Abstract
The regulation of gene expression is an important determinant of organismal phenotype and evolution. However, the widespread recognition of this fact occurred long after the synthesis of evolution and genetics. Here, we give a brief sketch of thoughts regarding gene regulation in the history of evolution and genetics. We then review the development of genome-wide studies of gene regulatory variation in the context of the location and mode of action of the causative genetic changes. In particular, we review mapping of the genetic basis of expression variation through expression quantitative trait locus studies and measuring the cis/trans component of expression variation in allele-specific expression studies. We conclude by proposing a systematic integration of ideas that combines global mapping studies, cis/trans tests and modern population genetics methodologies, in order to directly estimate the forces acting on regulatory variation within and between species.
References
Boyko A. R., 2008Assessing the evolutionary impact of amino acid mutations in the human genome. PLoS Genet. 4, e1000083. (doi:10.1371/journal.pgen.1000083). Crossref, PubMed, ISI, Google ScholarBray N. J., Buckland P. R., Owen M. J.& O'Donovan M. C. . 2003Cis-acting variation in the expression of a high proportion of genes in human brain. Hum. Genet. 113, 149–153. (doi:10.1007/s00439-003-0956-y). Crossref, PubMed, ISI, Google ScholarBrem R.& Kruglyak L. . 2005The landscape of genetic complexity across 5,700 gene expression traits in yeast. Proc. Natl Acad. Sci. USA 102, 1572–1577. (doi:10.1073/pnas.0408709102). Crossref, PubMed, ISI, Google ScholarBrem R. B., Yvert G., Clinton R.& Kruglyak L. . 2002Genetic dissection of transcriptional regulation in budding yeast. Science 296, 752–755. (doi:10.1126/science.1069516). Crossref, PubMed, ISI, Google ScholarBrem R., Storey J., Whittle J.& Kruglyak L. . 2005Genetic interactions between polymorphisms that affect gene expression in yeast. Nature 436, 701–703. (doi:10.1038/nature03865). Crossref, PubMed, ISI, Google ScholarBustamante C. D., Nielsen R., Sawyer S. A., Olsen K. M., Purugganan M. D.& Hartl D. L. . 2002The cost of inbreeding in Arabidopsis. Nature 416, 531–534. (doi:10.1038/416531a). Crossref, PubMed, ISI, Google ScholarCarroll S. B. . 2008Evo–devo and an expanding evolutionary synthesis: a genetic theory of morphological evolution. Cell 134, 25–36. (doi:10.1016/j.cell.2008.06.030). Crossref, PubMed, ISI, Google ScholarCharlesworth D.& Willis J. H. . 2009The genetics of inbreeding depression. Nat. Rev. Genet. 10, 783–796. (doi:10.1038/nrg2664). Crossref, PubMed, ISI, Google ScholarChurchill G., 2004The collaborative cross, a community resource for the genetic analysis of complex traits. Nat. Genet. 36, 1133–1137. (doi:10.1038/ng1104-1133). Crossref, PubMed, ISI, Google ScholarClark A. G., Hubisz M. J., Bustamante C. D., Williamson S. H.& Nielsen R. . 2005Ascertainment bias in studies of human genome-wide polymorphism. Genome Res. 15, 1496–1502. (doi:10.1101/gr.4107905). Crossref, PubMed, ISI, Google ScholarComfort N. C. . 1999‘The real point is control’: the reception of Barbara McClintock's controlling elements. J. Hist. Biol. 32, 133–162. (doi:10.1023/A:1004468625863). Crossref, PubMed, ISI, Google ScholarComfort N. C. . 2001aFrom controlling elements to transposons: Barbara McClintock and the Nobel prize. Trends Biochem. Sci. 26, 454–457. Crossref, PubMed, ISI, Google ScholarComfort N. C. . 2001bThe tangled field: Barbara McClintock's search for the patterns of genetic control.Cambridge, MA: Harvard University Press. Google ScholarCowles C., Hirschhorn J., Altshuler D.& Lander E. . 2002Detection of regulatory variation in mouse genes. Nat. Genet. 32, 432–437. (doi:10.1038/ng992). Crossref, PubMed, ISI, Google ScholarCrow J. F. . 199890 years ago: the beginning of hybrid maize. Genetics 148, 923–928. Crossref, PubMed, ISI, Google ScholarDamerval C., Maurice A., Josse J. M.& Devienne D. . 1994Quantitative trait loci underlying gene-product variation—a novel perspective for analyzing regulation of genome expression. Genetics 137, 289–301. Crossref, PubMed, ISI, Google ScholarDoss S., Schadt E., Drake T.& Lusis A. . 2005Cis-acting expression quantitative trait loci in mice. Genome Res. 15, 681–691. (doi:10.1101/gr.3216905). Crossref, PubMed, ISI, Google ScholarEmerson J. J., Cardoso-Moreira M., Borevitz J. O.& Long M. . 2008Natural selection shapes genome-wide patterns of copy-number polymorphism in Drosophila melanogaster. Science 320, 1629–1631. (doi:10.1126/science.1158078). Crossref, PubMed, ISI, Google ScholarEmerson J. J., Hsieh L.-C., Sung H.-M., Wang T.-Y., Huang C.-J., Lu H. H., Lu M.-Y., Wu S.-H.& Li W.-H. . 2010Natural selection on cis and trans regulation in yeasts. Genome Res. 20, 826–836. (doi:10.1101/gr.101576.109). Crossref, PubMed, ISI, Google ScholarFay J. C.& Wittkopp P. J. . 2008Evaluating the role of natural selection in the evolution of gene regulation. Heredity 100, 191–199. (doi:10.1038/sj.hdy.6801000). Crossref, PubMed, ISI, Google ScholarGilad Y., Oshlack A.& Rifkin S. A. . 2006Natural selection on gene expression. Trends Genet. 22, 456–461. (doi:10.1016/j.tig.2006.06.002). Crossref, PubMed, ISI, Google ScholarGilad Y., Rifkin S. A.& Pritchard J. K. . 2008Revealing the architecture of gene regulation: the promise of eQTL studies. Trends Genet. 24, 408–415. (doi:10.1016/j.tig.2008.06.001). Crossref, PubMed, ISI, Google ScholarGilbert S. F. . 1987In friendly disagreement—Wilson, Morgan, and the embryological origins of the gene theory. Am. Zool. 27, 797–806. Crossref, Google ScholarGuo M., Yang S., Rupe M., Hu B., Bickel D. R., Arthur L.& Smith O. . 2008Genome-wide allele-specific expression analysis using massively parallel signature sequencing (MPSSTM) reveals cis- and trans-effects on gene expression in maize hybrid meristem tissue. Plant Mol. Biol. 66, 551–563. (doi:10.1007/s11103-008-9290-z). Crossref, PubMed, ISI, Google ScholarHaldane J. . 1932The time of action of genes, and its bearing on some evolutionary problems. Am. Nat. 66, 5–24. Crossref, Google ScholarHarris H. . 1966Enzyme polymorphisms in man. Proc. R. Soc. Lond. B 164, 298–310. (doi:10.1098/rspb.1966.0032). Link, ISI, Google ScholarHoekstra H. E.& Coyne J. A. . 2007The locus of evolution: evo devo and the genetics of adaptation. Evol. Int. J. Organic Evol. 61, 995–1016. (doi:10.1111/j.1558-5646.2007.00105.x). Crossref, PubMed, ISI, Google ScholarHubby J. L.& Lewontin R. C. . 1966A molecular approach to study of genic heterozygosity in natural populations. I. Number of alleles at different loci in Drosophila pseudoobscura. Genetics 54, 577–594. Crossref, PubMed, ISI, Google ScholarJacob F.& Monod J. . 1961Genetic regulatory mechanisms in the synthesis of proteins. J. Mol. Biol. 3, 318–356. Crossref, PubMed, ISI, Google ScholarJeong Y., El-Jaick K., Roessler E., Muenke M.& Epstein D. J. . 2006A functional screen for sonic hedgehog regulatory elements across a 1 Mb interval identifies long-range ventral forebrain enhancers. Development 133, 761–772. (doi:10.1242/dev.02239). Crossref, PubMed, ISI, Google ScholarKeightley P. D.& Eyre-Walker A. . 2007Joint inference of the distribution of fitness effects of deleterious mutations and population demography based on nucleotide polymorphism frequencies. Genetics 177, 2251–2261. (doi:10.1534/genetics.107.080663). Crossref, PubMed, ISI, Google ScholarKing M. C.& Wilson A. C. . 1975Evolution at 2 levels in humans and chimpanzees. Science 188, 107–116. (doi:10.1126/science.1090005). Crossref, PubMed, ISI, Google ScholarKreitman M. E.& Aguade M. . 1986Excess polymorphism at the adh locus in Drosophila melanogaster. Genetics 114, 93–110. Crossref, PubMed, ISI, Google ScholarLandry C. R., Wittkopp P. J., Taubes C. H., Ranz J. M., Clark A. G.& Hartl D. L. . 2005Compensatory cis–trans evolution and the dysregulation of gene expression in interspecific hybrids of Drosophila. Genetics 171, 1813–1822. (doi:10.1534/genetics.105.047449). Crossref, PubMed, ISI, Google ScholarLettice L., 2002Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly. Proc. Natl Acad. Sci. USA 99, 7548–7553. (doi:10.1073/pnas.112212199). Crossref, PubMed, ISI, Google ScholarLewontin R. C. . 199125 years ago in genetics—electrophoresis in the development of evolutionary genetics—milestone or millstone. Genetics 128, 657–662. Crossref, PubMed, ISI, Google ScholarLewontin R. C.& Hubby J. L. . 1966A molecular approach to study of genic heterozygosity in natural populations. II. Amount of variation and degree of heterozygosity in natural populations of Drosophila pseudoobscura. Genetics 54, 595–609. Crossref, PubMed, ISI, Google ScholarLo H., Wang Z., Hu Y., Yang H., Gere S., Buetow K.& Lee M. . 2003Allelic variation in gene expression is common in the human genome. Genome Res. 13, 1855–1862. (doi:10.1101/gr.1006603). PubMed, ISI, Google ScholarLodish H., Berk A., Zipursky L., Matsudaira P., Baltimore D.& Darnell J. . 1999Molecular cell biology. New York, NY: W. H. Freeman. Google ScholarMacdonald S. J.& Long A. D. . 2007Joint estimates of quantitative trait locus effect and frequency using synthetic recombinant populations of Drosophila melanogaster. Genetics 176, 1261–1281. (doi:10.1534/genetics.106.069641). Crossref, PubMed, ISI, Google ScholarMain B. J., Bickel R. D., McIntyre L. M., Graze R. M., Calabrese P. P.& Nuzhdin S. V. . 2009Allele-specific expression assays using Solexa. BMC Genomics 10, (doi:10.1186/1471-2164-10-422). Crossref, ISI, Google ScholarMcClintock B. . 1956Controlling elements and the gene. Cold Spring Harb. Symp. Quant. Biol. 21, 197–216. (doi:10.1101/SQB.1956.021.01.017). Crossref, PubMed, Google ScholarMcClintock B. . 1961Some parallels between gene control systems in maize and in bacteria. Am. Nat. 95, 265–277. Crossref, Google ScholarMcDonald J. H.& Kreitman M. . 1991Adaptive protein evolution at the Adh locus in Drosophila. Nature 351, 652–654. (doi:10.1038/351652a0). Crossref, PubMed, ISI, Google ScholarMorgan T. H. . 1926Genetics and the physiology of development. Am. Nat. 60, 489–515. Crossref, Google ScholarNagalakshmi U., Wang Z., Waern K., Shou C., Raha D., Gerstein M.& Snyder M. . 2008The transcriptional landscape of the yeast genome defined by RNA sequencing. Science 320, 1344–1349. (doi:10.1126/science.1158441). Crossref, PubMed, ISI, Google ScholarNevo E., Beiles A.& Ben-Shlomo R. . 1984The evolutionary significance of genetic diversity: ecological, demographic and life history correlates. Lect. Notes Biomath. 53, 13–213. Crossref, Google ScholarOhno S. . 1970Evolution by gene duplication. Berlin, Germany: Springer-Verlag. Crossref, Google ScholarOhno S. . 1972An argument for genetic simplicity of man and other mammals. J. Hum. Evol. 1, 651–662. (doi:10.1016/0047-2484(72)90011-5). Crossref, ISI, Google ScholarRanz J. M.& Machado C. A. . 2006Uncovering evolutionary patterns of gene expression using microarrays. Trends Ecol. Evol. 21, 29–37. (doi:10.1016/j.tree.2005.09.002). Crossref, PubMed, ISI, Google ScholarRanz J. M., Castillo-Davis C. I., Meiklejohn C. D.& Hartl D. L. . 2003Sex-dependent gene expression and evolution of the Drosophila transcriptome. Science 300, 1742–1745. (doi:10.1126/science.1085881). Crossref, PubMed, ISI, Google ScholarRanz J. M., Namgyal K., Gibson G.& Hartl D. L. . 2004Anomalies in the expression profile of interspecific hybrids of Drosophila melanogaster and Drosophila simulans. Genome Res. 14, 373–379. (doi:10.1101/gr.2019804). Crossref, PubMed, ISI, Google ScholarRieseberg L. H., Widmer A., Arntz A. M.& Burke J. M. . 2003The genetic architecture necessary for transgressive segregation is common in both natural and domesticated populations. Phil. Trans. R. Soc. Lond. B 358, 1141–1147. (doi:10.1098/rstb.2003.1283). Link, ISI, Google ScholarRockman M. V.& Kruglyak L. . 2006Genetics of global gene expression. Nat. Rev. Genet. 7, 862–872. (doi:10.1038/nrg1964). Crossref, PubMed, ISI, Google ScholarRonald J., Akey J., Whittle J., Smith E., Yvert G.& Kruglyak L. . 2005aSimultaneous genotyping, gene-expression measurement, and detection of allele-specific expression with oligonucleotide arrays. Genome Res. 15, 284–291. (doi:10.1101/gr.2850605). Crossref, PubMed, ISI, Google ScholarRonald J., Brem R., Whittle J.& Kruglyak L. . 2005bLocal regulatory variation in Saccharomyces cerevisiae. PLoS Genet. 1, 213–222. (doi:10.1371/journal.pgen.0010025). Crossref, ISI, Google ScholarSapp J. . 1987Beyond the gene: cytoplasmic inheritance and the struggle for authority in genetics.Oxford, UK: Oxford University Press. Google ScholarSawyer S. A.& Hartl D. L. . 1992Population genetics of polymorphism and divergence. Genetics 132, 1161–1176. Crossref, PubMed, ISI, Google ScholarSerre D., 2008Differential allelic expression in the human genome: a robust approach to identify genetic and epigenetic Cis-acting mechanisms regulating gene expression. PLoS Biol. 4, e1000006 (doi:10.1371/journal.pgen.1000006). Google ScholarSpringer N. M.& Stupar R. M. . 2007aAllele-specific expression patterns reveal biases and embryo-specific parent-of-origin effects in hybrid maize. Plant Cell 19, 2391–2402. (doi:10.1105/tpc.107.052258). Crossref, PubMed, ISI, Google ScholarSpringer N. M.& Stupar R. M. . 2007bAllelic variation and heterosis in maize: how do two halves make more than a whole?Genome Res. 17, 264–275. (doi:10.1101/gr.5347007). Crossref, PubMed, ISI, Google ScholarStorey J., Akey J.& Kruglyak L. . 2005Multiple locus linkage analysis of genomewide expression in yeast. PLoS Biol. 3, 1380–1390. (doi:10.1371/journal.pbio.0030267). Crossref, ISI, Google ScholarStupar R. M.& Springer N. M. . 2006Cis-transcriptional variation in maize inbred lines B73 and Mo17 leads to additive expression patterns in the F-1 hybrid. Genetics 173, 2199–2210. (doi:10.1534/genetics.106.060699). Crossref, PubMed, ISI, Google ScholarStupar R. M., Hermanson P. J.& Springer N. M. . 2007Nonadditive expression and parent-of-origin effects identified by microarray and allele-specific expression profiling of maize endosperm. Plant Physiol. 145, 411–425. (doi:10.1104/pp.107.101428). Crossref, PubMed, ISI, Google ScholarStupar R. M., Gardiner J. M., Oldre A. G., Haun W. J., Chandler V. L.& Springer N. M. . 2008Gene expression analyses in maize inbreds and hybrids with varying levels of heterosis. BMC Plant Biol. 8, 33. (doi:10.1186/1471-2229-8-33). Crossref, PubMed, ISI, Google ScholarSung H.-M., 2009Roles of trans and cis variation in yeast intraspecies evolution of gene expression. Mol. Biol. Evol. 26, 2533–2538. (doi:10.1093/molbev/msp171). Crossref, PubMed, ISI, Google ScholarTirosh I., Reikhav S., Levy A. A.& Barkai N. . 2009A yeast hybrid provides insight into the evolution of gene expression regulation. Science 324, 659–662. (doi:10.1126/science.1169766). Crossref, PubMed, ISI, Google ScholarWest M. A. L., Kim K., Kliebenstein D. J., van Leeuwen H., Michelmore R. W., Doerge R. W.& Clair D. A. S. . 2007Global eQTL mapping reveals the complex genetic architecture of transcript-level variation in Arabidopsis. Genetics 175, 1441–1450. (doi:10.1534/genetics.106.064972). Crossref, PubMed, ISI, Google ScholarWilliamson S. H., Hernandez R., Fledel-Alon A., Zhu L., Nielsen R.& Bustamante C. D. . 2005Simultaneous inference of selection and population growth from patterns of variation in the human genome. Proc. Natl Acad. Sci. USA 102, 7882–7887. (doi:10.1073/pnas.0502300102). Crossref, PubMed, ISI, Google ScholarWinzeler E. A., 1998Direct allelic variation scanning of the yeast genome. Science 281, 1194–1197. (doi:10.1126/science.281.5380.1194). Crossref, PubMed, ISI, Google ScholarWittkopp P. J. . 2006Evolution of cis-regulatory sequence and function in Diptera. Heredity 97, 139–147. (doi:10.1038/sj.hdy.6800869). Crossref, PubMed, ISI, Google ScholarWittkopp P., Haerum B. K.& Clark A. G. . 2004Evolutionary changes in cis and trans gene regulation. Nature 430, 85–88. (doi:10.1038/nature02698). Crossref, PubMed, ISI, Google ScholarWittkopp P. J., Haerum B. K.& Clark A. G. . 2008Regulatory changes underlying expression differences within and between Drosophila species. Nat. Genet. 40, 346–350. (doi:10.1038/ng.77). Crossref, PubMed, ISI, Google ScholarWray G. A. . 2007The evolutionary significance of cis-regulatory mutations. Nat. Rev. Genet. 8, 206–216. (doi:10.1038/nrg2063). Crossref, PubMed, ISI, Google ScholarWray G. A., Hahn M. W., Abouheif E., Balhoff J. P., Pizer M., Rockman M. V.& Romano L. A. . 2003The evolution of transcriptional regulation in eukaryotes. Mol. Biol. Evol. 20, 1377–1419. (doi:10.1093/molbev/msg140). Crossref, PubMed, ISI, Google ScholarWright S. . 1934Genetics of abnormal growth in the guinea pig. Cold Spring Harb. Symp. Quant. Biol. 2, 137–147. (doi:10.1101/SQB.1934.002.01.019). Crossref, Google ScholarYan H., Yuan W., Velculescu V., Vogelstein B.& Kinzler K. . 2002Allelic variation in human gene expression. Science 297, 1143. (doi:10.1126/science.1072545). Crossref, PubMed, ISI, Google ScholarYvert G., Brem R., Whittle J., Akey J., Foss E., Smith E., Mackelprang R.& Kruglyak L. . 2003Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors. Nat. Genet. 35, 57–64. (doi:10.1038/ng1222). Crossref, PubMed, ISI, Google ScholarZhang X.& Borevitz J. O. . 2009Global analysis of allele-specific expression in Arabidopsis thaliana. Genetics 182, 943–954. (doi:10.1534/genetics.109.103499). Crossref, PubMed, ISI, Google Scholar


