Amino acid changes in disease-associated variants differ radically from variants observed in the 1000 genomes project dataset

PLoS Computational Biology
Tjaart A P de BeerJanet M Thornton

Abstract

The 1000 Genomes Project data provides a natural background dataset for amino acid germline mutations in humans. Since the direction of mutation is known, the amino acid exchange matrix generated from the observed nucleotide variants is asymmetric and the mutabilities of the different amino acids are very different. These differences predominantly reflect preferences for nucleotide mutations in the DNA (especially the high mutation rate of the CpG dinucleotide, which makes arginine mutability very much higher than other amino acids) rather than selection imposed by protein structure constraints, although there is evidence for the latter as well. The variants occur predominantly on the surface of proteins (82%), with a slight preference for sites which are more exposed and less well conserved than random. Mutations to functional residues occur about half as often as expected by chance. The disease-associated amino acid variant distributions in OMIM are radically different from those expected on the basis of the 1000 Genomes dataset. The disease-associated variants preferentially occur in more conserved sites, compared to 1000 Genomes mutations. Many of the amino acid exchange profiles appear to exhibit an anti-correlation, with ...Continue Reading

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Methods Mentioned

BETA
amino acid exchange
nucleotide exchange
PCA
dissection
X-ray

Software Mentioned

NACCESS
adjust
SDM
PolyPhen
GO
R
SIFT
Modeller
SNP
VEP

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