Different Pigmentation Risk Loci for High-Risk Monosomy 3 and Low-Risk Disomy 3 Uveal Melanomas.

BACKGROUND: Uveal melanoma (UM), a rare malignant tumor of the eye, is predominantly observed in populations of European ancestry. UMs carrying a monosomy 3 (M3) frequently relapse mainly in the liver, whereas UMs with disomy 3 (D3) are associated with more favorable outcome. Here, we explored the UM genetic predisposition factors in a large genome-wide association study (GWAS) of 1142 European UM patients and 882 healthy controls . METHODS: We combined 2 independent datasets (Global Screening Array) with the dataset described in a previously published GWAS in UM (Omni5 array), which were imputed separately and subsequently merged. Patients were stratified according to their chromosome 3 status, and identified UM risk loci were tested for differential association with M3 or D3 subgroups. All statistical tests were 2-sided. RESULTS: We recapitulated the previously identified risk locus on chromosome 5 on CLPTM1L (rs421284: odds ratio [OR] =1.58, 95% confidence interval [CI] = 1.35 to 1.86; P = 1.98 × 10-8) and identified 2 additional risk loci involved in eye pigmentation: IRF4 locus on chromosome 6 (rs12203592: OR = 1.76, 95% CI = 1.44 to 2.16; P = 3.55 × 10-8) and HERC2 locus on chromosome 15 (rs12913832: OR= 0.57, 95% CI = 0.48 to 0.67; P = 1.88 × 10-11). The IRF4 rs12203592 single-nucleotide polymorphism was found to be exclusively associated with risk for the D3 UM subtype (ORD3 = 2.73, 95% CI = 1.87 to 3.97; P = 1.78 × 10-7), and the HERC2 rs12913832 single-nucleotide polymorphism was exclusively associated with risk for the M3 UM subtype (ORM3 = 2.43, 95% CI = 1.79 to 3.29; P = 1.13 × 10-8). However, the CLPTM1L risk locus was equally statistically significant in both subgroups. CONCLUSIONS: This work identified 2 additional UM risk loci known for their role in pigmentation. Importantly, we demonstrate that UM tumor biology and metastatic potential are influenced by patients' genetic backgrounds.

Soft Selective Sweep on Chemosensory Genes Correlates with Ancestral Preference for Toxic Noni in a Specialist Drosophila Population.

Understanding how organisms adapt to environmental changes is a major question in evolution and ecology. In particular, the role of ancestral variation in rapid adaptation remains unclear because its trace on genetic variation, known as soft selective sweep, is often hardly recognizable from genome-wide selection scans. Here, we investigate the evolution of chemosensory genes in Drosophila yakuba mayottensis, a specialist subspecies on toxic noni (Morinda citrifolia) fruits on the island of Mayotte. We combine population genomics analyses and behavioral assays to evaluate the level of divergence in chemosensory genes and perception of noni chemicals between specialist and generalist subspecies of D. yakuba. We identify a signal of soft selective sweep on a handful of genes, with the most diverging ones involving a cluster of gustatory receptors expressed in bitter-sensing neurons. Our results highlight the potential role of ancestral genetic variation in promoting host plant specialization in herbivorous insects and identify a number of candidate genes underlying behavioral adaptation.