Langston, R. | bioRxiv Science

bioRxiv2019

Loss of Cdc13 causes genome instability by deficiency in replication-dependent telomere capping

In budding yeast, Cdc13, Stn1, and Ten1 form a telomere binding heterotrimer dubbed CST. Here we investigate the role of Cdc13/CST in maintaining genome stability, using a Chr VII disome system that can generate recombinants, loss, and enigmatic unstable chromosomes. In cells expressing a temperature sensitive CDC13 allele, cdc13F684S, unstable chromosomes frequently arise due to problems in or near a telomere. Hence, when Cdc13 is defective, passage through S phase causes Exo1-dependent ssDNA and unstable chromosomes, which then are the source for whole chromosome instability events (e.g. recombinants, chromosome truncations, dicentrics, and/or loss). Specifically, genome instability arises from a defect in Cdc13s replication-dependent telomere capping function, not Cdc13s putative post-replication telomere capping function. Furthermore, the unstable chromosomes form without involvement of homologous recombination nor non-homologous end joining. Our data suggest that a Cdc13/CST defect in semi-conservative replication near the telomere leads to ssDNA and unstable chromosomes, which then are lost or subject to complex rearrangements. This system defines a links between replication-dependent chromosome capping and genome stability in the form of unstable chromosomes.

genetics↗

bioRxiv2019

Genetic modifiers of risk and age at onset in GBA associated Parkinson disease and Lewy body dementia

Parkinsons disease (PD) is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of PD, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as PD and Lewy body dementia (LBD). These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known PD risk variants.\n\nUsing multiple, large case-control datasets, totalling 217,165 individuals (22,757 PD cases, 13,431 PD proxy cases, 622 LBD cases and 180,355 controls), we identified 1,772 PD cases, 711 proxy cases and 7,624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent PD-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall PD genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S neurons were shown to have decreased Cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated PD risk and age at onset and demonstrate that variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have important implications for selection of GBA carriers for therapeutic interventions.

genetics↗