Petrini, J. | bioRxiv Science

bioRxiv2018

Association of predicted deleterious single nucleotide polymorphisms with carcass traits in meat-type chickens

In previous studies, we used genome wide association (GWAS) to identify quantitative trait loci (QTL) associated with weight and yield of abdominal fat, drumstick, thigh and breast traits in chickens. However, this methodology assumes that the studied variants are in linkage disequilibrium with the causal mutation and consequently do not identify it. In an attempt to identify causal mutations in candidate genes for carcass traits in broilers, we selected 20 predicted deleterious SNPs within QTLs for association analysis. Additive, dominance and allele substitution effects were tested. From the 20 SNPs analyzed, we identified six SNPs with significant association (p-value <0.05) with carcass traits, and three are highlighted here. The SNP rs736010549 was associated with drumstick weight and yield with significant additive and dominance effects. The SNP rs739508259 was associated with thigh weight and yield, and with significant additive and allele substitution effects. The SNP rs313532967 was associated with breast weight and yield. The three SNPs that were associated with carcass traits (rs736010549, rs739508259 and rs313532967) are respectively located in the coding regions of the WDR77, VWA8 and BARL genes. These genes are involved in biological processes such as steroid hormone signaling pathway, estrogen binding, and regulation of cell proliferation. Our strategy allowed the identification of putative casual mutations associated with muscle growth.

genetics↗

bioRxiv2017

Therapeutic targeting of PGBD5-induced DNA repair dependency in pediatric solid tumors

Despite intense efforts, the cure rates of childhood and adult solid tumors are not satisfactory. Resistance to intensive chemotherapy is common, and targets for molecular therapies are largely undefined. We have now found that the majority of childhood solid tumors, including rhabdoid tumors, neuroblastoma, medulloblastoma and Ewing sarcoma, express an active DNA transposase PGBD5 that can promote site-specific genomic rearrangements in human cells. Using functional genetic approaches, we found that mouse and human cells deficient in non-homologous end joining (NHEJ) DNA repair cannot tolerate the expression of PGBD5. In a chemical screen of DNA damage signaling inhibitors, we identified AZD6738 as a specific sensitizer of PGBD5-dependent DNA damage and apoptosis. We found that expression of PGBD5, but not its nuclease activity-deficient mutant, was sufficient to induce hypersensitivity to AZD6738. Depletion of endogenous PGBD5 conferred resistance to AZD6738 in human tumor cells. PGBD5-expressing tumor cells accumulated unrepaired DNA damage in response to AZD6738 treatment, and underwent apoptosis in both dividing and G1 phase cells in the absence of immediate DNA replication stress. Accordingly, AZD6738 exhibited nanomolar potency against the majority of neuroblastoma, medulloblastoma, Ewing sarcoma and rhabdoid tumor cells tested, while sparing non-transformed human and mouse embryonic fibroblasts in vitro. Finally, treatment with AZD6738 induced apoptosis and regression of human neuroblastoma and medulloblastoma tumors engrafted in immunodeficient mice in vivo. This effect was potentiated by combined treatment with cisplatin, including significant anti-tumor activity against patient-derived primary neuroblastoma xenografts. These findings delineate a therapeutically actionable synthetic dependency induced in PGBD5-expressing solid tumors.

cancer biology↗