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Abundant raw material for cis-regulatory evolution in humans.

Publication ,  Journal Article
Rockman, MV; Wray, GA
Published in: Molecular biology and evolution
November 2002

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.

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Published In

Molecular biology and evolution

DOI

EISSN

1537-1719

ISSN

0737-4038

Publication Date

November 2002

Volume

19

Issue

11

Start / End Page

1991 / 2004

Related Subject Headings

  • Retroelements
  • Response Elements
  • Polymorphism, Genetic
  • Phenotype
  • Microsatellite Repeats
  • Humans
  • Genotype
  • Genomics
  • Genome, Human
  • Genetics, Population
 

Citation

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Rockman, M. V., & Wray, G. A. (2002). Abundant raw material for cis-regulatory evolution in humans. Molecular Biology and Evolution, 19(11), 1991–2004. https://doi.org/10.1093/oxfordjournals.molbev.a004023
Rockman, Matthew V., and Gregory A. Wray. “Abundant raw material for cis-regulatory evolution in humans.Molecular Biology and Evolution 19, no. 11 (November 2002): 1991–2004. https://doi.org/10.1093/oxfordjournals.molbev.a004023.
Rockman MV, Wray GA. Abundant raw material for cis-regulatory evolution in humans. Molecular biology and evolution. 2002 Nov;19(11):1991–2004.
Rockman, Matthew V., and Gregory A. Wray. “Abundant raw material for cis-regulatory evolution in humans.Molecular Biology and Evolution, vol. 19, no. 11, Nov. 2002, pp. 1991–2004. Epmc, doi:10.1093/oxfordjournals.molbev.a004023.
Rockman MV, Wray GA. Abundant raw material for cis-regulatory evolution in humans. Molecular biology and evolution. 2002 Nov;19(11):1991–2004.
Journal cover image

Published In

Molecular biology and evolution

DOI

EISSN

1537-1719

ISSN

0737-4038

Publication Date

November 2002

Volume

19

Issue

11

Start / End Page

1991 / 2004

Related Subject Headings

  • Retroelements
  • Response Elements
  • Polymorphism, Genetic
  • Phenotype
  • Microsatellite Repeats
  • Humans
  • Genotype
  • Genomics
  • Genome, Human
  • Genetics, Population