In PLOS Genetics, researchers from the Jackson Laboratory and elsewhere describe a transcriptomics-based strategy to explore the genetic heterogeneity and modifiers of late-onset Alzheimer's disease (LOAD). Using gene co-expression modules found in more than 2,100 post-mortem human brain samples, the researchers came up with a quantitative phenotype approach to assess LOAD heterogeneity within submodules — an approach they used to find several LOAD subtypes with whole-genome and post-mortem RNA sequences from Alzheimer's disease samples in three collections. "We demonstrate the effectiveness of our submodules by identifying associated variants that are either novel or have been implicated previously in late-onset Alzheimer's disease," they report, noting that "systems-level understanding of the transcriptome is especially important for translating human disease-associated variants into models that can accelerate the development of therapies."
A team from the UK, Cameroon, and the US explore insecticide resistance diversity and evolution in Africa, focusing on the malaria vector mosquito Anopheles funestus, for another paper in PLOS Genetics. Using reduced representation double digest restriction-site associated DNA sequencing and pooled whole-genome sequencing on almost 200 An. funestus mosquitoes collected in Ghana, Cameroon, Uganda, Malawi, and Zambia, the researchers assessed population structure, gene flow, and potential selection signatures in mosquitoes in West, Central, East, and Southern Africa. Along with regional genetic differences in mosquito populations, and other insecticide resistance-related patterns, the authors note that "[f]ine-scale analysis of the major pyrethroid resistance-associated genomic regions revealed complex molecular evolution with evidence of copy number variation, transposon insertion, and a gene conversion highlighting the risk that if this level of selection and spread of resistance continues unabated, our ability to control malaria with current interventions will be compromised."
For a paper in PLOS One, investigators at the University of Bonn and elsewhere take a look at de novo mutations contributing to an upper digestive tract malformation called esophageal atresia with or without tracheoesophageal fistula (EA/TEF) using a combination of exome sequencing on affected families and follow-up expression analyses on mouse embryo models. With exome sequence data representing dozens of children with EA/TEF and their unaffected parents, the team saw new or rare de novo variants in 20 candidate genes and used in silico prediction analyses and additional mouse expression data to narrow in on suspicious de novo variants in the ZFHX3, TRPS1, and CDH7 genes. Although further EA/TEF-related variants in ZFHX3 did not turn up when the authors did targeted sequencing on that gene in 192 more individuals with the condition, their broader results led them to speculate that EA/TEF may stem from "rare mutational de novo events in genes involved in foregut development."