Conserved noncoding sequences are selectively constrained and not mutation cold spots

被引:178
作者
Drake, JA
Bird, C
Nemesh, J
Thomas, DJ
Newton-Cheh, C
Reymond, A
Excoffier, L
Attar, H
Antonarakis, SE
Dermitzakis, ET
Hirschhorn, JN
机构
[1] Childrens Hosp, Program Genom, Boston, MA 02115 USA
[2] Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA
[3] Harvard Univ, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02139 USA
[4] MIT, Cambridge, MA 02139 USA
[5] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England
[6] Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA
[7] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA
[8] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA
[9] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland
[10] Univ Bern, Inst Zool, CH-3012 Bern, Switzerland
[11] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA
基金
英国惠康基金;
关键词
D O I
10.1038/ng1710
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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(1-4), 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.
引用
收藏
页码:223 / 227
页数:5
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