Human‐specific Accelerated Evolution of Noncoding Sequences

Abstract

Mutations in functional noncoding elements are likely to be responsible for a large fraction of phenotypic evolution. There is considerable interest in identifying genes and genomic regions under positive selection on the human lineage, as they may govern the traits that make us unique. Several studies have attempted to identify functional noncoding elements under positive selection in the human lineage by identifying those with evidence of accelerated evolutionary rates since the common ancestor of humans and chimpanzees. These studies have identified a catalogue of human‐accelerated regions (HARs). Two of the most extremely accelerated HARs are implicated in controlling human‐specific morphology and cognition. However, detailed analyses of the forces governing the evolution of HARs suggest that a number of different processes distinct from positive selection may be involved in their accelerated rates. These include relaxation of constraint, variation in mutation rate and GC‐biased gene conversion.

Key Concepts:

  • Noncoding genomic regions under evolutionary constraint are likely to be functional elements such as the transcription binding sites.

  • Evolutionarily constrained elements that have undergone accelerated evolution on the human lineage are candidates for governing human‐specific traits.

  • Positive selection represents a bias towards fixation of alleles conferring an increased fitness.

  • GC‐biased gene conversion (gBGC) is a recombination‐associated process that increases the probabilty of fixation of G and C nucleotides independent of their fitness.

  • Multiple processes, including positive selection and gBGC are implicated in governing the evolution of human‐accelerated regions.

Keywords: natural selection; recombination; evolution; gene conversion; mutation

Figure 1.

Phylogenetic tree of the 17 vertebrates used by Pollard et al. to identify HARs. Initially, alignments of chimpanzee, rat and mouse genomes were compared to identify approximately 35 000 conserved elements. Subsequently, these elements were analysed for evidence of increased substitution rate along the human lineage since the human–chimpanzee split (highlighted in grey). For this analysis, the chimpanzee, rat and mouse genomes were excluded because they were used to infer conservation (along with rabbits and macaques that share internal branches between human and the excluded genomes). A total of 49 HARs were identified with an FDR of 5%.

Figure 2.

A proposed model of gBGC. The two pairs of lines represent both strands of DNA from two parental chromosomes. (a) Consider homologous chromosomes that are heterozygous for an SNP where one allele is G:C and the other is A:T. (b) A double‐stranded break (DSB) occurs in one chromosome. (c) A strand from the unbroken chromosome invades the DSB. A G:T base mismatch is created in a region of pairing between strands from both the chromosomes. (d) The unbroken DNA is used as a template to synthesise new DNA (dotted lines) to repair the gap. The G:T mismatch is preferentially replaced by a G:C pair by repair enzymes. (e) The DNA molecules are cut and the Holliday junctions are resolved as either crossing over or as a gene conversion event. Both alleles of the SNP are now G:C. This process therefore leads to a bias in the transmission of G:C alleles. In addition to this process, DSBs have been observed to preferentially occur at A:T alleles at one hotspot (Jeffreys and Neumann, ), which also results in a bias in favour of GC.

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Coop G and Przeworski M (2007) An evolutionary view of human recombination. Nature Reviews Genetics 8: 23–34.

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Pollard KS (2009) What makes us human? Scientific American 300: 44–49.

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Webster, Matthew T(Apr 2013) Human‐specific Accelerated Evolution of Noncoding Sequences. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020849.pub2]