A powerful score test to detect positive selection in genome-wide scans.
One of the surest signatures of recent positive selection is a local elevation of advantageous allele frequency and linkage disequilibrium (LD). We proposed to detect such hitchhiking effects by using extended stretches of homozygosity as a surrogate indicator of recent positive selection. An extended haplotype-based homozygosity score test (EHHST) was developed to detect excess homozygosity. The EHHST conditioned on existing LD and it tested the haplotype version of the Hardy-Weinberg equilibrium. Compared with existing popular tests, which usually lack clear distribution, the EHHST is asymptotically normal, which makes analysis and applications easier. In particular, the EHHST facilitates the computation of an asymptotic P-value instead of an empirical P-value, using simulations. We evaluated by simulation that the EHHST led to appropriate false-positive rates, and it had higher or similar power as the existing popular methods. The method was applied to HapMap Phase II data. We were able to replicate previous findings of strong positive selection in 17 autosome genomic regions out of 20 reported candidates. On the basis of high EHHST values and population differentiations, we identified 15 new candidate regions that could undergo recent selection.
Zhong
Ming
M
Department of Statistics, The Texas A&M University, College Station, TX 77843-3143, USA.
Lange
Kenneth
K
Papp
Jeanette C
JC
Fan
Ruzong
R
D000483:Alleles; D002874:Chromosome Mapping / Q000379:methods*; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D057225:Data Mining; D005787:Gene Frequency; D005828:Genetics, Population / Q000379:methods; D015894:Genome, Human; D055106:Genome-Wide Association Study / Q000379:methods*; D023281:Genomics; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D044382:Population Groups / Q000235:genetics; D012641:Selection, Genetic
Genome Res. 2005 Nov;15(11):1566-75
16251466
Bioinformatics. 2004 Dec 12;20(18):3673-5
15271777
Genetics. 2007 Mar;175(3):1395-406
17194788
PLoS Biol. 2007 Jul;5(7):e171
17579516
Nature. 2002 Oct 24;419(6909):832-7
12397357
Genetics. 1987 May;116(1):153-9
3110004
Am J Hum Genet. 1995 Mar;56(3):799-810
7887436
Annu Rev Genomics Hum Genet. 2000;1:539-59
11701640
Annu Rev Genet. 2005;39:197-218
16285858
Nature. 2007 Oct 18;449(7164):851-61
17943122
Genetics. 1993 Mar;133(3):693-709
8454210
Science. 2005 Dec 16;310(5755):1782-6
16357253
Theor Popul Biol. 1975 Apr;7(2):256-76
1145509
Am J Hum Genet. 2006 Jan;78(1):153-9
16385459
Am J Hum Genet. 2004 Jun;74(6):1111-20
15114531
Proc Natl Acad Sci U S A. 2006 Jan 3;103(1):135-40
16371466
Genetics. 1994 Apr;136(4):1329-40
8013910
PLoS Biol. 2004 Oct;2(10):e286
15361935
Genome Res. 2002 Dec;12(12):1805-14
12466284
Genetics. 2000 Jul;155(3):1405-13
10880498
Nat Rev Genet. 2003 Feb;4(2):99-111
12560807
Hum Mol Genet. 2006 Mar 1;15(5):789-95
16436455
Nature. 2007 Oct 18;449(7164):913-8
17943131
Am J Hum Genet. 1999 Jun;64(6):1764-72
10330364
PLoS Biol. 2006 Mar;4(3):e72
16494531
Genetics. 2002 Mar;160(3):1179-89
11901132
Ann Hum Genet. 2003 Jul;67(Pt 4):298-311
12914565
Science. 2006 Jun 16;312(5780):1614-20
16778047
PLoS Genet. 2007 Jun;3(6):e90
17542651
Hum Genomics. 2005 Jun;2(2):113-25
16004726
Genetics. 2004 Jul;167(3):1513-24
15280259
Bioinformatics. 2002 Feb;18(2):337-8
11847089
Genetics. 1989 Dec;123(4):887-99
2612899
Genome Res. 2006 Jun;16(6):702-12
16687733
Genetics. 2003 Sep;165(1):287-97
14504236
Genetics. 2005 Jul;170(3):1401-10
15911584
Nat Genet. 2002 Feb;30(2):233-7
11788828
Evolution. 1984 Nov;38(6):1358-1370
28563791
Genet Res. 1974 Feb;23(1):23-35
4407212
Genetics. 1989 Nov;123(3):585-95
2513255
Hum Mol Genet. 2004 Oct 1;13 Spec No 2:R245-54
15358731
PLoS Biol. 2005 Nov;3(11):e378
16248677
Bioinformatics. 2008 Jul 15;24(14):1596-602
18487240