Schematic illustration of one trial of the monetary incentive delay (MID) task performed by subjects in the MRI scanner.

<p>Schematic illustration of one trial of the monetary incentive delay (MID) task performed by subjects in the MRI scanner.</p

BOLD signal parameter estimates from anatomical regions during gain anticipation in different (68-bp VNTR) prodynorphin promoter polymorphism genotypes (LL-, LH-, or HH-alleles).

<p>The HH (“high level pDYN expression”) group shows significantly higher activation (see *) in the mOFC compared to the LL (“low level pDYN expression”) and LH groups.</p

Whole brain activation of all 71 participants for reward and loss anticipation conditions.

<p>(<b>a</b>) The comparison between gain and neutral anticipation (GA>NA) conditions and between loss and neutral anticipation (GA>LA) conditions showed activation in bilateral striatum, amygdala, insula, midbrain, anterior cingulate cortex and cerebellum in both incentive conditions relative to the neutral no outcome control condition. (<b>b</b>) The contrast between gain anticipation and loss anticipation (GA>LA) revealed activation in ventral striatum, ventro-medial prefrontal cortex VMPFC, thalamus and posterior cortex (PC). The threshold is p = 0.05, corrected for multiple comparisons on the voxel level (see methods).</p

The PPI analysis during gain anticipation shows higher functional coupling of the anterior mOFC seed region of the HH group with the ventral striatum (a), subgenual anterior cingulate cortex and VMPFC (b) regions compared to the LL genotype group.

<p>The threshold is p = 0.05 cluster level corrected for multiple comparisons (see methods).</p

The Human 68-bp Element Increases Induced <i>PDYN</i> Expression

<div><p>We tested four 3-kb constructs, encompassing the region shown in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0030387#pbio-0030387-g001" target="_blank">Figure 1</a>.</p> <p>(A) The human and chimpanzee constructs differ at the sites indicated by vertical bars. The two chimeric constructs incorporated the human 68-bp element or the human DRE (DREAM binding site) into the chimpanzee construct.</p> <p>(B and C) Panels show luciferase activity for each construct (± SEM, five to seven transfections), standardized to that observed for promoterless luciferase vectors (white bars), in SH-SY5Y and JAR cells, with and without added caffeine, which causes the release of intracellular Ca²⁺ and the release of DREAM from the DRE.</p></div

Altered Variation at the <i>PDYN</i> Microsatellite

<div><p>(A) The allele frequency distribution of the <i>PDYN</i> 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.</p> <p>(B) The empirical probability density of lnRV for a panel of genomically distributed microsatellites is plotted for each population, using panel A as the color 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 <i>PDYN</i> microsatellite for each population, in the left tails of the distributions, indicating a locus-specific reduction in repeat-number variance.</p> <p>(C) The empirical probability density for lnRH. Again, the <i>PDYN</i> microsatellite exhibits significantly negative lnRH values, indicating a locus-specific reduction in heterozygosity at <i>PDYN</i> in the non-West African populations.</p></div

Elevated Differentiation at <i>PDYN</i>

<div><p>(A–D) In four pairwise comparisons, <i>F_ST</i> at the <i>PDYN</i> 68-bp element (red) is markedly elevated above the <i>F_ST</i> estimated from 18 candidate neutral markers (blue) typed in the same individuals.</p> <p>(E) Genetic differentiation between European- and Chinese-Americans, measured as a 15-SNP running <i>F_ST</i> average, for the entire p-arm of Chromosome 20. <i>PDYN</i> falls under a large <i>F_ST</i> peak (shaded), high above the arm average (red line). The RefSeq and chromosome band annotation is from the University of California, Santa Cruz Human Genome Browser (hg17), <a href="http://genome.ucsc.edu" target="_blank">http://genome.ucsc.edu</a> [<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0030387#pbio-0030387-b79" target="_blank">79</a>]. Perlegen SNP positions were matched to the hg17 assembly by the UCSC LiftOver utility.</p> <p>(F) A finer-scale sliding window analysis shows that the region of elevated <i>F_ST</i> includes only two genes, <i>PDYN</i> and <i>STK35,</i> shown according to their RefSeq annotations.</p> <p>(G) <i>F_ST</i> 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 <i>PDYN</i> and <i>STK35.</i> The contours define the genome-wide density of <i>F_ST</i> conditioned on heterozygosity; for each heterozygosity, the lines represent the <i>F_ST</i> of SNPs in the specified <i>F_ST</i> percentile.</p></div

Divergence of the 68-bp Element in Humans

<p>Arrows indicate five differences fixed on the human lineage. The asterisk indicates a site that varies among human repeats. In the sample of 74 human haplotypes, all one-repeat and most two-repeat alleles bear G at this site. Complete haplotype data are given in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0030387#st001" target="_blank">Table S1</a>. Below, schematic of the study region showing the position of the element and the non-coding first exon with respect to the start of transcription.</p

<i>RBFOX1and RBFOX3</i> variants and phenotype of index-patients.

<p>Survey on <i>RBFOX1</i> and <i>RBFOX3</i> variants in patients. Seizure type and comorbidity overview of variant carrier. Abbreviations: RE = rolandic epilepsy; CTS = centrotemporal spikes; ESES = epileptic encephalopathy with status epilepticus during sleep.</p

Summary of previous studies referenced at the HGMD specific for each identified variant.

<p>Summary of previous studies referenced at the HGMD specific for each identified variant.</p