Choi J, Zhang T, Vu A, Ablain J, Makowski MM, Colli LM, Xu M, Hennessey RC, Yin J, Rothschild H, Gräwe C, Kovacs MA, Funderburk KM, Brossard M, Taylor J, Pasaniuc B, Chari R, Chanock SJ, Hoggart CJ, Demenais F, Barrett JH, Law MH, Iles MM, Yu K, Vermeulen M, Zon LI, Brown KM. 2020. Massively parallel reporter assays of melanoma risk variants identify MX2 as a gene promoting melanoma. Nature communications. 11(1):2718. Pubmed: 32483191 DOI:10.1038/s41467-020-16590-1


Genome-wide association studies (GWAS) have identified ~20 melanoma susceptibility loci, most of which are not functionally characterized. Here we report an approach integrating massively-parallel reporter assays (MPRA) with cell-type-specific epigenome and expression quantitative trait loci (eQTL) to identify susceptibility genes/variants from multiple GWAS loci. From 832 high-LD variants, we identify 39 candidate functional variants from 14 loci displaying allelic transcriptional activity, a subset of which corroborates four colocalizing melanocyte cis-eQTL genes. Among these, we further characterize the locus encompassing the HIV-1 restriction gene, MX2 (Chr21q22.3), and validate a functional intronic variant, rs398206. rs398206 mediates the binding of the transcription factor, YY1, to increase MX2 levels, consistent with the cis-eQTL of MX2 in primary human melanocytes. Melanocyte-specific expression of human MX2 in a zebrafish model demonstrates accelerated melanoma formation in a BRAF background. Our integrative approach streamlines GWAS follow-up studies and highlights a pleiotropic function of MX2 in melanoma susceptibility.

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The Zon laboratory aims to dissect how assaults to the hematopoietic system cause severe diseases such as leukemias, lymphomas, and anemias. They investigate hematopoietic development and disease using chemical screens, genetic screens, and analysis of novel transgenic lines in zebrafish.

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