Global Patterns of Diversity and Selection in Human Tyrosinase Gene

<div><p>Global variation in skin pigmentation is one of the most striking examples of environmental adaptation in humans. More than two hundred loci have been identified as candidate genes in model organisms and a few tens of these have been found to be significantly associated with human skin pigmentation in genome-wide association studies. However, the evolutionary history of different pigmentation genes is rather complex: some loci have been subjected to strong positive selection, while others evolved under the relaxation of functional constraints in low UV environment. Here we report the results of a global study of the human tyrosinase gene, which is one of the key enzymes in melanin production, to assess the role of its variation in the evolution of skin pigmentation differences among human populations. We observe a higher rate of non-synonymous polymorphisms in the European sample consistent with the relaxation of selective constraints. A similar pattern was previously observed in the <i>MC1R</i> gene and concurs with UV radiation-driven model of skin color evolution by which mutations leading to lower melanin levels and decreased photoprotection are subject to purifying selection at low latitudes while being tolerated or even favored at higher latitudes because they facilitate UV-dependent vitamin D production. Our coalescent date estimates suggest that the non-synonymous variants, which are frequent in Europe and North Africa, are recent and have emerged after the separation of East and West Eurasian populations.</p> </div

Ancestral recombination graph of <i>TYR</i> haplotypes.

<p>The tree is rooted by the chimpanzee sequence and presents recombination history of 942 worldwide samples (1884 chromosomes). Haplogroup frequency by populations is shown below the tree. Haplogroup names are shaded in yellow. Green arrows show the origin of recombination prefixes, blue arrows show the origin of recombination suffixes. Recombination points are shown by rectangles. Numerical superscript prefixes to the left of rs identifiers correspond to the relative physical position of SNPs. SNPs which were out of the range of our re-sequencing alignment are marked with superscript suffixes to the right of respective rs identifiers and correspond to the following phylogenetic equivalents in our re-sequencing data: A – rs12799137, B – rs7108676, C – rs12799347, D – rs12417632, E and F – rs5021654, G – rs7934747, H – rs1126809. Non-synonymous mutations or their phylogenetic equivalents are shown in red font with amino-acid substitutions specified. 95% confidence intervals for the detected haplogroup frequencies are given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0074307#pone.0074307.s011" target="_blank">Table S6</a>.</p

Sliding window analysis of pairwise nucleotide differences in the 5’ flanking region of the <i>TYR</i> gene.

<p>Average estimates of pairwise differences (π) at exons, introns and the complete 5’ flanking region are provided for reference. Pairwise differences in six regional population groups are shown separately. Approximate locations of previously known regulatory elements (TDE, TPE and h5’URS) are marked with red diamonds. A newly identified region with decreased genetic variability is marked with a blue diamond. Position numbers are shown relative to the first codon of the <i>TYR</i> gene. Sliding window size is 1500 bp and step size is 375 bp.</p

Median-joining network of <i>TYR</i> haplotypes.

<p>The network is based on the analysis of sequence data of the first haplotype block of 8634 bp length in 81 samples (162 chromosomes), color-coded by the geographic region of origin of the samples. Chimpanzee sequence (white circle) was used as an outgroup and chimpanzee specific variants have been excluded from the network output.</p

Association of rs1426654 genotypes with melanin index.

<p>(A) Distribution of melanin index (MI) in 1228 individuals of Cohort A. The two dotted black lines represent approximately 10% thresholds for the low (MI<38) and high (MI>50) MI groups, which were used to assess genotype-phenotype association using a logistic regression model. (B) Distribution of mean melanin index for the genotypes of rs1426654. The mean melanin indices for each genotype, as obtained separetely for males and females are shown together with their 95% confidence intervals, as estimated by multiple imputation model (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003912#pgen.1003912.s008" target="_blank">Table S3A</a>).</p

Heat map showing the intra- and inter-population variation measured by average pairwise sequence differences of the <i>SLC24A5</i> gene.

<p>The upper triangle of the matrix (green) shows average pairwise differences between populations (PiXY). The average number of pairwise differences (PiX) within each population is shown along the diagonal (orange). The lower triangle of the matrix (blue) shows differences between populations based on Nei's distance, i.e., corrected average pairwise differences (PiXY−(PiX+PiY)/2).</p

Global range of human skin pigmentation assessed by the melanin index (MI).

<p>Global range of human skin pigmentation assessed by the melanin index (MI).</p

The structure of the human <i>SLC24A5</i> gene (Chromosome 15q21.1, 48409019 to 48434692).

<p>Exons of the gene are shown in yellow, introns in blue and 5′ flanking region in pink. The black lines underneath the gene show the regions resequenced in this study (total of 11741 bp) spanning 25674 bp. rs1426654 is the functional SNP located in the third exon.</p

Body mass index stratified meta-analysis of genome-wide association studies of polycystic ovary syndrome in women of European ancestry

Background Polycystic ovary syndrome (PCOS) is a complex multifactorial disorder with a substantial genetic component. However, the clinical manifestations of PCOS are heterogeneous with notable differences between lean and obese women, implying a different pathophysiology manifesting in differential body mass index (BMI). We performed a meta-analysis of genome-wide association study (GWAS) data from six well-characterised cohorts, using a case–control study design stratified by BMI, aiming to identify genetic variants associated with lean and overweight/obese PCOS subtypes. Results The study comprised 254,588 women (5,937 cases and 248,651 controls) from individual studies performed in Australia, Estonia, Finland, the Netherlands and United States of America, and separated according to three BMI stratifications (lean, overweight and obese). Genome-wide association analyses were performed for each stratification within each cohort, with the data for each BMI group meta-analysed using METAL software. Almost half of the total study population (47%, n = 119,584) were of lean BMI (≤ 25 kg/m2). Two genome-wide significant loci were identified for lean PCOS, led by rs12000707 within DENND1A (P = 1.55 × 10–12) and rs2228260 within XBP1 (P = 3.68 × 10–8). One additional locus, LINC02905, was highlighted as significantly associated with lean PCOS through gene-based analyses (P = 1.76 × 10–6). There were no significant loci observed for the overweight or obese sub-strata when analysed separately, however, when these strata were combined, an association signal led by rs569675099 within DENND1A reached genome-wide significance (P = 3.22 × 10–9) and a gene-based association was identified with ERBB4 (P = 1.59 × 10–6). Nineteen of 28 signals identified in previous GWAS, were replicated with consistent allelic effect in the lean stratum. There were less replicated signals in the overweight and obese groups, and only 4 SNPs were replicated in each of the three BMI strata. Conclusions Genetic variation at the XBP1, LINC02905 and ERBB4 loci were associated with PCOS within unique BMI strata, while DENND1A demonstrated associations across multiple strata, providing evidence of both distinct and shared genetic features between lean and overweight/obese PCOS-affected women. This study demonstrated that PCOS-affected women with contrasting body weight are not only phenotypically distinct but also show variation in genetic architecture; lean PCOS women typically display elevated gonadotrophin ratios, lower insulin resistance, higher androgen levels, including adrenal androgens, and more favourable lipid profiles. Overall, these findings add to the growing body of evidence supporting a genetic basis for PCOS as well as differences in genetic patterns relevant to PCOS BMI-subtype.</p