Allele frequencies of variants in ultra conserved elements identify selective pressure on transcription factor binding

PLoS One. 2014 Nov 4;9(11):e110692. doi: 10.1371/journal.pone.0110692. eCollection 2014.

Abstract

Ultra-conserved genes or elements (UCGs/UCEs) in the human genome are extreme examples of conservation. We characterized natural variations in 2884 UCEs and UCGs in two distinct populations; Singaporean Chinese (n = 280) and Italian (n = 501) by using a pooled sample, targeted capture, sequencing approach. We identify, with high confidence, in these regions the abundance of rare SNVs (MAF<0.5%) of which 75% is not present in dbSNP137. UCEs association studies for complex human traits can use this information to model expected background variation and thus necessary power for association studies. By combining our data with 1000 Genome Project data, we show in three independent datasets that prevalent UCE variants (MAF>5%) are more often found in relatively less-conserved nucleotides within UCEs, compared to rare variants. Moreover, prevalent variants are less likely to overlap transcription factor binding site. Using SNPfold we found no significant influence of RNA secondary structure on UCE conservation. All together, these results suggest UCEs are not under selective pressure as a stretch of DNA but are under differential evolutionary pressure on the single nucleotide level.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Conserved Sequence / genetics*
  • Gene Frequency
  • Genome, Human
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Nucleic Acid Conformation
  • Polymorphism, Single Nucleotide
  • Protein Binding
  • RNA / chemistry
  • RNA / metabolism
  • Sequence Analysis, DNA
  • Transcription Factors / chemistry*
  • Transcription Factors / metabolism

Substances

  • Transcription Factors
  • RNA

Grants and funding

This work was supported by the Duke-NUS Signature Research Program and the Singapore Ministry of Health's National Medical Research Council (grant MOE2010-2-006 to PMV), and the Estonian Research Council postdoctoral research program “MOBILITAS” (grant MJD147 to TS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.