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Weghorn, Donate

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Author's Publications: search.filters.isAuthorOfPublication.e8ab8f74-54a8-477d-b1a8-ece1b5edbe20

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    Identifying DNase I hypersensitive sites as driver distal regulatory elements in breast cancer
    (Nature Publishing Group UK, 2017) D′Antonio, Matteo; Weghorn, Donate; D′Antonio-Chronowska, Agnieszka; Coulet, Florence; Olson, Katrina M.; DeBoever, Christopher; Drees, Frauke; Arias, Angelo; Alakus, Hakan; Richardson, Andrea L.; Schwab, Richard B.; Farley, Emma K.; Sunyaev, Shamil; Frazer, Kelly A
    Efforts to identify driver mutations in cancer have largely focused on genes, whereas non-coding sequences remain relatively unexplored. Here we develop a statistical method based on characteristics known to influence local mutation rate and a series of enrichment filters in order to identify distal regulatory elements harboring putative driver mutations in breast cancer. We identify ten DNase I hypersensitive sites that are significantly mutated in breast cancers and associated with the aberrant expression of neighboring genes. A pan-cancer analysis shows that three of these elements are significantly mutated across multiple cancer types and have mutation densities similar to protein-coding driver genes. Functional characterization of the most highly mutated DNase I hypersensitive sites in breast cancer (using in silico and experimental approaches) confirms that they are regulatory elements and affect the expression of cancer genes. Our study suggests that mutations of regulatory elements in tumors likely play an important role in cancer development.
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    Estimating the Selective Effects of Heterozygous Protein Truncating Variants from Human Exome Data
    (2017) Cassa, Christopher; Weghorn, Donate; Balick, Daniel; Jordan, Daniel M.; Nusinow, David; Samocha, Kaitlin E.; O’Donnell-Luria, Anne; MacArthur, Daniel; Daly, Mark; Beier, David R.; Sunyaev, Shamil
    The dispensability of individual genes for viability has interested generations of geneticists. For some genes it is essential to maintain two functional chromosomal copies, while others may tolerate the loss of one or both copies. Exome sequence data from 60,706 individuals provide sufficient observations of rare protein truncating variants (PTVs) to make genome-wide estimates of selection against heterozygous loss of gene function. The cumulative frequency of rare deleterious PTVs is primarily determined by the balance between incoming mutations and purifying selection rather than genetic drift. This enables the estimation of the genome-wide distribution of selection coefficients for heterozygous PTVs and corresponding Bayesian estimates for individual genes. The strength of selection can discriminate the severity, age of onset, and mode of inheritance in Mendelian exome sequencing cases. We find that genes under the strongest selection are enriched in embryonic lethal mouse knockouts, putatively cell-essential genes, Mendelian disease genes, and regulators of transcription. Screening by essentiality, we find a large set of genes under strong selection that likely have critical function but have not yet been extensively annotated in published literature.