The Ashkenazi Jewish (AJ) population is a genetic isolate close to European and Middle Eastern groups, with genetic diversity patterns conducive to disease mapping. Here we report high-depth sequencing of 128 complete genomes of AJ controls. Compared with European samples, our AJ panel has 47% more novel variants per genome and is eightfold more effective at filtering benign variants out of AJ clinical genomes. Our panel improves imputation accuracy for AJ SNP arrays by 28%, and covers at least one haplotype in E67% of any AJ genome with long, identical-bydescent segments. Reconstruction of recent AJ history from such segments confirms a recent bottleneck of merely E350 individuals. Modelling of ancient histories for AJ and European populations using their joint allele frequency spectrum determines AJ to be an even admixture of European and likely Middle Eastern origins. We date the split between the two ancestral populations to E12-25 Kyr, suggesting a predominantly Near Eastern source for the repopulation of Europe after the Last Glacial Maximum.

Purpose Carrier screening programs that identify the presence of known mutations have been effective for reducing the incidence of autosomal recessive conditions in the Ashkenazi Jewish population and other populations. Yet, these programs have not realized their full potential. Furthermore, many known autosomal recessive and dominant conditions are not screened for and the molecular basis of other conditions for which screening might be offered is unknown. Methods Through literature review and annotation of full sequenced genomes from healthy individuals, we expanded the list of mutations. Mutations were identified in a sample of 128 fully sequenced Ashkenazi Jewish genomes that were filtered through clinical databases and curated manually for clinical validity and utility using the American College of Medical Genetics scoring (ACMG) system. Other known mutations were identified through literature review. Results A panel of 203 mutations was identified for 92 autosomal recessive, 24 autosomal dominant, and 4 X-linked disorders. Conclusion Screening for a broader range of disorders could not only further reduce the incidence of autosomal recessive disorders, but could also offer the benefits of early or presymptomatic diagnosis.

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Copy number alterations(CNAs) are the most common genetic changes observed in many cancers, reflecting the innate chromosomal instability of this disorder. Yet, how these alterations affect gene function to promote metastases across different tumor types has not been established. In this study, we developed a pan-cancer metastasis potential score (panMPS) based on observed CNAs. panMPS predicts metastasis and metastasis-free survival in cohorts of patients with prostate cancer, triple negative breast cancer and lung adenocarcinoma, and overall survival in the Metabric breast cancer cohort and three cohorts from The Cancer Genome Atlas (TCGA), including prostate, breast and lung adenocarcinoma. These CNAs are present in cell lines of metastatic tumors from eight different origins, reflected by an elevated panMPS for all cell lines. Many copy number alterations involve large chromosomal segments that encompass multiple genes (“clumps”). We show that harnessing this structural information to select only one gene per clump captures the contributions of other genes within the clump, resulting in a robust predictor of metastasis outcome. These sets of selected genes are distinct from cancer drivers that undergo mutation, and in fact, metastasis-related functions have been published for over half of them.