2001 Dec;159(4):1805-17
references.pmid: 11779816
references.citation: J Lipid Res. 1998 Apr;39(4):834-44
references.pmid: 9555947
references.citation: J Pediatr. 1996 Nov;129(5):637-42
references.pmid: 8917226
references.citation: Pharm Res. 1998 Jun;15(6):944-9
references.pmid: 9647363
references.citation: Science. 2008 Feb 22;319(5866):1100-4
references.pmid: 18292342
references.citation: Diabetes. 2002 Nov;51(11):3331-5
references.pmid: 12401727
references.citation: Nat Genet. 2006 Dec;38(12):1457-62
references.pmid: 17115056
references.citation: J Biol Chem. 2001 May 25;276(21):18633-9
references.pmid: 11278935
references.citation: J Clin Invest. 1998 Oct 1;102(7):1345-51
references.pmid: 9769326
references.citation: J Appl Physiol (1985). 2002 Mar;92(3):1111-8
references.pmid: 11842047
references.citation: Am J Hum Genet. 2001 Apr;68(4):978-89
references.pmid: 11254454
references.citation: Proc Natl Acad Sci U S A. 2010 May 11;107 Suppl 2:8924-30
references.pmid: 20445095
references.citation: FEBS Lett. 1997 May 12;408(1):39-42
references.pmid: 9180264
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6062-7
references.pmid: 15075390
references.citation: Nat Genet. 2007 Apr;39(4):513-6
references.pmid: 17322881
references.citation: Science. 2002 Apr 12;296(5566):261-2
references.pmid: 11954565
references.citation: Biochem Biophys Res Commun. 1997 Nov 7;240(1):222-7
references.pmid: 9367914
references.citation: FEBS Lett. 2002 Mar 27;515(1-3):109-13
references.pmid: 11943204
references.citation: FEBS Lett. 1999 Jul 9;454(3):201-6
references.pmid: 10431807
references.citation: Genetics. 2010 Aug;185(4):1411-23
references.pmid: 20516501
references.citation: Physiol Rev. 2004 Jan;84(1):277-359
references.pmid: 14715917
references.citation: FEBS Lett. 1999 Dec 31;464(3):189-93
references.pmid: 10618503
references.citation: Am J Hum Genet. 2006 Aug;79(2):230-7
references.pmid: 16826514
references.citation: Nat Rev Genet. 2009 Nov;10(11):745-55
references.pmid: 19823195
references.citation: Nat Genet. 2007 Jan;39(1):31-40
references.pmid: 17159977
references.citation: J Clin Invest. 2003 Feb;111(4):479-86
references.pmid: 12588886
references.citation: Am J Physiol Endocrinol Metab. 2001 Nov;281(5):E975-82
references.pmid: 11595653
references.citation: Genetics. 2005 Apr;169(4):2335-52
references.pmid: 15716498
references.citation: Genetics. 2001 Feb;157(2):875-84
references.pmid: 11157004
references.citation: Am J Clin Nutr. 1997 Sep;66(3):531-8
references.pmid: 9280169
references.citation: Am J Hum Genet. 1964 Dec;16:435-50
references.pmid: 14250424
references.citation: Prog Lipid Res. 2006 Jan;45(1):17-41
references.pmid: 16384603
references.citation: Nat Genet. 1997 Mar;15(3):269-72
references.pmid: 9054939
references.citation: Science. 2004 Aug 6;305(5685):869-72
references.pmid: 15297675
references.citation: Obes Rev. 2009 Mar;10(2):218-26
references.pmid: 19021870
references.citation: Genome Res. 2005 Nov;15(11):1576-83
references.pmid: 16251467
references.citation: J Clin Invest. 2007 Jul;117(7):1995-2003
references.pmid: 17571165
references.citation: Curr Biol. 2010 Feb 23;20(4):R208-15
references.pmid: 20178769
references.citation: Am J Clin Nutr. 2002 Apr;75(4):714-9
references.pmid: 11916758
references.citation: Obes Res. 1995 Sep;3 Suppl 2:261s-265s
references.pmid: 8581785
references.citation: Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):118-22
references.pmid: 11756659
references.citation: Obes Res. 1997 Jul;5(4):321-5
references.pmid: 9285838
references.citation: J Clin Endocrinol Metab. 2003 Dec;88(12):5661-7
references.pmid: 14671150
references.citation: Clin Genet. 2008 Feb;73(2):179-84
references.pmid: 18199144
references.citation: Bioinformatics. 2002 Feb;18(2):337-8
references.pmid: 11847089
references.citation: Obes Rev. 2009 Sep;10(5):519-26
references.pmid: 19413708
references.citation: J Clin Endocrinol Metab. 1999 Mar;84(3):906-11
references.pmid: 10084569
references.citation: Nat Genet. 2001 Jun;28(2):178-83
references.pmid: 11381268
references.citation: PLoS Genet. 2006 Dec 15;2(12):e186
references.pmid: 17173482
references.citation: Nature. 1997 May 1;387(6628):90-4
references.pmid: 9139827
references.citation: Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15942-7
references.pmid: 16243969
references.citation: Am J Dig Dis. 1970 Aug;15(8):695-710
references.pmid: 5468838
references.citation: Biochem Soc Trans. 2001 Nov;29(Pt 6):768-73
references.pmid: 11709072
references.citation: Diabetes. 1999 Jan;48(1):146-9
references.pmid: 9892236
references.citation: Nature. 2008 Feb 21;451(7181):998-1003
references.pmid: 18288195
references.citation: Am J Clin Nutr. 1999 Jul;70(1):13-20
references.pmid: 10393133
references.citation: N Engl J Med. 2009 Apr 9;360(15):1509-17
references.pmid: 19357406
references.citation: Evolution. 2005 Nov;59(11):2312-23
references.pmid: 16396172
references.citation: Genetics. 2002 Jul;161(3):1209-18
references.pmid: 12136023
references.citation: J Pediatr. 1996 Nov;129(5):643-7
references.pmid: 8917227
references.citation: Genetics. 1989 Nov;123(3):585-95
references.pmid: 2513255
references.citation: Int J Obes Relat Metab Disord. 2001 Apr;25(4):472-7
references.pmid: 11319649
references.citation: PLoS Genet. 2010 Apr 01;6(4):e1000888
references.pmid: 20369019
references.citation: Biochem J. 2002 Jan 1;361(Pt 1):49-56
references.pmid: 11743882
references.citation: Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18508-13
references.pmid: 16352722
references.citation: Nat Rev Genet. 2007 Nov;8(11):857-68
references.pmid: 17943193
references.citation: Ann Hum Genet. 2006 Nov;70(Pt 6):841-7
references.pmid: 17044859
references.citation: Physiol Genomics. 2005 Jul 14;22(2):197-203
references.pmid: 15870396
references.citation: Int J Obes Relat Metab Disord. 1996 Dec;20(12):1062-6
references.pmid: 8968850
references.citation: FEBS Lett. 1999 Dec 3;462(3):257-60
references.pmid: 10622707
references.citation: N Engl J Med. 2009 Apr 9;360(15):1518-25
references.pmid: 19357407