Positive Selection and the Evolution of Prodynorphin

Abstract

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..

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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]