title: Variation in heterozygosity predicts variation in human substitution rates between populations, individuals and genomic regions.
abstract: The "heterozygote instability" (HI) hypothesis suggests that gene conversion events focused on heterozygous sites during meiosis locally increase the mutation rate, but this hypothesis remains largely untested. As humans left Africa they lost variability, which, if HI operates, should have reduced the mutation rate in non-Africans. Relative substitution rates were quantified in diverse humans using aligned whole genome sequences from the 1,000 genomes project. Substitution rate is consistently greater in Africans than in non-Africans, but only in diploid regions of the genome, consistent with a role for heterozygosity. Analysing the same data partitioned into a series of non-overlapping 2 Mb windows reveals a strong, non-linear correlation between the amount of heterozygosity lost "out of Africa" and the difference in substitution rate between Africans and non-Africans. Putative recent mutations, derived variants that occur only once among the 80 human chromosomes sampled, occur preferentially at the centre of 2 Kb windows that have elevated heterozygosity compared both with the same region in a closely related population and with an immediately adjacent region in the same population. More than half of all substitutions appear attributable to variation in heterozygosity. This observation provides strong support for HI with implications for many branches of evolutionary biology.
authors: Department of Zoology, Cambridge University, Cambridge, Cambridgeshire, United Kingdom. w.amos@zoo.cam.ac.uk
authors: William
authors: W
authors: Amos
mesh_terms: D000818:Animals; D019295:Computational Biology / Q000379:methods; D030561:Databases, Nucleic Acid; D019143:Evolution, Molecular; D005785:Gene Conversion; D014644:Genetic Variation; D005828:Genetics, Population; D015894:Genome, Human; D023281:Genomics; D006579:Heterozygote; D006801:Humans; D059645:Mutation Rate
references: Bioessays. 2010 Jan;32(1):82-90
references: 19967709
references: Curr Biol. 2011 Jun 21;21(12):1051-4
references: 21636278
references: Curr Biol. 2005 Mar 8;15(5):R159-60
references: 15753023
references: Nature. 2007 Jul 19;448(7151):346-8
references: 17637668
references: Bioessays. 2009 Sep;31(9):912-20
references: 19644920
references: Philos Trans R Soc Lond B Biol Sci. 2011 Sep 12;366(1577):2503-13
references: 21807731
references: Mutat Res. 2003 Sep;544(1):65-85
references: 12888108
references: J Mol Evol. 2011 Feb;72(2):215-21
references: 21161201
references: BMC Genet. 2008 Nov 14;9:72
references: 19014581
references: Crit Rev Biochem Mol Biol. 2007 Jul-Aug;42(4):247-58
references: 17687667
references: Mol Gen Genet. 1996 Jul 19;251(5):503-8
references: 8709955
references: Science. 2010 May 7;328(5979):710-722
references: 20448178
references: Genetics. 1995 Sep;141(1):75-86
references: 8536992
references: Proc Biol Sci. 2010 Jan 7;277(1678):131-7
references: 19812086
references: Nat Genet. 1997 Jan;15(1):99-102
references: 8988178
references: Proc Biol Sci. 2010 May 7;277(1686):1443-9
references: 20071383
references: Trends Genet. 2009 Dec;25(12):523-7
references: 19853958
references: Nature. 2008 Sep 4;455(7209):105-8
references: 18641631
references: Nat Genet. 2011 Jun 12;43(7):712-4
references: 21666693
references: Nature. 2010 Oct 28;467(7319):1061-73
references: 20981092
references: Proc Biol Sci. 2011 May 22;278(1711):1587-94
references: 21068042
references: Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1370-5
references: 16432233
references: J Evol Biol. 2008 Mar;21(2):541-50
references: 18205779
references: Cell. 1995 Jul 28;82(2):309-19
references: 7628019
references: Am J Hum Genet. 2006 Aug;79(2):230-7
references: 16826514
references: Proc Natl Acad Sci U S A. 2011 Jul 19;108(29):11983-8
references: 21730125
references: Science. 2010 Jan 1;327(5961):78-81
references: 19892942
references: Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12849-54
references: 16118275
references: Annu Rev Genomics Hum Genet. 2000;1:361-85
references: 11701634
references: Am J Phys Anthropol. 2005 Oct;128(2):415-23
references: 15795887
references: Cell. 1983 May;33(1):25-35
references: 6380756
references: Genetics. 1993 Oct;135(2):599-607
references: 8244016
references: Genetics. 2007 Nov;177(3):1499-507
references: 17947436
references: Nature. 2007 Feb 22;445(7130):915-918
references: 17287725