Molecular Biology and Evolution 19:1991-2004 (2002)
© 2002 Society for Molecular Biology and Evolution
Abundant Raw Material for Cis-Regulatory Evolution in Humans
Department of Biology, Duke University
Changes in gene expression and regulation—due in particular to the evolution of cis-regulatory DNA sequences—may underlie many evolutionary changes in phenotypes, yet little is known about the distribution of such variation in populations. We present in this study the first survey of experimentally validated functional cis-regulatory polymorphism. These data are derived from more than 140 polymorphisms involved in the regulation of 107 genes in Homo sapiens, the eukaryote species with the most available data. We find that functional cis-regulatory variation is widespread in the human genome and that the consequent variation in gene expression is twofold or greater for 63% of the genes surveyed. Transcription factor-DNA interactions are highly polymorphic, and regulatory interactions have been gained and lost within human populations. On average, humans are heterozygous at more functional cis-regulatory sites (>16,000) than at amino acid positions (<13,000), in part because of an overrepresentation among the former in multiallelic tandem repeat variation, especially (AC)n dinucleotide microsatellites. The role of microsatellites in gene expression variation may provide a larger store of heritable phenotypic variation, and a more rapid mutational input of such variation, than has been realized. Finally, we outline the distinctive consequences of cis-regulatory variation for the genotype-phenotype relationship, including ubiquitous epistasis and genotype-by-environment interactions, as well as underappreciated modes of pleiotropy and overdominance. Ordinary small-scale mutations contribute to pervasive variation in transcription rates and consequently to patterns of human phenotypic variation.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. D. Vinces, M. Legendre, M. Caldara, M. Hagihara, and K. J. Verstrepen Unstable Tandem Repeats in Promoters Confer Transcriptional Evolvability Science, May 29, 2009; 324(5931): 1213 - 1216. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. K. de Vooght, R. van Wijk, and W. W. van Solinge Management of Gene Promoter Mutations in Molecular Diagnostics Clin. Chem., April 1, 2009; 55(4): 698 - 708. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Torkamani and N. J. Schork Predicting functional regulatory polymorphisms Bioinformatics, August 15, 2008; 24(16): 1787 - 1792. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Feng, A. Vetro, E. Kiss, K. Kapornai, G. Daroczi, L. Mayer, Z. Tamas, I. Baji, J. Gadoros, N. King, et al. Association of the Neurotrophic Tyrosine Kinase Receptor 3 (NTRK3) Gene and Childhood-Onset Mood Disorders Am J Psychiatry, May 1, 2008; 165(5): 610 - 616. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Hile and K. A. Eckert DNA polymerase kappa produces interrupted mutations and displays polar pausing within mononucleotide microsatellite sequences Nucleic Acids Res., February 2, 2008; 36(2): 688 - 696. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Genissel, L. M. McIntyre, M. L. Wayne, and S. V. Nuzhdin Cis and Trans Regulatory Effects Contribute to Natural Variation in Transcriptome of Drosophila melanogaster Mol. Biol. Evol., January 1, 2008; 25(1): 101 - 110. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. K. Bayele, C. Peyssonnaux, A. Giatromanolaki, W. W. Arrais-Silva, H. S. Mohamed, H. Collins, S. Giorgio, M. Koukourakis, R. S. Johnson, J. M. Blackwell, et al. HIF-1 regulates heritable variation and allele expression phenotypes of the macrophage immune response gene SLC11A1 from a Z-DNA forming microsatellite Blood, October 15, 2007; 110(8): 3039 - 3048. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Wang, H.-M. Sung, T.-Y. Wang, C.-J. Huang, P. Yang, T. Chang, Y.-C. Wang, D.-L. Tseng, J.-P. Wu, T.-C. Lee, et al. Expression evolution in yeast genes of single-input modules is mainly due to changes in trans-acting factors Genome Res., August 1, 2007; 17(8): 1161 - 1169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Nei The new mutation theory of phenotypic evolution PNAS, July 24, 2007; 104(30): 12235 - 12242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tsuritani, T. Irie, R. Yamashita, Y. Sakakibara, H. Wakaguri, A. Kanai, J. Mizushima-Sugano, S. Sugano, K. Nakai, and Y. Suzuki Distinct class of putative "non-conserved" promoters in humans: Comparative studies of alternative promoters of human and mouse genes Genome Res., July 1, 2007; 17(7): 1005 - 1014. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Sakakibara, T. Irie, Y. Suzuki, R. Yamashita, H. Wakaguri, A. Kanai, J. Chiba, T. Takagi, J. Mizushima-Sugano, S.-i. Hashimoto, et al. Intrinsic Promoter Activities of Primary DNA Sequences in the Human Genome DNA Res, May 23, 2007; (2007) dsm006v1. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Prud'homme, N. Gompel, and S. B. Carroll Colloquium Papers: Emerging principles of regulatory evolution PNAS, May 15, 2007; 104(suppl_1): 8605 - 8612. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Lynch Colloquium Papers: The frailty of adaptive hypotheses for the origins of organismal complexity PNAS, May 15, 2007; 104(suppl_1): 8597 - 8604. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Wilkins, L. Southam, A. J. Price, Z. Mustafa, A. Carr, and J. Loughlin Extreme context specificity in differential allelic expression Hum. Mol. Genet., March 1, 2007; 16(5): 537 - 546. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Seoighe, V. Nembaware, and K. Scheffler Maximum likelihood inference of imprinting and allele-specific expression from EST data Bioinformatics, December 15, 2006; 22(24): 3032 - 3039. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. W. Hay and K. Docherty Comparative Analysis of Insulin Gene Promoters: Implications for Diabetes Research Diabetes, December 1, 2006; 55(12): 3201 - 3213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Loisel, M. V. Rockman, G. A. Wray, J. Altmann, and S. C. Alberts Ancient polymorphism and functional variation in the primate MHC-DQA1 5' cis-regulatory region PNAS, October 31, 2006; 103(44): 16331 - 16336. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Pinsonneault, A. C. Papp, and W. Sadee Allelic mRNA expression of X-linked monoamine oxidase a (MAOA) in human brain: dissection of epigenetic and genetic factors Hum. Mol. Genet., September 1, 2006; 15(17): 2636 - 2649. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. A. Wray The evolution of embryonic gene expression in sea urchins Integr. Comp. Biol., June 1, 2006; 46(3): 233 - 242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. W. Hahn Accurate Inference and Estimation in Population Genomics Mol. Biol. Evol., May 1, 2006; 23(5): 911 - 918. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Pastinen, B. Ge, and T. J. Hudson Influence of human genome polymorphism on gene expression. Hum. Mol. Genet., April 15, 2006; 15(suppl_1): R9 - R16. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J Stover Influence of human genetic variation on nutritional requirements Am. J. Clinical Nutrition, February 1, 2006; 83(2): 436S - 442S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G. Woo, L. M. Dolan, R. Deka, R. D. Kaushal, Y. Shen, P. Pal, S. R. Daniels, and L. J. Martin Interactions Between Noncontiguous Haplotypes in the Adiponectin Gene ACDC Are Associated With Plasma Adiponectin Diabetes, February 1, 2006; 55(2): 523 - 529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Anderle, C. U. Nielsen, J. Pinsonneault, P. L. Krog, B. Brodin, and W. Sadee Genetic Variants of the Human Dipeptide Transporter PEPT1 J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 636 - 646. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Lynch The Origins of Eukaryotic Gene Structure Mol. Biol. Evol., February 1, 2006; 23(2): 450 - 468. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. R. Landry, P. J. Wittkopp, C. H. Taubes, J. M. Ranz, A. G. Clark, and D. L. Hartl Compensatory cis-trans Evolution and the Dysregulation of Gene Expression in Interspecific Hybrids of Drosophila Genetics, December 1, 2005; 171(4): 1813 - 1822. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Ge, S. Gurd, T. Gaudin, C. Dore, P. Lepage, E. Harmsen, T. J. Hudson, and T. Pastinen Survey of allelic expression using EST mining Genome Res., November 1, 2005; 15(11): 1584 - 1591. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Sadee and Z. Dai Pharmacogenetics/genomics and personalized medicine Hum. Mol. Genet., October 15, 2005; 14(suppl_2): R207 - R214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Belanger, P. Beaulieu, C. Moreau, D. Labuda, T. J. Hudson, and D. Sinnett Functional promoter SNPs in cell cycle checkpoint genes Hum. Mol. Genet., September 15, 2005; 14(18): 2641 - 2648. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kirst, C. J. Basten, A. A. Myburg, Z.-B. Zeng, and R. R. Sederoff Genetic Architecture of Transcript-Level Variation in Differentiating Xylem of a Eucalyptus Hybrid Genetics, April 1, 2005; 169(4): 2295 - 2303. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Hinojos, E. Boerwinkle, M. Fornage, and P. A. Doris Combined Genealogical, Mapping, and Expression Approaches to Identify Spontaneously Hypertensive Rat Hypertension Candidate Genes Hypertension, April 1, 2005; 45(4): 698 - 704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. N. Lerman and M. E. Feder Naturally Occurring Transposable Elements Disrupt hsp70 Promoter Function in Drosophila melanogaster Mol. Biol. Evol., March 1, 2005; 22(3): 776 - 783. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Pastinen and T. J. Hudson Cis-Acting Regulatory Variation in the Human Genome Science, October 22, 2004; 306(5696): 647 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. R. Buckland Allele-specific gene expression differences in humans Hum. Mol. Genet., October 1, 2004; 13(suppl_2): R255 - R260. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Suzuki, R. Yamashita, M. Shirota, Y. Sakakibara, J. Chiba, J. Mizushima-Sugano, K. Nakai, and S. Sugano Sequence Comparison of Human and Mouse Genes Reveals a Homologous Block Structure in the Promoter Regions Genome Res., September 1, 2004; 14(9): 1711 - 1718. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Guo, M. A. Rupe, C. Zinselmeier, J. Habben, B. A. Bowen, and O. S. Smith Allelic Variation of Gene Expression in Maize Hybrids PLANT CELL, July 1, 2004; 16(7): 1707 - 1716. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. W. Hahn, M. V. Rockman, N. Soranzo, D. B. Goldstein, and G. A. Wray Population Genetic and Phylogenetic Evidence for Positive Selection on Regulatory Mutations at the Factor VII Locus in Humans Genetics, June 1, 2004; 167(2): 867 - 877. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. MacArthur and J. F. Y. Brookfield Expected Rates and Modes of Evolution of Enhancer Sequences Mol. Biol. Evol., June 1, 2004; 21(6): 1064 - 1073. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H. Kohn, S. Fang, and C.-I Wu Inference of Positive and Negative Selection on the 5' Regulatory Regions of Drosophila Genes Mol. Biol. Evol., February 1, 2004; 21(2): 374 - 383. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Pastinen, R. Sladek, S. Gurd, A.'a Sammak, B. Ge, P. Lepage, K. Lavergne, A. Villeneuve, T. Gaudin, H. Brandstrom, et al. A survey of genetic and epigenetic variation affecting human gene expression Physiol Genomics, January 15, 2004; 16(2): 184 - 193. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Yang, R. Lusk, and W.-H. Li Organismal complexity, protein complexity, and gene duplicability PNAS, December 23, 2003; 100(26): 15661 - 15665. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. A. Romano and G. A. Wray Conservation of Endo16 expression in sea urchins despite evolutionary divergence in both cis and trans-acting components of transcriptional regulation Development, September 1, 2003; 130(17): 4187 - 4199. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. WINDEMUTH, M. KUMAR, K. NANDABALAN, B. KOSHY, C. XU, M. PUNGLIYA, and R. JUDSON Genome-wide Association of Haplotype Markers to Gene Expression Levels Cold Spring Harb Symp Quant Biol, January 1, 2003; 68(0): 89 - 108. [Abstract] [PDF]
|
|