The obligate intracellular bacterium Wolbachia pipientis strain wPip induces cytoplasmic incompatibility (CI), patterns of crossing sterility, in the Culex pipiens group of mosquitoes. The complete sequence is presented of the 1.48-Mbp genome of wPip which encodes 1386 coding sequences (CDSs), representing the first genome sequence of a B-supergroup Wolbachia. Comparisons were made with the smaller genomes of Wolbachia strains wMel of Drosophila melanogaster, an A-supergroup Wolbachia that is also a CI inducer, and wBm, a mutualist of Brugia malayi nematodes that belongs to the D-supergroup of Wolbachia. Despite extensive gene order rearrangement, a core set of Wolbachia genes shared between the 3 genomes can be identified and contrasts with a flexible gene pool where rapid evolution has taken place. There are much more extensive prophage and ankyrin repeat encoding (ANK) gene components of the wPip genome compared with wMel and wBm, and both are likely to be of considerable importance in wPip biology. Five WO-B–like prophage regions are present and contain some genes that are identical or highly similar in multiple prophage copies, whereas other genes are unique, and it is likely that extensive recombination, duplication, and insertion have occurred between copies. A much larger number of genes encode ankyrin repeat (ANK) proteins in wPip, with 60 present compared with 23 in wMel, many of which are within or close to the prophage regions. It is likely that this pattern is partly a result of expansions in the wPip lineage, due for example to gene duplication, but their presence is in some cases more ancient. The wPip genome underlines the considerable evolutionary flexibility of Wolbachia, providing clear evidence for the rapid evolution of ANK-encoding genes and of prophage regions. This host–Wolbachia system, with its complex patterns of sterility induced between populations, now provides an excellent model for unraveling the molecular systems underlying host reproductive manipulation.

Surveillance of CDNK2A mutation carriers is relatively successful, detecting most PDACs at a resectable stage. The benefit of surveillance in families with FPC is less evident.

Urothelial bladder cancer (UBC) is heterogeneous at the clinical, pathological, and genetic levels. Tumor invasiveness (T) and grade (G) are the main factors associated with outcome and determine patient management (1). A discovery exome sequencing screen (n=17), followed by a prevalence screen (n=60), identified new genes mutated in this tumor coding for proteins involved in chromatin modification (MLL2, ASXL2, BPTF), cell division (STAG2, SMC1A, SMC1B), and DNA repair (ATM, ERCC2, FANCA). STAG2, a subunit of cohesin, was significantly and commonly mutated/lost in UBC, mainly in tumors of low stage/grade, and its loss was associated with improved outcome. Loss of expression was often observed in chromosomally-stable tumors and STAG2 knockdown in bladder cancer cells did not increase aneuploidy. STAG2 reintroduction in non-expressing cells led to reduced colony formation. Our findings indicate that STAG2 is a novel UBC tumor suppressor acting through mechanisms that are different from its role to prevent aneuploidy.

Mosaic loss of the Y chromosome (mLOY) leading to gonosomal XY/XO commonly occurs during aging, particularly in smokers. We investigated whether mLOY was associated with non-hematologic cancer in three prospective cohorts (8,679 cancer cases and 5,110 cancer-free controls), and genetic susceptibility to mLOY. Overall, mLOY was observed in 7% of men and increased with age (per year OR=1.13, 95%CI=1.12–1.15; P<2×10−16), reaching 18.7% among men over age 80. mLOY was associated with current smoking (OR=2.35, 95%CI=1.82–3.03; P=5.55×10−11); however, the association weakened with years after cessation. mLOY was not consistently associated with overall or specific cancer risk (e.g. for bladder, lung, or prostate) nor with cancer survival after diagnosis (multivariate-adjusted hazard ratio=0.87, 95% CI=0.73–1.04, P=0.12). In a genome-wide association study, we observed the first example of a common susceptibility locus for genetic mosaicism, specifically mLOY, which maps to the T-cell leukemia/lymphoma 1A (TCL1A) gene on 14q32.13, marked by rs2887399 (OR=1.55, 95%CI=1.36–1.78; P=1.37×10−10).