Biology subjects

Davies, B.

Publications and source records attributed to Davies, B..

3 recordsLinked to original sources

bioRxiv2018

Loss of ZnT8 function protects against diabetes by enhanced insulin secretion

A rare loss-of-function variant p.Arg138* in SLC30A8 encoding the zinc transporter 8 (ZnT8) enriched in Western Finland protects against type 2 diabetes (T2D). We recruited relatives of the identified carriers and showed that protection was associated with better insulin secretion due to enhanced glucose responsiveness and proinsulin conversion, especially compared with individuals matched for the genotype of a common T2D risk variant in SLC30A8, p.Arg325. In genome-edited human IPS-derived {beta}-like cells, we establish that the p.Arg138* variant results in reduced SLC30A8 expression due to haploinsufficiency. In human {beta}-cells loss of SLC30A8 leads to increased glucose responsiveness and reduced KATP channel function, which was also seen in isolated islets from carriers of the T2D-protective allele p.Trp325. These data position ZnT8 as an appealing target for treatment aiming at maintaining insulin secretion capacity in T2D.

genetics↗

bioRxiv2018

A high-resolution map of non-crossover events in mice reveals impacts of genetic diversity on meiotic recombination

During meiotic recombination in most mammals, hundreds of programmed DNA Double-Strand Breaks (DSBs) occur across all chromosomes in each cell at sites bound by the protein PRDM9. Faithful DSB repair using the homologous chromosome is essential for fertility, yielding either non-crossovers, which are frequent but difficult to detect, or crossovers. In certain hybrid mice, high sequence divergence causes PRDM9 to bind each homologue at different sites, \"asymmetrically\", and these mice exhibit meiotic failure and infertility, by unknown mechanisms. To investigate the impact of local sequence divergence on recombination, we intercrossed two mouse subspecies over five generations and deep-sequenced 119 offspring, whose high heterozygosity allowed detection of thousands of crossover and non-crossover events with unprecedented power and spatial resolution. Both crossovers and non-crossovers are strongly depleted at individual asymmetric sites, revealing that PRDM9 not only positions DSBs but also promotes their homologous repair by binding to the unbroken homologue at each site. Unexpectedly, we found that non-crossovers containing multiple mismatches repair by a different mechanism than single-mismatch sites, which undergo GC-biased gene conversion. These results demonstrate that local genetic diversity profoundly alters meiotic repair pathway decisions via at least two distinct mechanisms, impacting genome evolution and Prdm9-related hybrid infertility.

genetics↗

bioRxiv2018

Dexi disruption depletes gut microbial metabolites and accelerates autoimmune diabetes

Non-coding genetic variants in the CLEC16A gene on human chromosome 16p13.13 are associated with risk of autoimmune diseases, including type 1 diabetes and multiple sclerosis. In this region, we previously identified DEXI, a candidate causal gene of unknown function, which alters the risk of type 1 diabetes, where the T1D predisposing allele is associated with lower DEXI expression. Here, we demonstrate by CRISPR mutagenesis in vivo and deep phenotyping that disrupted Dexi expression accelerates diabetes in the non-obese diabetic (NOD) mouse, a spontaneous model of autoimmune pancreatic beta-cell destruction. Mutant mice have increased serum IgM and IgA concentrations compared to wild-type NOD mice, as well as changes in both the gut microbiome and molecular metabolites associated with microbial metabolism. These findings suggest that the mechanism by which DEXI alters diabetes risk involves the composition and function of the microbiome and its impact on host metabolites. Such metabolites, including short chain fatty acids such as butyrate, have been shown to alter the activity of the immune cells involved in beta-cell destruction and susceptibility of the beta cells to autoimmune attack.\n\nOne Sentence Summary: Disruption of the Dexi gene leads to accelerated diabetes in the non-obese diabetic (NOD) mouse, accompanied by changes in serum immunoglobulins, gut microbiome and microbial metabolites.

genetics↗