Multiple functional variants in cis modulate PDYN expression

Courtney C. Babbitt, Jesse S. Silverman, Ralph Haygood, Jennifer M. Reininga, Matthew Rockman, Gregory A. Wray

Research output: Contribution to journalArticle

Abstract

Understanding genetic variation and its functional consequences within cis-regulatory regions remains an important challenge in human genetics and evolution. Here, we present a fine-scale functional analysis of segregating variation within the cis-regulatory region of prodynorphin, a gene that encodes an endogenous opioid precursor with roles in cognition and disease. In order to characterize the functional consequences of segregating variation in cis in a region under balancing selection in different human populations, we examined associations between specific polymorphisms and gene expression in vivo and in vitro. We identified five polymorphisms within the 5′ flanking region that affect transcript abundance: a 68-bp repeat recognized in prior studies, as well as two microsatellites and two single nucleotide polymorphisms not previously implicated as functional variants. The impact of these variants on transcription differs by brain region, sex, and cell type, implying interactions between cis genotype and the differentiated state of cells. The effects of individual variants on expression level are not additive in some combinations, implying epistatic interactions between nearby variants. These data reveal an unexpectedly complex relationship between segregating genetic variation and its expression-trait consequences and highlights the importance of close functional scrutiny of natural genetic variation within even relatively well-studied cis-regulatory regions.

Original languageEnglish (US)
Pages (from-to)465-479
Number of pages15
JournalMolecular Biology and Evolution
Volume27
Issue number2
DOIs
StatePublished - Feb 2010

Fingerprint

Nucleic Acid Regulatory Sequences
genetic variation
polymorphism
genetic polymorphism
Molecular Evolution
5' Flanking Region
cognition
Medical Genetics
narcotics
Cell Communication
human population
Microsatellite Repeats
Cognition
Opioid Analgesics
single nucleotide polymorphism
gene expression
Single Nucleotide Polymorphism
brain
genotype
transcription (genetics)

Keywords

  • Cis-regulation
  • Functional variation
  • Human gene expression
  • Polymorphism

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics

Cite this

Babbitt, C. C., Silverman, J. S., Haygood, R., Reininga, J. M., Rockman, M., & Wray, G. A. (2010). Multiple functional variants in cis modulate PDYN expression. Molecular Biology and Evolution, 27(2), 465-479. https://doi.org/10.1093/molbev/msp276

Multiple functional variants in cis modulate PDYN expression. / Babbitt, Courtney C.; Silverman, Jesse S.; Haygood, Ralph; Reininga, Jennifer M.; Rockman, Matthew; Wray, Gregory A.

In: Molecular Biology and Evolution, Vol. 27, No. 2, 02.2010, p. 465-479.

Research output: Contribution to journalArticle

Babbitt, CC, Silverman, JS, Haygood, R, Reininga, JM, Rockman, M & Wray, GA 2010, 'Multiple functional variants in cis modulate PDYN expression', Molecular Biology and Evolution, vol. 27, no. 2, pp. 465-479. https://doi.org/10.1093/molbev/msp276
Babbitt, Courtney C. ; Silverman, Jesse S. ; Haygood, Ralph ; Reininga, Jennifer M. ; Rockman, Matthew ; Wray, Gregory A. / Multiple functional variants in cis modulate PDYN expression. In: Molecular Biology and Evolution. 2010 ; Vol. 27, No. 2. pp. 465-479.
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