Human‐specific Accelerated Evolution of Noncoding Sequences


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.



Arndt PF, Petrov DA and Hwa T (2003) Distinct changes of genomic biases in nucleotide substitution at the time of mammalian radiation. Molecular Biology and Evolution 20: 1887–1896.

Bailey JA and Eichler EE (2006) Primate segmental duplications: crucibles of evolution, diversity and disease. Nature Reviews Genetics 7: 552–564.

Berglund J, Pollard KS and Webster MT (2009) Hotspots of biased nucleotide substitution in human genes. PLoS Biology 7: e1000026.

Birdsell JA (2002) Integrating genomics, bioinformatics, and classical genetics to study the effects of recombination on genome evolution. Molecular Biology and Evolution 19: 1181–1197.

Brown TC and Jiricny J (1988) Different base/base mispairs are corrected with different efficiencies and specificities in monkey kidney cells. Cell 54: 705–711.

Bustamante CD, Fledel‐Alon A, Williamson S et al. (2005) Natural selection on protein‐coding genes in the human genome. Nature 437: 1153–1157.

Capra JA and Pollard KS (2011) Substitution patterns are GC‐biased in divergent sequences across the metazoans. Genome Biology Evolution 3: 516–527. PMID: 21670083. doi:10.1093/gbe/evr051.

Chimpanzee Sequencing and Analysis Consortium (2005) Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437: 69–87.

Clark AG, Glanowski S, Nielsen R et al. (2003) Inferring nonneutral evolution from human–chimp–mouse orthologous gene trios. Science 302: 1960–1963.

Deacon T (1998) The Symbolic Species: The Co‐evolution of Language and the Brain. London: Penguin Books.

Deininger PL and Batzer MA (2002) Mammalian retroelements. Genome Research 12: 1455–1465.

Dennis K, Hubisz MJ, Siepel A and Pollard KS (2012) The role of GC‐biased gene conversion in shaping the fastest evolving regions of the human genome. Molecular Biology and Evolution 29(3): 1047–1057. doi:10.1093/molbev/msr279.

Dreszer TR, Wall GD, Haussler D and Pollard KS (2007) Biased clustered substitutions in the human genome: the footprints of male‐driven biased gene conversion. Genome Research 17: 1420–1430.

Duret L and Arndt PF (2008) The impact of recombination on nucleotide substitutions in the human genome. PLoS Genetics 4: e1000071. PMID: 18464896.

Duret L and Galtier N (2009) Biased gene conversion and the evolution of mammalian genomic landscapes. Annual Review of Genomics and Human Genetics 10: 285–311. PMID: 19630562. doi:10.1146/annurev‐genom‐082908‐150001.

Duret L, Semon M, Piganeau G, Mouchiroud D and Galtier N (2002) Vanishing GC‐rich isochores in mammalian genomes. Genetics 162: 1837–1847.

Enard W, Przeworski M, Fisher SE et al. (2002) Molecular evolution of FOXP2, a gene involved in speech and language. Nature 418: 869–872.

Galtier N (2003) Gene conversion drives GC content evolution in mammalian histones. Trends in Genetics 19: 65–68.

Galtier N and Duret L (2007) Adaptation or biased gene conversion? Extending the null hypothesis of molecular evolution. Trends in Genetics 23: 273–277.

Galtier N, Duret L, Glemin S and Ranwez V (2009) GC‐biased gene conversion promotes the fixation of deleterious amino acid changes in primates. Trends in Genetics:TIG 25: 1–5. PMID: 19027980. doi:10.1016/j.tig.2008.10.011.

Gibbs RA, Rogers J, Katze MG et al. (2007) Evolutionary and biomedical insights from the rhesus macaque genome. Science 316: 222–234.

Gilbert W (1978) Why genes in pieces? Nature 271: 501.

Hellmann I, Ebersberger I, Ptak SE, Paabo S and Przeworski M (2003) A neutral explanation for the correlation of diversity with recombination rates in humans. American Journal of Human Genetics 72: 1527–1535.

Jeffreys AJ and Neumann R (2002) Reciprocal crossover asymmetry and meiotic drive in a human recombination hot spot. Nature Genetics 31: 267–271.

Katzman S, Capra JA, Haussler D and Pollard KS (2011) Ongoing GC‐biased evolution is widespread in the human genome and enriched near recombination hotspots. Genome Biology and Evolution 3: 614–626. PMID: 21697099. doi:10.1093/gbe/evr058.

Katzman S, Kern AD, Pollard KS, Salama SR and Haussler D (2010) GC‐biased evolution near human accelerated regions. PLoS Genetics 6: e1000960. PMID: 20502635. doi:10.1371/journal.pgen.1000960.

Keightley PD, Lercher MJ and Eyre‐Walker A (2005) Evidence for widespread degradation of gene control regions in hominid genomes. PLoS Biology 3: e42.

Kim SY and Pritchard JK (2007) Adaptive evolution of conserved noncoding elements in mammals. PLoS Genetics 3: e147.

King MC and Wilson AC (1975) Evolution at two levels in humans and chimpanzees. Science 188: 107–116.

Kong A, Gudbjartsson DF, Sainz J et al. (2002) A high‐resolution recombination map of the human genome. Nature Genetics 31: 241–247.

Kosiol C, Vinar T, da Fonseca RR et al. (2008) Patterns of positive selection in six Mammalian genomes. PLoS Genetics 4: e1000144. PMID: 18670650. doi:10.1371/journal.pgen.1000144.

Lercher MJ and Hurst LD (2002) Human SNP variability and mutation rate are higher in regions of high recombination. Trends in Genetics 18: 337–340.

Lindblad‐Toh K, Garber M, Zuk O et al. (2011) A high‐resolution map of human evolutionary constraint using 29 mammals. Nature 478: 476–482. PMID: 21993624. doi:10.1038/nature10530.

Mekel‐Bobrov N, Gilbert SL, Evans PD et al. (2005) Ongoing adaptive evolution of ASPM, a brain size determinant in Homo sapiens. Science 309: 1720–1722.

Meunier J and Duret L (2004) Recombination drives the evolution of GC‐content in the human genome. Molecular Biology and Evolution 21: 984–990.

Montoya‐Burgos JI, Boursot P and Galtier N (2003) Recombination explains isochores in mammalian genomes. Trends in Genetics 19: 128–130.

Myers S, Bowden R, Tumian A et al. (2010) Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination. Science 327: 876–879. PMID: 20044541. doi:10.1126/science.1182363.

Nagylaki T (1983) Evolution of a finite population under gene conversion. Proceedings of the National Academy of Sciences of the USA 80: 6278–6281.

Nielsen R, Bustamante C, Clark AG et al. (2005) A scan for positively selected genes in the genomes of humans and chimpanzees. PLoS Biology 3: e170.

Ohno S (1970) Evolution by Gene Duplication. New York: Springer.

Pinker S (1995) The Language Instinct: The New Science of Language and Mind. London: Penguin Books.

Pollard KS, Salama SR, King B et al. (2006a) Forces shaping the fastest evolving regions in the human genome. PLoS Genetics 2: e168.

Pollard KS, Salama SR, Lambert N et al. (2006b) An RNA gene expressed during cortical development evolved rapidly in humans. Nature 443: 167–172.

Prabhakar S, Noonan JP, Paabo S and Rubin EM (2006) Accelerated evolution of conserved noncoding sequences in humans. Science 314: 786.

Prabhakar S, Visel A, Akiyama JA et al. (2008) Human‐specific gain of function in a developmental enhancer. Science 321: 1346–1350. PMID: 18772437. doi:10.1126/science.1159974.

Ratnakumar A, Mousset S, Glemin S et al. (2010) Detecting positive selection within genomes: the problem of biased gene conversion. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 365: 2571–2580. PMID: 20643747. doi:10.1098/rstb.2010.0007.

Sabeti PC, Schaffner SF, Fry B et al. (2006) Positive natural selection in the human lineage. Science 312: 1614–1620.

Siepel A, Bejerano G, Pedersen JS et al. (2005) Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Research 15: 1034–1050.

Silva JC and Kondrashov AS (2002) Patterns in spontaneous mutation revealed by human–baboon sequence comparison. Trends in Genetics 18: 544–547.

Smith JM and Haigh J (1974) The Hitchhiking effect of a favourable gene. Genetical Research 23: 23–35.

Strathern JN, Shafer BK and McGill CB (1995) DNA synthesis errors associated with double‐strand‐break repair. Genetics 140: 965–972.

The ENCODE Project Consortium (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489(7414): 57–74. doi:10.1038/nature11247.

Webster MT and Hurst LD (2012) Direct and indirect consequences of meiotic recombination: implications for genome evolution. Trends in Genetics: TIG 28: 101–109. PMID: 22154475. doi:10.1016/j.tig.2011.11.002.

Webster MT and Smith NG (2004) Fixation biases affecting human SNPs. Trends in Genetics 20: 122–126.

Webster MT, Smith NG and Ellegren H (2003) Compositional evolution of noncoding DNA in the human and chimpanzee genomes. Molecular Biology and Evolution 20: 278–286.

Webster MT, Smith NG, Hultin‐Rosenberg L, Arndt PF and Ellegren H (2005) Male‐driven biased gene conversion governs the evolution of base composition in human alu repeats. Molecular Biology and Evolution 22: 1468–1474.

Webster MT, Smith NG, Lercher MJ and Ellegren H (2004) Gene expression, synteny, and local similarity in human noncoding mutation rates. Molecular Biology and Evolution 21: 1820–1830.

Further Reading

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

Hurst LD (2009) Genetics and the understanding of selection. Nature Reviews Genetics 10: 83–93.

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

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

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