Abundant raw material for cis-regulatory evolution in humans

Matthew V. Rockman, Gregory A. Wray

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1991-2004
Number of pages14
JournalMolecular Biology and Evolution
Volume19
Issue number11
StatePublished - Nov 2002

Fingerprint

Gene expression
gene expression
raw materials
Raw materials
phenotypic variation
phenotype
Genes
polymorphism
genotype
Polymorphism
genetic polymorphism
microsatellite repeats
Microsatellite Repeats
pleiotropy
epistasis
DNA
overdominance
tandem repeat sequences
gene
Genotype

Keywords

  • Evolution of development
  • Gene network
  • Gene regulation
  • Polymorphism
  • Promoter
  • Transcription

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Ecology, Evolution, Behavior and Systematics
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Genetics
  • Molecular Biology
  • Genetics(clinical)

Cite this

Abundant raw material for cis-regulatory evolution in humans. / Rockman, Matthew V.; Wray, Gregory A.

In: Molecular Biology and Evolution, Vol. 19, No. 11, 11.2002, p. 1991-2004.

Research output: Contribution to journalArticle

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