title: Inferring causality and functional significance of human coding DNA variants.
abstract: Sequencing technology enables the complete characterization of human genetic variation. Statistical genetics studies identify numerous loci linked to or associated with phenotypes of direct medical interest. The major remaining challenge is to characterize functionally significant alleles that are causally implicated in the genetic basis of human traits. Here, I review three sources of evidence for the functional significance of human DNA variants in protein-coding genes. These include (i) statistical genetics considerations such as co-segregation with the phenotype, allele frequency in unaffected controls and recurrence; (ii) in vitro functional assays and model organism experiments; and (iii) computational methods for predicting the functional effect of amino acid substitutions. In spite of many successes of recent studies, functional characterization of human allelic variants remains problematic.
authors.affiliation: Genetics Division, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. ssunyaev@rics.bwh.harvard.edu
authors.forename: Shamil R
authors.initials: SR
authors.lastname: Sunyaev
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D004247:DNA / Q000235:genetics; D059472:Exome / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D020125:Mutation, Missense; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: D004247:DNA