Abstract
Databases of disease-associated or disease-causing mutations allow the study, not only of the molecular mechanisms underlying the primary lesions at the DNA level, but also of the functional consequences of mutation at the phenotypic level. The Human Gene Mutation Database (HGMD) and the bioinformatics analyses of its content provide an illustrative example of this indirect approach to molecular genetic epidemiology. In fact, the Bayesian type of reasoning underlying previous scientific analyses of HGMD data is also reflected in current software tools used to predict the likely disease relevance of a newly detected genetic variant. After a brief resume of the past scientific utility of HGMD, we, therefore, shortly review three representative and commonly used examples of these tools, namely SIFT, PolyPhen-2 and NNSplice.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249
Ball EV, Stenson PD, Abeysinghe SS, Krawczak M, Cooper DN, Chuzhanova NA (2005) Microdeletions and microinsertions causing human genetic disease: common mechanisms of mutagenesis and the role of local DNA sequence complexity. Hum Mutat 26:205–213
Baralle D, Lucassen A, Buratti E (2009) Missed threads. The impact of pre-mRNA splicing defects on clinical practice. EMBO Rep 10:810–816
Benzer S (1961) On the topography of the genetic fine structure. Proc Natl Acad Sci USA 47:403–415
Cooper DN, Krawczak M (1990) The mutational spectrum of single base-pair substitutions causing human genetic disease: patterns and predictions. Hum Genet 85:55–74
Cooper DN, Chen JM, Ball EV, Howells K, Mort M, Phillips AD, Chuzhanova N, Krawczak M, Kehrer-Sawatzki H, Stenson PD (2010) Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics. Hum Mutat 31:631–655
Cooper DN, Bacolla A, Férec C, Vasquez KM, Kehrer-Sawatzki H, Chen JM (2011) On the sequence-directed nature of human gene mutation: the role of genomic architecture and the local DNA sequence environment in mediating gene mutations underlying human inherited disease. Hum Mutat 32:1075–1099
Frousios K, Iliopoulos CS, Schlitt T, Simpson MA (2013) Predicting the functional consequences of non-synonymous DNA sequence variants—evaluation of bioinformatics tools and development of a consensus strategy. Genomics 102:223–228
Grantham R (1974) Amino acid difference formula to help explain protein evolution. Science 185:862–864
Johnston JJ, Biesecker LG (2013) Databases of genomic variation and phenotypes: existing resources and future needs. Hum Mol Genet 22(R1):R27–R31
Krawczak M, Cooper DN (1991) Gene deletions causing human genetic disease: mechanisms of mutagenesis and the role of the local DNA sequence environment. Hum Genet 86:425–441
Krawczak M, Reiß J, Cooper DN (1992) The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet 90:41–54
Krawczak M, Ball EV, Cooper DN (1998) Neighboring nucleotide effects on the rates of germline single base-pair substitution in human genes. Am J Hum Genet 63:474–488
Kwok SC, Chan SJ, Rubenstein AH, Poucher R, Steiner DF (1981) Loss of a restriction endonuclease cleavage site in the gene of a structurally abnormal human insulin. Biochem Biophys Res Commun 98:844–849
Ng PC, Henikoff S (2001) Predicting deleterious amino acid substitutions. Genome Res 11:863–874
Ng PC, Henikoff S (2006) Predicting the effects of amino acid substitutions on protein function. Annu Rev Genomics Hum Genet 7:61–80
Olatubosun A, Väliaho J, Härkönen J, Thusberg J, Vihinen M (2012) PON-P: integrated predictor for pathogenicity of missense variants. Hum Mutat 33:1166–1174
Peterson TA, Doughty E, Kann MG (2013) Towards precision medicine: advances in computational approaches for the analysis of human variants. J Mol Biol 425:4047–4063
Reese MG, Eeckman FH, Kulp D, Haussler D (1997) Improved splice site detection in Genie. J Comp Biol 4:311–323
Stenson PD, Mort M, Ball EV, Shaw K, Phillips AD, Cooper DN (2013) The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet (in press). doi:10.1007/s00439-013-1358-4
Thusberg J, Vihinen M (2009) Pathogenic or not? And if so, then how? Studying the effects of missense mutations using bioinformatics methods. Hum Mutat 30:703–714
Thusberg J, Olatubosun A, Vihinen M (2011) Performance of mutation pathogenicity prediction methods on missense variants. Hum Mutat 32:358–368
Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38:e164
Wu J, Jiang R (2013) Prediction of deleterious nonsynonymous single-nucleotide polymorphism for human diseases. ScientificWorldJournal 2013:675851
Acknowledgments
The authors are most grateful to Amke Caliebe, Kiel, for her support and for helpful comments of the manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Knecht, C., Krawczak, M. Molecular genetic epidemiology of human diseases: from patterns to predictions. Hum Genet 133, 425–430 (2014). https://doi.org/10.1007/s00439-013-1396-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-013-1396-y