title: Conserved noncoding sequences are selectively constrained and not mutation cold spots.
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.
authors.affiliation: Program in Genomics and Division of Endocrinology, Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Jared A
authors.initials: JA
authors.lastname: Drake
authors.forename: Christine
authors.initials: C
authors.lastname: Bird
authors.forename: James
authors.initials: J
authors.lastname: Nemesh
authors.forename: Daryl J
authors.initials: DJ
authors.lastname: Thomas
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
authors.forename: Alexandre
authors.initials: A
authors.lastname: Reymond
authors.forename: Laurent
authors.initials: L
authors.lastname: Excoffier
authors.forename: Homa
authors.initials: H
authors.lastname: Attar
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
mesh_terms: D017124:Conserved Sequence / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044382:Population Groups / Q000235:genetics; D012641:Selection, Genetic