Extreme evolutionary disparities seen in positive selection across seven complex diseases.
Positive selection is known to occur when the environment that an organism inhabits is suddenly altered, as is the case across recent human history. Genome-wide association studies (GWASs) have successfully illuminated disease-associated variation. However, whether human evolution is heading towards or away from disease susceptibility in general remains an open question. The genetic-basis of common complex disease may partially be caused by positive selection events, which simultaneously increased fitness and susceptibility to disease. We analyze seven diseases studied by the Wellcome Trust Case Control Consortium to compare evidence for selection at every locus associated with disease. We take a large set of the most strongly associated SNPs in each GWA study in order to capture more hidden associations at the cost of introducing false positives into our analysis. We then search for signs of positive selection in this inclusive set of SNPs. There are striking differences between the seven studied diseases. We find alleles increasing susceptibility to Type 1 Diabetes (T1D), Rheumatoid Arthritis (RA), and Crohn's Disease (CD) underwent recent positive selection. There is more selection in alleles increasing, rather than decreasing, susceptibility to T1D. In the 80 SNPs most associated with T1D (p-value <7.01 x 10(-5)) showing strong signs of positive selection, 58 alleles associated with disease susceptibility show signs of positive selection, while only 22 associated with disease protection show signs of positive selection. Alleles increasing susceptibility to RA are under selection as well. In contrast, selection in SNPs associated with CD favors protective alleles. These results inform the current understanding of disease etiology, shed light on potential benefits associated with the genetic-basis of disease, and aid in the efforts to identify causal genetic factors underlying complex disease.
Corona
Erik
E
Lucile Packard Children's Hospital, Stanford, California, United States of America.
Dudley
Joel T
JT
Butte
Atul J
AJ
D000483:Alleles; D016022:Case-Control Studies; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D004194:Disease / Q000235:genetics*; D019143:Evolution, Molecular; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D012641:Selection, Genetic
Nature. 1994 Nov 3;372(6501):32
7969410
J Rheumatol. 2005 Dec;32(12):2432-3
16331777
Nucleic Acids Res. 2001 Jan 1;29(1):308-11
11125122
Curr Opin Genet Dev. 2006 Dec;16(6):630-6
17055247
J Mol Biol. 2006 May 19;358(5):1390-404
16584746
Bioinformatics. 2005 Jan 1;21(1):131-4
15333454
PLoS Genet. 2006 Sep 22;2(9):e148
17044736
J Infect. 2005 May;50(4):370-1
15845443
Genetics. 2008 Sep;180(1):301-16
18716333
Science. 2009 Apr 17;324(5925):387-9
19264985
Hum Genet. 2006 Mar;119(1-2):92-102
16362345
Am J Hum Genet. 2002 Jan;70(1):207-23
11741197
Genes Immun. 2010 Sep;11(6):467-78
20200544
Proc Natl Acad Sci U S A. 2007 Jan 9;104(2):570-5
17197413
Curr Biol. 2008 Jun 24;18(12):883-9
18571414
Pharmacogenet Genomics. 2008 Mar;18(3):169-79
18300938
MMWR Morb Mortal Wkly Rep. 2004 Aug 6;53(30):683-6
15295313
Diabetologia. 2009 Jun;52(6):1143-51
19266182
Nature. 2007 Oct 18;449(7164):913-8
17943131
Med Hypotheses. 2004;62(5):839-43
15082117
Clin Infect Dis. 2005 Aug 1;41 Suppl 3:S208-12
15983902
PLoS Biol. 2006 Mar;4(3):e72
16494531
Science. 2006 Jun 16;312(5780):1614-20
16778047
PLoS Genet. 2009 Dec;5(12):e1000792
20041220
Nature. 2002 Oct 24;419(6909):832-7
12397357
Bioinformatics. 2009 Jun 15;25(12):i21-9
19477990
Nat Rev Genet. 2003 Aug;4(8):587-97
12897771
Mol Biol Evol. 2010 Apr;27(4):934-41
19955474
Science. 2001 Nov 23;294(5547):1719-23
11721056
Nature. 2007 Jun 7;447(7145):661-78
17554300
World J Gastroenterol. 2001 Apr;7(2):175-84
11819757
BMC Med Genomics. 2008 Jun 04;1:22
18533027
Proc Natl Acad Sci U S A. 2004 Oct 26;101(43):15398-403
15492219
Nature. 2003 Dec 18;426(6968):789-96
14685227
Nat Rev Genet. 2009 Dec;10(12):872-8
19859063
Genes Immun. 2009 Mar;10(2):188-91
19110536
Arthritis Rheum. 2005 Jul;52(7):1986-92
15986370
Semin Arthritis Rheum. 1992 Dec;22(3):181-7
1295091
Genome Biol Evol. 2010 Jan 18;2:67-79
20333225