Inferring causality and functional significance of human coding DNA variants.

Hum Mol Genet 2012 Oct 17;21(R1):R10-7. Epub 2012 Sep 17.

Genetics Division, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.

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.

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http://dx.doi.org/10.1093/hmg/dds385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459643PMC
October 2012
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References

(Supplied by CrossRef)

Durbin et al.
Nature; Physical Science (London) 2010

Science 2012

Plon et al.
Human mutation 2008

Ng et al.
Nature genetics 2010

Science 2010

Neale et al.
Nature; Physical Science (London) 2012

O'Roak et al.
Nature; Physical Science (London) 2012

Sanders et al.
Nature; Physical Science (London) 2012

Xu et al.
Nature genetics 2011

Kondrashov et al.
Human mutation 2003

2000

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