Predicting functionally important SNP classes based on negative selection.
BACKGROUND
With the advent of cost-effective genotyping technologies, genome-wide association studies allow researchers to examine hundreds of thousands of single nucleotide polymorphisms (SNPs) for association with human disease. Recently, many researchers applying this strategy have detected strong associations to disease with SNP markers that are either not in linkage disequilibrium with any nonsynonymous SNP or large distances from any annotated gene. In such cases, no well-established standard practice for effective SNP selection for follow-up studies exists. We aim to identify and prioritize groups of SNPs that are more likely to affect phenotypes in order to facilitate efficient SNP selection for follow-up studies.


RESULTS
Based on the annotations available in the Ensembl database, we categorized SNPs in the human genome into classes related to regulatory attributes, such as epigenetic modifications and transcription factor binding sites, in addition to classes related to gene structure and cross-species conservation. Using the distribution of derived allele frequencies (DAF) within each class, we assessed the strength of natural selection for each class relative to the genome as a whole. We applied this DAF analysis to Perlegen resequenced SNPs genome-wide. Regulatory elements annotated by Ensembl such as specific histone methylation sites as well as classes defined by cross-species conservation showed negative selection in comparison to the genome as a whole.


CONCLUSIONS
These results highlight which annotated classes are under purifying selection, have putative functional importance, and contain SNPs that are strong candidates for follow-up studies after genome-wide association. Such SNP annotation may also be useful in interpreting results of whole-genome sequencing studies.
Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Mark A
MA
Levenstien
Robert J
RJ
Klein
D044127:Epigenesis, Genetic; D005787:Gene Frequency; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D058977:Molecular Sequence Annotation; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic
Nat Biotechnol. 2008 Oct;26(10):1125-33
18846086
Science. 2007 Jun 1;316(5829):1341-5
17463248
PLoS One. 2008 Sep 10;3(9):e3137
18781197
Nature. 2007 Jun 28;447(7148):1087-93
17529967
Genome Res. 2008 Nov;18(11):1814-28
18849524
Genome Res. 2005 Jul;15(7):901-13
15965027
Science. 2005 Apr 15;308(5720):421-4
15761121
Cell. 2007 Mar 23;128(6):1231-45
17382889
Nat Genet. 2007 Aug;39(8):954-6
17618282
Genet Epidemiol. 2007 Nov;31(7):741-7
17549760
PLoS Biol. 2004 Sep;2(9):E268
15340491
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D68-73
16381958
Science. 2005 Apr 15;308(5720):419-21
15761120
Curr Opin Genet Dev. 2003 Dec;13(6):562-8
14638315
Nat Genet. 2007 Aug;39(8):989-94
17618283
Hum Mol Genet. 2001 Mar 15;10(6):591-7
11230178
Genome Res. 2004 Apr;14(4):517-27
15059992
Science. 2005 Apr 15;308(5720):385-9
15761122
Nat Genet. 2008 Jul;40(7):897-903
18552846
PLoS Biol. 2004 Nov;2(11):e363
15502875
Nucleic Acids Res. 2003 Jul 1;31(13):3812-4
12824425
Science. 2007 Jun 8;316(5830):1488-91
17478681
J Biol Chem. 2005 May 6;280(18):17732-6
15760899
Science. 2008 Nov 7;322(5903):881-8
18988837
Genome Res. 2010 Mar;20(3):301-10
20067941
Nucleic Acids Res. 2008 Jan;36(Database issue):D149-53
18158296
Science. 2007 Aug 17;317(5840):915
17702936
Nat Rev Genet. 2006 Nov;7(11):885-91
17047687
N Engl J Med. 2010 Apr 1;362(13):1181-91
20220177
Proc Natl Acad Sci U S A. 2005 Jun 21;102(25):8949-54
15956201
Am J Hum Genet. 2007 Aug;81(2):397-404
17668389
N Engl J Med. 2007 Aug 2;357(5):443-53
17634449
Science. 2005 Feb 18;307(5712):1072-9
15718463
Nat Biotechnol. 2008 Oct;26(10):1135-45
18846087
Genetics. 1999 Jan;151(1):221-38
9872962
Nat Genet. 2006 Dec;38(12):1452-6
17072316
Hum Mol Genet. 2008 Oct 15;17(R2):R102-8
18852197
Science. 2007 Jun 1;316(5829):1331-6
17463246
Cell. 2007 May 18;129(4):823-37
17512414
Hum Mol Genet. 2008 Oct 15;17(R2):R109-15
18852198
Science. 2007 Jun 8;316(5830):1491-3
17478679
Annu Rev Genomics Hum Genet. 2006;7:61-80
16824020
Nat Genet. 2008 May;40(5):623-30
18372905
Nat Genet. 2006 Feb;38(2):223-7
16380714
Genome Res. 2010 Mar;20(3):311-9
20032171
BMC Bioinformatics. 2006 Mar 22;7:166
16551372
Am J Hum Genet. 2006 Feb;78(2):243-52
16400608
Nucleic Acids Res. 2017 Jan 4;45(D1):D896-D901
27899670
Bioinformatics. 2005 Jun 15;21(12):2814-20
15827081
Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):14068-73
16945910
Nature. 2008 Nov 6;456(7218):66-72
18987736
Nature. 2004 Apr 1;428(6982):493-521
15057822
Am J Hum Genet. 2007 Apr;80(4):692-704
17357075
BMC Genomics. 2009 Dec 16;10:614
20015390
Genome Biol. 2003;5(1):R1
14709173
Genome Res. 2003 Jan;13(1):13-26
12529302
Nat Genet. 2006 Jun;38(6):652-8
16682969
Hum Mol Genet. 2008 Oct 15;17(R2):R116-21
18852199
Genet Epidemiol. 2007 Dec;31(8):871-82
17654612
J Natl Cancer Inst. 2008 Jul 2;100(13):962-6
18577746
Science. 2007 Jun 1;316(5829):1336-41
17463249
Nature. 2002 Dec 5;420(6915):520-62
12466850
Cell. 2008 Jan 25;132(2):311-22
18243105