Conserved noncoding sequences are selectively constrained and not mutation cold spots

Drake, J. A.; Bird, Christine; Nemesh, James; Thomas, D. J.; Newton-Cheh, Christopher; Reymond, Alexandre; Excoffier, Laurent Georges Louis; Attar, Homa; Antonarakis, Stylianos; Dermitzakis, Emmanouil; Hirschhorn, J. N.

doi:10.1038/ng1710

Scientific article

English

Conserved noncoding sequences are selectively constrained and not mutation cold spots

Contributors

Drake, J. A.; Bird, Christine; Nemesh, James; Thomas, D. J.; Newton-Cheh, Christopher; Reymond, Alexandre; Excoffier, Laurent Georges Louis; Attar, Homa; Antonarakis, Stylianos; Dermitzakis, Emmanouil; Hirschhorn, J. N.

Published in

Nature genetics, vol. 38, no. 2, p. 223-227

Publication date

2006

Abstract

Noncoding genetic variants are likely to influence human biology and disease, but recognizing functional noncoding variants is difficult. Approximately 3% of noncoding sequence is conserved among distantly related mammals, suggesting that these evolutionarily conserved noncoding regions (CNCs) are selectively constrained and contain functional variation. However, CNCs could also merely represent regions with lower local mutation rates. Here we address this issue and show that CNCs are selectively constrained in humans by analyzing HapMap genotype data. Specifically, new (derived) alleles of SNPs within CNCs are rarer than new alleles in nonconserved regions (P = 3 x 10(-18)), indicating that evolutionary pressure has suppressed CNC-derived allele frequencies. Intronic CNCs and CNCs near genes show greater allele frequency shifts, with magnitudes comparable to those for missense variants. Thus, conserved noncoding variants are more likely to be functional. Allele frequency distributions highlight selectively constrained genomic regions that should be intensively surveyed for functionally important variation.

Keywords

Conserved Sequence/ genetics
Gene Frequency/genetics
Humans
Mutation/ genetics
Polymorphism, Single Nucleotide/genetics
Population Groups/genetics
Selection, Genetic

UNIGE affiliation entities

Faculté de médecine / Section de médecine clinique / Département de médecine

Citation (ISO format)

DRAKE, J. A. et al. Conserved noncoding sequences are selectively constrained and not mutation cold spots. In: Nature genetics, 2006, vol. 38, n° 2, p. 223–227. doi: 10.1038/ng1710

Article

Identifiers

PID : unige:8730
DOI : 10.1038/ng1710
PMID : 16380714

Additional URL for this publication

http://www.nature.com/ng/journal/v38/n2/pdf/ng1710.pdf

Journal ISSN

1061-4036

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Conserved noncoding sequences are selectively constrained and not mutation cold spots

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Abstract

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UNIGE affiliation entities

Citation (ISO format)

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First validation

Update

Status update

Last indexation