Despite the wide range of skin pigmentation in humans, little is known about its genetic basis in global populations. Examining ethnically diverse African genomes, we identify variants in or near SLC24A5, MFSD12, DDB1, TMEM138, OCA2 and HERC2 that are significantly associated with skin pigmentation. Genetic evidence indicates that the light pigmentation variant at SLC24A5 was introduced into East Africa by gene flow from non-Africans. At all other loci, variants associated with dark pigmentation in Africans are identical by descent in southern Asian and Australo-Melanesian populations. Functional analyses indicate that MFSD12 encodes a lysosomal protein that affects melanogenesis in zebrafish and mice, and that mutations in melanocyte-specific regulatory regions near DDB1/TMEM138 correlate with expression of UV response genes under selection in Eurasians.

Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases1, while rare variants in CDK4, BRCA2, BAP1, and the promoter of TERT, have also been linked to the disease2-5. Here we set out to identify novel high-penetrance susceptibility genes in unexplained cases by sequencing 184 melanoma patients from 105 pedigrees recruited in the United Kingdom, the Netherlands, and Australia that were negative for variants in known predisposition genes. We identify families where melanoma co-segregates with loss-of-function variants in the protection of telomeres 1 (POT1) gene, a proportion of members presenting with an early age of onset and multiple primaries. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide-/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding, leading to increased telomere length. Thus, POT1 variants predispose to melanoma formation via a direct effect on telomeres.

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 melanoma cases (67% newly-genotyped) and 375,188 controls identified 54 significant loci with 68 independent SNPs. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with nevus count and hair color GWAS, and transcriptome association approaches, uncovered 31 potential secondary loci, for a total of 85 cutaneous melanoma susceptibility loci. These findings provide substantial insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation, and telomere maintenance together with identifying potential new pathways for cutaneous melanoma pathogenesis.

Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10−10), 3p22.1 (rs67311347, P=2.5 × 10−8), 3q26.2 (rs10936602, P=8.8 × 10−9), 8p21.3 (rs2241261, P=5.8 × 10−9), 10q24.33-q25.1 (rs11813268, P=3.9 × 10−8), 11q22.3 (rs74911261, P=2.1 × 10−10) and 14q24.2 (rs4903064, P=2.2 × 10−24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.

Our findings add to the growing support for telomere dysregulation as a key process associated with melanoma susceptibility.

Subscribe to PCMR and stay up-to-date with the only journal committed to publishing basic research in melanoma and pigment cell biology As a member of the IFPCS or the SMR you automatically get online access to PCMR. Sign up as a member today at www.ifpcs.org or at www.societymelanomaresarch.org A cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma transcript. Somatic loss of the wild-type allele was also confirmed in the UMM and paraganglioma tumors. Our findings further support BAP1 as a melanoma susceptibility gene and extend the potential predisposition spectrum to paraganglioma.

The male-specific lethal (MSL) complex, which includes two noncoding RNA on X (roX)1 and roX2 RNAs, induces histone H4-Lys16 acetylation for twofold hypertranscription of the male X chromosome in Drosophila melanogaster. To characterize the role of roX RNAs in this process, we have identified evolutionarily conserved functional domains of roX RNAs in several Drosophila species (eight for roX1 and nine for roX2). Despite low homology between them, male-specific expression and X chromosome-specific binding are conserved. Within roX RNAs of all Drosophila species, we found conserved primary sequences, such as GUUNUACG, in the 39 end of both roX1 (three repeats) and roX2 (two repeats). A predicted stem-loop structure of roX2 RNA contains this sequence in the 39 stem region. Six tandem repeats of this stem-loop region (72 nt) of roX2 were enough for targeting the MSL complex and inducing H4-Lys16 acetylation on the X chromosome without other parts of roX2 RNA, suggesting that roX RNAs might play important roles in regulating enzymatic activity of the MSL complex.

7 These authors contributed equally to this work 8 These authors co-supervised this work 9,10 A complete list of consortium authors appears at the end of this paper Corresponding authors: bpavan@mail.nih.gov, kevin.brown3@nih.gov RUNNING TITLE: Cell-type specific melanocyte eQTL dataset KEY WORDS: eQTL, Melanocyte, Melanoma, cell-type specific peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/231423 doi: bioRxiv preprint first posted online 2 ABSTRACT Most expression quantitative trait loci (eQTL) studies to date have been performed in heterogenous tissues as opposed to specific cell types. To better understand the cell-type specific regulatory landscape of human melanocytes, which give rise to melanoma but account for <5% of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335 cis-eQTLs and 4,997 eGenes (FDR<0.05), which are higher numbers than any GTEx tissue type with a similar sample size.Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissues, including skin. Over a third of melanocyte eGenes including key genes in melanin synthesis pathways were not observed in two types of GTEx skin tissues or melanoma samples. The melanocyte dataset also identified cell-type specific trans-eQTL of a pigmentation-associated SNP for four genes, likely through its cis-regulation of IRF4, encoding a transcription factor implicated in human pigmentation phenotypes. Melanocyte eQTLs are enriched in cis-regulatory signatures found in melanocytes as well as melanoma-associate variants identified through genome-wide association studies (GWAS). Co-localization of melanoma GWAS variants and eQTLs from melanocyte and skin eQTL datasets identified candidate melanoma susceptibility genes for most of the known GWAS loci including unique genes identified by the melanocyte dataset.Further, a transcriptome-wide association study using published melanoma GWAS data uncovered four new loci, where imputed expression levels of five genes (ZFP90, HEBP1, MSC, CBWD1, and RP11-383H13.1) were associated with melanoma at genome-wide significant Pvalues. Our data highlights the utility of lineage-specific eQTL resources for annotating GWAS findings and present a robust database for genomic research of melanoma risk and melanocyte biology.