Evolution of Human Gene Expression Control


The evolutionary history of our species is associated with the emergence of numerous phenotypic traits thought to be unique to humans. Comparative analysis of gene expression between human and nonhuman primates has revealed thousands of genes differentially expressed across multiple tissues. Comparative and functional genomic studies have implicated variation in cis‐regulatory regions, or enhancer elements, as a major component of species‐specific expression differences. Additionally, adaptive evolution between modern human populations has also been attributed to variation in cis‐regulatory regions of the genome. Despite these advances, the genetic basis of most derived human traits, population‐specific differences and heritable variation in gene expression remains unidentified. Gene regulation is known to proceed through the combinatorial interaction of multiple loci, acting cooperatively or redundantly, to regulate contextual gene expression in different tissues or at different times during development. The role of epistasis, the genetic interaction between loci, may, therefore, have a significant influence on the evolution of regulatory elements underlying trait difference between primate species and human populations.

Key Concepts:

  • Numerous highly conserved noncoding elements are rapidly evolving in humans and many function as tissue‐specific developmental enhancers.

  • Variation in phenotypic traits, including disease susceptibility, has been mapped to noncoding, cis‐regulatory loci.

  • Comparison of multiple primate genomes has enabled the identification of loci under both adaptive evolution (positive selection) and evolutionary constraint (negative selection).

  • Natural selection within protein‐coding and noncoding regions of genome is not uniform but more preferentially targets certain biological categories of genes.

  • The role of epistasis in the evolution of human gene expression control is unknown for most traits but may be significant.

Keywords: cis‐regulation; functional genomics; human evolution; gene expression; polymorphism; epistasis; human populations; enhancer; natural selection


Barreiro LB, Laval G, Quach H, Patin E and Quintana‐Murci L (2008) Natural selection has driven population differentiation in modern humans. Nature Genetics 40: 340–345.

Bird CP, Stranger BE, Liu M et al. (2007) Fast‐evolving noncoding sequences in the human genome. Genome Biology 8: R118.

Blekhman R, Marioni JC, Zumbo P, Stephens M and Gilad Y (2010) Sex‐specific and lineage‐specific alternative splicing in primates. Genome Research 20: 180–189.

Degner JF, Pai AA, Pique‐Regi R et al. (2012) DNase I sensitivity QTLs are a major determinant of human expression variation. Nature 482: 390–394.

Enattah NS, Sahi T, Savilahti E et al. (2002) Identification of a variant associated with adult‐type hypolactasia. Nature Genetics 30: 233–237.

ENCODE Project Consortium, Dunham I, Kundaje A et al. (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489: 57–74.

Frankel N, Erezyilmaz DF, McGregor AP et al. (2011) Morphological evolution caused by many subtle‐effect substitutions in regulatory DNA. Nature 474: 598–603.

Grundberg E, Small KS, Hedman AK et al. (2012) Mapping cis‐ and trans‐regulatory effects across multiple tissues in twins. Nature Genetics 44: 1084–1089.

Hamblin MT, Thompson EE and Di Rienzo A (2002) Complex signatures of natural selection at the Duffy blood group locus. American Journal of Human Genetics 70: 369–383.

Haygood R, Babbitt CC, Fedrigo O and Wray GA (2010) Contrasts between adaptive coding and noncoding changes during human evolution. Proceedings of the National Academy of Sciences of the USA 107: 7853–7857.

Haygood R, Fedrigo O, Hanson B, Yokoyama K‐D and Wray GA (2007) Promoter regions of many neural‐ and nutrition‐related genes have experienced positive selection during human evolution. Nature Genetics 39: 1140–1144.

Hong J‐W, Hendrix DA and Levine MS (2008) Shadow enhancers as a source of evolutionary novelty. Science 321: 1314.

Hu HY, Guo S, Xi J et al. (2011) MicroRNA expression and regulation in human, chimpanzee, and macaque brains. PLoS Genetics 7: e1002327.

Hu HY, He L, Fominykh K et al. (2012) Evolution of the human‐specific microRNA miR‐941. Nature Communications 3: 1145.

Huang W, Richards S, Carbone MA et al. (2012) Epistasis dominates the genetic architecture of Drosophila quantitative traits. Proceedings of the National Academy of Sciences of the USA 109: 15553–15559.

Johnson MB, Kawasawa YI, Mason CE et al. (2009) Functional and evolutionary insights into human brain development through global transcriptome analysis. Neuron 62: 494–509.

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

Kudaravalli S, Veyrieras JB, Stranger BE, Dermitzakis ET and Pritchard JK (2008) Gene expression levels are a target of recent natural selection in the human genome. Molecular Biology and Evolution 26: 649–658.

Lambert N, Lambot M‐A, Bilheu A et al. (2011) Genes expressed in specific areas of the human fetal cerebral cortex display distinct patterns of evolution. PLoS One 6: e17753.

Lettice LA, Heaney SJH, Purdie LA et al. (2003) A long‐range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Human Molecular Genetics 12: 1725–1735.

Lin L, Shen S, Jiang P et al. (2010) Evolution of alternative splicing in primate brain transcriptomes. Human Molecular Genetics 19: 2958–2973.

Lindblad‐Toh K, Garber M, Zuk O et al. (2011) A high‐resolution map of human evolutionary constraint using 29 mammals. Nature 478(7370): 476–482.

Maurano MT, Humbert R, Rynes E et al. (2012) Systematic localization of common disease‐associated variation in regulatory DNA. Science 337: 1190–1195.

McLean CY, Reno PL, Pollen AA et al. (2011) Human‐specific loss of regulatory DNA and the evolution of human‐specific traits. Nature 471: 216–219.

Montavon T, Soshnikova N, Mascrez B et al. (2011) A regulatory archipelago controls Hox genes transcription in digits. Cell 147: 1132–1145.

Neph S, Vierstra J, Stergachis AB et al. (2012) An expansive human regulatory lexicon encoded in transcription factor footprints. Nature 489: 83–90.

Pennacchio LA, Ahituv N, Moses AM et al. (2006) In vivo enhancer analysis of human conserved non‐coding sequences. Nature 444: 499–502.

Perry GH, Dominy NJ, Claw KG et al. (2007) Diet and the evolution of human amylase gene copy number variation. Nature Genetics 39: 1256–1260.

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

Prabhakar S (2006) Close sequence comparisons are sufficient to identify human cis‐regulatory elements. Genome Research 16: 855–863.

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

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

Sanyal A, Lajoie BR, Jain G and Dekker J (2012) The long‐range interaction landscape of gene promoters. Nature 489: 109–113.

Shibata Y, Sheffield NC, Fedrigo O et al. (2012) Extensive evolutionary changes in regulatory element activity during human origins are associated with altered gene expression and positive selection. PLoS Genetics 8: e1002789.

Somel M, Liu X, Tang L et al. (2011) MicroRNA‐driven developmental remodeling in the brain distinguishes humans from other primates. PLoS Biology 9: e1001214.

Sumiyama K and Saitou N (2011) Loss‐of‐function mutation in a repressor module of human‐specifically activated enhancer HACNS1. Molecular Biology and Evolution 28: 3005–3007.

Tishkoff SA, Reed FA, Ranciaro A et al. (2007) Convergent adaptation of human lactase persistence in Africa and Europe. Nature Genetics 39: 31–40.

Tournamille C, Blancher A, Le Van Kim C et al. (2004) Sequence, evolution and ligand binding properties of mammalian Duffy antigen/receptor for chemokines. Immunogenetics 55: 682–694.

Tung J, Primus A, Bouley AJ et al. (2009) Evolution of a malaria resistance gene in wild primates. Nature 460: 388–391.

Visel A, Blow MJ, Li Z et al. (2009) ChIP‐seq accurately predicts tissue‐specific activity of enhancers. Nature 457: 854–858.

Wang J, Cao X, Zhang Y and Su B (2012) Genome‐wide DNA methylation analyses in the brain reveal four differentially methylated regions between humans and non‐human primates. BMC Evolutionary Biology 12: 144.

Zeng J, Konopka G, Hunt BG et al. (2012) Divergent whole‐genome methylation maps of human and chimpanzee brains reveal epigenetic basis of human regulatory evolution. American Journal of Human Genetics 91: 455–465.

Zimmerman PA, Woolley I, Masinde GL et al. (1999) Emergence of FY*A(null) in a Plasmodium vivax‐endemic region of Papua New Guinea. Proceedings of the National Academy of Sciences of the USA 96: 13973–13977.

Further Reading

Bulger M and Groudine M (2011) Functional and mechanistic diversity of distal transcription enhancers. Cell 144: 327–339.

O'Bleness M, Searles VB, Varki A, Gagneux P and Sikela JM (2012) Evolution of genetic and genomic features unique to the human lineage. Nature Reviews Genetics 13: 853–866.

Wittkopp PJ and Kalay G (2012) Cis‐regulatory elements: molecular mechanisms and evolutionary processes underlying divergence. Nature Reviews Genetics 13: 59–69.

Wray GA (2007) The evolutionary significance of cis‐regulatory mutations. Nature Reviews Genetics 8: 206–216.

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Boyd, J Lomax, and Wray, Gregory A(Feb 2014) Evolution of Human Gene Expression Control. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020769.pub2]