Genome bioinformatic analysis of nonsynonymous SNPs.
BACKGROUND
Genome-wide association studies of common diseases for common, low penetrance causal variants are underway. A proportion of these will alter protein sequences, the most common of which is the non-synonymous single nucleotide polymorphism (nsSNP). It would be an advantage if the functional effects of an nsSNP on protein structure and function could be predicted, both for the final identification process of a causal variant in a disease-associated chromosome region, and in further functional analyses of the nsSNP and its disease-associated protein.


RESULTS
In the present report we have compared and contrasted structure- and sequence-based methods of prediction to over 5500 genes carrying nearly 24,000 nsSNPs, by employing an automatic comparative modelling procedure to build models for the genes. The nsSNP information came from two sources, the OMIM database which are rare (minor allele frequency, MAF, < 0.01) and are known to cause penetrant, monogenic diseases. Secondly, nsSNP information came from dbSNP125, for which the vast majority of nsSNPs, mostly MAF > 0.05, have no known link to a disease. For over 40% of the nsSNPs, structure-based methods predicted which of these sequence changes are likely to either disrupt the structure of the protein or interfere with the function or interactions of the protein. For the remaining 60%, we generated sequence-based predictions.


CONCLUSIONS
We show that, in general, the prediction tools are able distinguish disease causing mutations from those mutations which are thought to have a neutral affect. We give examples of mutations in genes that are predicted to be deleterious and may have a role in disease. Contrary to previous reports, we also show that rare mutations are consistently predicted to be deleterious as often as commonly occurring nsSNPs.
Burke
David F
DF
Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1GA, UK. dave@cryst.bioc.cam.ac.uk
Worth
Catherine L
CL
Priego
Eva-Maria
EM
Cheng
Tammy
T
Smink
Luc J
LJ
Todd
John A
JA
Blundell
Tom L
TL
D000465:Algorithms; D002874:Chromosome Mapping / Q000379:methods*; D019295:Computational Biology / Q000379:methods*; D004252:DNA Mutational Analysis / Q000379:methods*; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods*
D011506:Proteins
Curr Opin Struct Biol. 2002 Feb;12(1):21-7
11839485
Bioinformatics. 2004 Nov 22;20(17):3206-13
15231534
Bioinformatics. 2005 Mar 1;21(5):694-5
15509599
Proc Natl Acad Sci U S A. 2004 Oct 12;101(41):14754-9
15456910
Protein Sci. 1992 Feb;1(2):216-26
1304904
Proteins. 1999;Suppl 3:55-60
10526352
Structure. 2005 Jan;13(1):121-30
15642267
Faraday Discuss. 1992;(93):25-34
1290936
Bioinformatics. 2005 Jun 15;21(12):2814-20
15827081
Nucleic Acids Res. 2002 Jan 1;30(1):387-91
11752345
Proteins. 2001;Suppl 5:92-7
11835486
Hum Mol Genet. 2006 Nov 1;15(21):3263-71
17000706
Science. 1991 Jul 12;253(5016):164-70
1853201
Genes Immun. 2005 Mar;6(2):145-52
15674389
Hum Mol Genet. 2001 Mar 15;10(6):591-7
11230178
Nucleic Acids Res. 2003 Jul 1;31(13):3812-4
12824425
Annu Rev Biophys Biomol Struct. 2000;29:291-325
10940251
Protein Eng. 1997 Jan;10(1):7-21
9051729
J Mol Biol. 1993 Dec 5;234(3):779-815
8254673
J Mol Biol. 2001 Jun 29;310(1):243-57
11419950
Trends Genet. 2003 Sep;19(9):505-13
12957544
Cancer Epidemiol Biomarkers Prev. 2005 Nov;14(11 Pt 1):2598-604
16284384
Genome Res. 1998 Dec;8(12):1229-31
9872978
J Mol Biol. 2001 Apr 13;307(5):1487-502
11292355
Nucleic Acids Res. 2004 Jan 1;32(Database issue):D129-33
14681376
J Mol Biol. 1993 Jan 5;229(1):194-220
8421300
Nature. 2005 Oct 27;437(7063):1299-320
16255080
Bioinformatics. 2005 Sep 1;21 Suppl 2:ii54-8
16204125
Nucleic Acids Res. 2000 Jan 1;28(1):352-5
10592272
Nucleic Acids Res. 2002 Sep 1;30(17):3894-900
12202775
Annu Rev Immunol. 1998;16:495-521
9597139
Am J Hum Genet. 2007 Feb;80(2):273-90
17236132
J Mol Biol. 1996 Mar 29;257(2):342-58
8609628
Proc Biol Sci. 1990 Aug 22;241(1301):132-45
1978340
J Mol Biol. 2004 Oct 1;342(5):1487-504
15364576
Genome Res. 2001 May;11(5):863-74
11337480
Genome Res. 2002 Mar;12(3):436-46
11875032
Protein Eng. 2000 Dec;13(12):839-47
11239083
Nat Genet. 2000 Jun;25(2):187-91
10835634
Diabetes. 2003 Jun;52(6):1579-82
12765974
Hum Mutat. 2003 Jun;21(6):577-81
12754702
Nat Genet. 2005 Nov;37(11):1243-6
16228001
Proteins. 2006 Mar 1;62(4):1125-32
16372356