Population genetic analysis of the uncoupling proteins supports a role for UCP3 in human cold resistance.
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.
Hancock
Angela M
AM
Department of Human Genetics, University of Chicago, USA.
Clark
Vanessa J
VJ
Qian
Yudong
Y
Di Rienzo
Anna
A
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
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
J Clin Invest. 2009 Jan;119(1):70-9
19075393
J Comp Physiol B. 2008 Mar;178(3):269-77
17987299
Br Med J. 1954 Feb 6;1(4857):290-4
13115700
Mol Biol Evol. 2006 May;23(5):1076-84
16520336
Diabetes. 2009 Jul;58(7):1526-31
19401428
Int J Obes Relat Metab Disord. 1999 Dec;23(12):1242-5
10643679
Obes Res. 1997 Jan;5(1):1-8
9061709
Mol Biol Evol. 1992 Jan;9(1):138-51
1552836
Theor Popul Biol. 1975 Apr;7(2):256-76
1145509
PLoS Genet. 2008 Feb;4(2):e32
18282109
Nat Med. 2000 Oct;6(10):1115-20
11017142
J Clin Endocrinol Metab. 2009 Jul;94(7):2537-43
19351729
Nat Rev Mol Cell Biol. 2005 Mar;6(3):248-61
15738989
Genetics. 1994 Apr;136(4):1329-40
8013910
Diabetes. 1999 Sep;48(9):1890-5
10480626
Am J Hum Biol. 2007 Mar-Apr;19(2):165-80
17286259
Exp Biol Med (Maywood). 2001 Feb;226(2):78-84
11446442
FEBS Lett. 1999 Feb 12;444(2-3):250-4
10050769
Maturitas. 2003 May 30;45(1):39-45
12753942
J Biol Chem. 1997 Sep 26;272(39):24129-32
9305858
Aging Cell. 2005 Jun;4(3):147-55
15924571
Metabolism. 2008 Mar;57(3):410-5
18249216
J Biol Chem. 2001 Jun 8;276(23):20240-4
11274222
Genetics. 2001 Dec;159(4):1805-17
11779816
J Lipid Res. 1998 Apr;39(4):834-44
9555947
J Pediatr. 1996 Nov;129(5):637-42
8917226
Pharm Res. 1998 Jun;15(6):944-9
9647363
Science. 2008 Feb 22;319(5866):1100-4
18292342
Diabetes. 2002 Nov;51(11):3331-5
12401727
Nat Genet. 2006 Dec;38(12):1457-62
17115056
J Biol Chem. 2001 May 25;276(21):18633-9
11278935
J Clin Invest. 1998 Oct 1;102(7):1345-51
9769326
J Appl Physiol (1985). 2002 Mar;92(3):1111-8
11842047
Am J Hum Genet. 2001 Apr;68(4):978-89
11254454
Proc Natl Acad Sci U S A. 2010 May 11;107 Suppl 2:8924-30
20445095
FEBS Lett. 1997 May 12;408(1):39-42
9180264
Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6062-7
15075390
Nat Genet. 2007 Apr;39(4):513-6
17322881
Science. 2002 Apr 12;296(5566):261-2
11954565
Biochem Biophys Res Commun. 1997 Nov 7;240(1):222-7
9367914
FEBS Lett. 2002 Mar 27;515(1-3):109-13
11943204
FEBS Lett. 1999 Jul 9;454(3):201-6
10431807
Genetics. 2010 Aug;185(4):1411-23
20516501
Physiol Rev. 2004 Jan;84(1):277-359
14715917
FEBS Lett. 1999 Dec 31;464(3):189-93
10618503
Am J Hum Genet. 2006 Aug;79(2):230-7
16826514
Nat Rev Genet. 2009 Nov;10(11):745-55
19823195
Nat Genet. 2007 Jan;39(1):31-40
17159977
J Clin Invest. 2003 Feb;111(4):479-86
12588886
Am J Physiol Endocrinol Metab. 2001 Nov;281(5):E975-82
11595653
Genetics. 2005 Apr;169(4):2335-52
15716498
Genetics. 2001 Feb;157(2):875-84
11157004
Am J Clin Nutr. 1997 Sep;66(3):531-8
9280169
Am J Hum Genet. 1964 Dec;16:435-50
14250424
Prog Lipid Res. 2006 Jan;45(1):17-41
16384603
Nat Genet. 1997 Mar;15(3):269-72
9054939
Science. 2004 Aug 6;305(5685):869-72
15297675
Obes Rev. 2009 Mar;10(2):218-26
19021870
Genome Res. 2005 Nov;15(11):1576-83
16251467
J Clin Invest. 2007 Jul;117(7):1995-2003
17571165
Curr Biol. 2010 Feb 23;20(4):R208-15
20178769
Am J Clin Nutr. 2002 Apr;75(4):714-9
11916758
Obes Res. 1995 Sep;3 Suppl 2:261s-265s
8581785
Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):118-22
11756659
Obes Res. 1997 Jul;5(4):321-5
9285838
J Clin Endocrinol Metab. 2003 Dec;88(12):5661-7
14671150
Clin Genet. 2008 Feb;73(2):179-84
18199144
Bioinformatics. 2002 Feb;18(2):337-8
11847089
Obes Rev. 2009 Sep;10(5):519-26
19413708
J Clin Endocrinol Metab. 1999 Mar;84(3):906-11
10084569
Nat Genet. 2001 Jun;28(2):178-83
11381268
PLoS Genet. 2006 Dec 15;2(12):e186
17173482
Nature. 1997 May 1;387(6628):90-4
9139827
Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15942-7
16243969
Am J Dig Dis. 1970 Aug;15(8):695-710
5468838
Biochem Soc Trans. 2001 Nov;29(Pt 6):768-73
11709072
Diabetes. 1999 Jan;48(1):146-9
9892236
Nature. 2008 Feb 21;451(7181):998-1003
18288195
Am J Clin Nutr. 1999 Jul;70(1):13-20
10393133
N Engl J Med. 2009 Apr 9;360(15):1509-17
19357406
Evolution. 2005 Nov;59(11):2312-23
16396172
Genetics. 2002 Jul;161(3):1209-18
12136023
J Pediatr. 1996 Nov;129(5):643-7
8917227
Genetics. 1989 Nov;123(3):585-95
2513255
Int J Obes Relat Metab Disord. 2001 Apr;25(4):472-7
11319649
PLoS Genet. 2010 Apr 01;6(4):e1000888
20369019
Biochem J. 2002 Jan 1;361(Pt 1):49-56
11743882
Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18508-13
16352722
Nat Rev Genet. 2007 Nov;8(11):857-68
17943193
Ann Hum Genet. 2006 Nov;70(Pt 6):841-7
17044859
Physiol Genomics. 2005 Jul 14;22(2):197-203
15870396
Int J Obes Relat Metab Disord. 1996 Dec;20(12):1062-6
8968850
FEBS Lett. 1999 Dec 3;462(3):257-60
10622707
N Engl J Med. 2009 Apr 9;360(15):1518-25
19357407