Fast-evolving noncoding sequences in the human genome
1 The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK
2 Center for Biomolecular Science and Engineering, University of California Santa Cruz, Santa Cruz, CA 95064, USA
3 Department of Computer Science & Engineering, Pennsylvania State University, University Park, PA 16802, USA
Genome Biology 2007, 8:R118 doi:10.1186/gb-2007-8-6-r118Published: 19 June 2007
Gene regulation is considered one of the driving forces of evolution. Although protein-coding DNA sequences and RNA genes have been subject to recent evolutionary events in the human lineage, it has been hypothesized that the large phenotypic divergence between humans and chimpanzees has been driven mainly by changes in gene regulation rather than altered protein-coding gene sequences. Comparative analysis of vertebrate genomes has revealed an abundance of evolutionarily conserved but noncoding sequences. These conserved noncoding (CNC) sequences may well harbor critical regulatory variants that have driven recent human evolution.
Here we identify 1,356 CNC sequences that appear to have undergone dramatic human-specific
changes in selective pressures, at least 15% of which have substitution rates significantly
above that expected under neutrality. The 1,356 'accelerated CNC' (ANC) sequences
are enriched in recent segmental duplications, suggesting a recent change in selective
constraint following duplication. In addition, single nucleotide polymorphisms within
ANC sequences have a significant excess of high frequency derived alleles and high
STvalues relative to controls, indicating that acceleration and positive selection are
recent in human populations. Finally, a significant number of single nucleotide polymorphisms
within ANC sequences are associated with changes in gene expression. The probability
of variation in an ANC sequence being associated with a gene expression phenotype
is fivefold higher than variation in a control CNC sequence.
Our analysis suggests that ANC sequences have until very recently played a role in human evolution, potentially through lineage-specific changes in gene regulation.