Positive Selection and the Evolution of Prodynorphin


Positive natural selection has shaped the cis‐regulation of human prodynorphin, the precursor molecule for a suite of opioid neuropeptides with roles in perception. Population genetic data suggest that after the split between the human and chimpanzee lineages, selection drove multiple substitutions in a regulatory element upstream of prodynorphin. The substitutions fall within a cis‐regulatory tandem repeat polymorphism segregating in contemporary populations. The repeat polymorphism is also seen by selection, and differing repeat allele frequencies in different parts of the globe reflect the varying pattern of positive selection.

Keywords: prodynorphin; cis‐regulation; positive selection; evolutionary genetics; opioids

Figure 1.

Substitutions in the 68‐bp element. Arrows indicate five differences fixed on the human lineage. The asterisk indicates a site that varies among human repeats. Below, a schematic of the PDYNcis‐regulatory region showing the position of the element and the noncoding first exon with respect to the start of transcription. Reproduced from Rockman et al..

Figure 2.

Allele frequency differentiation at PDYN. (a) Genetic differentiation between European‐ and Chinese‐Americans, measured as a 15‐SNP running FST average, for the entire p‐arm of chromosome 20. PDYN falls under a large FST peak (shaded), high above the arm average (red line). (b) A finer‐scale sliding window analysis shows that the region of elevated FST includes only two genes, PDYN and STK35, shown according to their RefSeq annotations. (c) FST as a function of expected global heterozygosity. Red triangles represent the 52 SNPs in the Perlegen dataset in the 170 kb interval bounded by the 3′ ends of PDYN and STK35. The contours define the genomewide density of FST conditioned on heterozygosity; for each heterozygosity, the lines represent the FST of SNPs in the specified FST percentile. Note that the median FST is below 0.06 for all heterozygosities. Reproduced from Rockman et al..

Figure 3.

Reduced diversity at a PDYN‐linked microsatellite. (a) The allele frequency distribution of the PDYN microsatellite for six populations. The most common allele has 18 CA repeats in each population except Papua New Guinea, where the 22‐repeat allele is most common; the overall range is 13 to 27 repeats. The distributions show a reduction in allelic variation outside of the Cameroon population. (b) The empirical probability density of lnRV, a measure of microsatellite repeat‐number variance, for a panel of genomically distributed microsatellites is plotted for each population, using panel A as the colour key. The distributions are based on 193 microsatellite loci for Ethiopia and 377 loci for the other populations. For clarity, a single negative outlier from the New Guinea population has been omitted from the figure. The arrows indicate lnRV of the PDYN microsatellite for each population, in the left tails of the distributions, indicating a locus‐specific reduction in repeat‐number variance. (c) The empirical probability density for lnRH, a measure of microsatellite heterozygosity. Again, the PDYN microsatellite exhibits significantly negative lnRH values, indicating a locus‐specific reduction in heterozygosity at PDYN in the non‐West African populations. Reproduced from Rockman et al..



Carrion AM, Link WA, Ledo F, Mellstrom B and Naranjo JR (1999) DREAM is a CA2+‐regulated transcriptional repressor. Nature 398: 80–84.

Cavalleri GL, Lynch JM, Depondt C et al. (2005) Failure to replicate previously reported genetic associations with sporadic temporal lobe epilepsy: where to from here? Brain 128(part 8): 1832–1840.

Chen AC, LaForge KS, Ho A et al. (2002) Potentially functional polymorphism in the promoter region of prodynorphin gene may be associated with protection against cocaine dependence or abuse. American Journal of Medical Genetics 114(4): 429–435.

Cheng HY, Pitcher GM, Laviolette SR et al. (2002) DREAM is a critical transcriptional repressor for pain modulation. Cell 108(1): 31–43.

Cirulli ET and Goldstein DB (2007) In vitro assays fail to predict in vivo effects of regulatory polymorphisms. Human Molecular Genetics Epub ahead of print.

De Vries TJ and Shippenberg TS (2002) Neural systems underlying opiate addiction. Journal of Neuroscience 22(9): 3321–3325.

Fay JC and Wu CI (2000) Hitchhiking under positive Darwinian selection. Genetics 155(3): 1405–1413.

Hinds DA, Stuve LL, Nilsen GB et al. (2005) Whole‐genome patterns of common DNA variation in three human populations. Science 307(5712): 1072–1079.

Kovacs KM, Szakall I, O'Brien D et al. (2005) Decreased oral self‐administration of alcohol in kappa‐opioid receptor knock‐out mice. Alcoholism, Clinical and Experimental Research 29(5): 730–738.

Moles A, Kieffer BL and D'Amato FR (2004) Deficit in attachment behavior in mice lacking the mu‐opioid receptor gene. Science 304(5679): 1983–1986.

Muse SV and Gaut BS (1997) Comparing patterns of nucleotide substitution rates among chloroplast loci using the relative ratio test. Genetics 146(1): 393–399.

Nikoshkov A, Hurd YL, Yakovleva T et al. (2005) Prodynorphin transcripts and proteins differentially expressed and regulated in the adult human brain. FASEB Journal 19: 1543–1545.

Nomura A, Ujike H, Tanaka Y et al. (2006) Genetic variant of prodynorphin gene is risk factor for methamphetamine dependence. Neuroscience Letters 400(1–2): 158–162.

Rockman MV, Hahn MW, Soranzo N et al. (2005) Ancient and recent positive selection transformed opioid cis‐regulation in humans. PLoS Biology 3: e387.

Roth BL, Baner K, Westkaemper R et al. (2002) Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist. Proceedings of the National Academy of Science of the USA 99(18): 11934–11939.

Schlotterer C (2002) A microsatellite‐based multilocus screen for the identification of local selective sweeps. Genetics 160(2): 753–763.

Stogmann E, Zimprich A, Baumgartner C et al. (2002) A functional polymorphism in the prodynorphin gene promoter is associated with temporal lobe epilepsy. Annals of Neurology 51(2): 260–263.

Tilgen N, Rebstock J, Horvath S et al. (2003) Prodynorphin gene promoter polymorphism and temporal lobe epilepsy. Annals of Neurology 53(2): 280–282.

Ventriglia M, Bocchio Chiavetto L, Bonvicini C et al. (2002) Allelic variation in the human prodynorphin gene promoter and schizophrenia. Neuropsychobiology 46(1): 17–21.

Wagner JJ, Terman GW and Chavkin C (1993) Endogenous dynorphins inhibit excitatory neurotransmission and block LTP induction in the hippocampus. Nature 363(6428): 451–454.

Williamson SH, Hubisz MJ, Clark AG et al. (2007) Localizing recent adaptive evolution in the human genome. PLoS Genetics 3: e90.

Xuei X, Dick D, Flury‐Wetherill L et al. (2006) Association of the kappa‐opioid system with alcohol dependence. Molecular Psychiatry 11(11): 1016–1024.

Zhang CS, Tan Z, Lu L et al. (2004) Polymorphism of prodynorphin promoter is associated with schizophrenia in Chinese population. Acta Pharmacologica Sinica 25(8): 1022–1026.

Zimprich A, Kraus J, Woltje M et al. (2000) An allelic variation in the human prodynorphin gene promoter alter stimulus‐induced expression. Journal of Neurochemistry 74: 472–477.

Further Reading

Hahn MW (2007) Detecting natural selection on cis‐regulatory DNA. Genetica 129: 7–18.

King MC and Wilson AC (1975) Evolution at two levels in humans and chimpanzees. Science 188(4184): 107–116.

Rockman MV and Wray GA (2002) Abundant raw material for cis‐regulatory evolution in humans. Molecular Biology and Evolution 19(11): 1991–2004.

Rodgers RJ and Cooper SJ (eds) (1988) Endorphins, Opiates and Behavioral Processes. New York: Wiley, 361pp.

Wray GA (2007) The evolutionary significance of cis‐regulatory mutations. Nature Reviews Genetics 8: 206–216.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Rockman, Matthew V(Mar 2008) Positive Selection and the Evolution of Prodynorphin. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020790]