Recurrent deletions of chromosome 15q13.3 associate with intellectual disability, schizophrenia, autism and epilepsy. To gain insight into its instability, we sequenced the region in patients, normal individuals and nonhuman primates. We discovered five structural configurations of the human chromosome 15q13.3 region ranging in size from 2 to 3 Mbp. These configurations arose recently (~0.5–0.9 million years ago) as a result of human-specific expansions of segmental duplications and two independent inversion events. All inversion breakpoints map near GOLGA8 core duplicons—a ~14 kbp primate-specific chromosome 15 repeat that became organized into larger palindromic structures. GOLGA8-flanked palindromes also demarcate the breakpoints of recurrent 15q13.3 microdeletions, the expansion of chromosome 15 segmental duplications in the human lineage, and independent structural changes in apes. The significant clustering (p=0.002) of breakpoints provides mechanistic evidence for the role of this core duplicon and its palindromic architecture in promoting evolutionary and disease-related instability of chromosome 15.

The UK Biobank is an unprecedented resource for human disease research. In March 2019, 49,997 exomes were made publicly available to investigators. Here we note that thousands of variant calls are unexpectedly absent from the current dataset, with 641 genes showing zero variation. We show that the reason for this was an erroneous read alignment to the GRCh38 reference. The missing variants can be recovered by modifying read alignment parameters to correctly handle the expanded set of contigs available in the human genome reference. Main TextThe UK Biobank (UKB) is a resource of unprecedented size, scope and openness, making available to researchers deep genetic and phenotypic data from approximately half a million individuals 1 . The genetic data released thus far include array-based genotypes on 488,000 individuals and exome sequencing on 49,997 of these, with further exome sequences to be released in 2020. Such comprehensive cataloging of protein-coding variation across the entire allele frequency spectrum, attached to extensive clinical phenotyping, has the potential to accelerate biomedical discovery, as evidenced by recent successes with other exome

The UK Biobank is an unprecedented resource for human disease research. In March 2019, 49,997 exomes were made publicly available to investigators. Here we note that thousands of variant calls are unexpectedly absent from this dataset, with 641 genes showing zero variation. We show that the reason for this was an erroneous read alignment to the GRCh38 reference. The missing variants can be recovered by modifying read alignment parameters to correctly handle the expanded set of contigs available in the human genome reference. Given the size and complexity of such population scale datasets, we propose a simple heuristic that can uncover systematic errors using summary data accessible to most investigators. K E Y W O R D SDNA, exome, genetics, sequence alignment, sequence analysis 214

Cell-cycle control is accomplished by cyclin-dependent kinases (CDKs), motivating extensive research into CDK targeting small-molecule drugs as cancer therapeutics. Here we use combinatorial CRISPR/Cas9 perturbations to uncover an extensive network of functional interdependencies among CDKs and related factors, identifying 43 synthetic-lethal and 12 synergistic interactions. We dissect CDK perturbations using single-cell RNAseq, for which we develop a novel computational framework to precisely quantify cell-cycle effects and diverse cell states orchestrated by specific CDKs. While pairwise disruption of CDK4/6 is synthetic-lethal, only CDK6 is required for normal cell-cycle progression and transcriptional activation. Multiple CDKs (CDK1/7/9/12) are synthetic-lethal in combination with PRMT5, independent of cell-cycle control. In-depth analysis of mRNA expression and splicing patterns provides multiple lines of evidence that the CDK-PRMT5 dependency is due to aberrant transcriptional regulation resulting in premature termination. These inter-dependencies translate to drug–drug synergies, with therapeutic implications in cancer and other diseases.