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Human Molecular Genetics, 2001, Vol. 10, No. 6 591-597
© 2001 Oxford University Press

Prediction of deleterious human alleles

Shamil Sunyaev1,2,3, Vasily Ramensky3, Ina Koch3, Warren Lathe III1,2, Alexey S. Kondrashov4 and Peer Bork1,2,+

1European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg, Germany, 2Max-Delbrueck Centre for Molecular Medicine, Robert-Roessle-Strasse 10, D-13122 Berlin, Germany, 3Engelhardt Institute of Molecular Biology, Vavilova 32, D-117984 Moscow, Russia and 4National Center for Biotechnology Information, National Institutes of Health, 45 Center Drive, MSC 6510, Bethesda, MD 20892-6510, USA

Single nucleotide polymorphisms (SNPs) constitute the bulk of human genetic variation, occurring with an average density of ~1/1000 nucleotides of a genotype. SNPs are either neutral allelic variants or are under selection of various strengths, and the impact of SNPs on fitness remains unknown. Identification of SNPs affecting human phenotype, especially leading to risks of complex disorders, is one of the key problems of medical genetics. SNPs in protein-coding regions that cause amino acid variants (non-synonymous cSNPs) are most likely to affect phenotypes. We have developed a straightforward and reliable method based on physical and comparative considerations that estimates the impact of an amino acid replacement on the three-dimensional structure and function of the protein. We estimate that ~20% of common human non-synonymous SNPs damage the protein. The average minor allele frequency of such SNPs in our data set was two times lower than that of benign non-synonymous SNPs. The average human genotype carries approximately 103 damaging non-synonymous SNPs that together cause a substantial reduction in fitness.

+ To whom correspondence should be addressed. Tel: +49 6221 387526; Fax: +49 6221 387517; Email: bork@embl-heidelberg.de


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