PLoS Genetics

Polygenic scores (PGS) are measures of genetic risk, derived from the results of genome wide association studies (GWAS). Previous work has proposed the coefficient of determination (R2) as an appropriate measure by which to compare PGS performance in a validation dataset. Here we propose correlation-based methods for evaluating PGS performance by adapting previous work which produced a statistical framework and robust test statistics for the comparison of multiple correlation measures in multiple populations...

Animals often grow and develop in unpredictable environments where factors like food availability, temperature, and oxygen levels can fluctuate dramatically. To ensure proper sexual maturation into adulthood, juvenile animals need to adapt their growth and developmental rates to these fluctuating environmental conditions. Failure to do so can result in impaired maturation and incorrect body size. Here we describe a mechanism by which Drosophila larvae adapt their development in low oxygen (hypoxia). During normal development, larvae grow and increase in mass until they reach critical weight (CW), after which point a neuroendocrine circuit triggers the production of the steroid hormone ecdysone from the prothoracic gland (PG), which promotes maturation to the pupal stage...

The health risks that arise from environmental exposures vary widely within and across human populations, and these differences are largely determined by genetic variation and gene-by-environment (gene-environment) interactions. However, risk assessment in laboratory mice typically involves isogenic strains and therefore, does not account for these known genetic effects. In this context, genetically heterogenous cell lines from laboratory mice are promising tools for population-based screening because they provide a way to introduce genetic variation in risk assessment without increasing animal use...

Cell adhesion requires linkage of transmembrane receptors to the cytoskeleton through intermediary linker proteins. Integrin-based adhesion to the extracellular matrix (ECM) involves large adhesion complexes that contain multiple cytoskeletal adapters that connect to the actin cytoskeleton. Many of these adapters, including the essential cytoskeletal linker Talin, have been shown to contain multiple actin-binding sites (ABSs) within a single protein. To investigate the possible role of having such a variety of ways of linking integrins to the cytoskeleton, we generated mutations in multiple actin binding sites in Drosophila talin...

An animal's skin provides a first point of contact with the sensory environment, including noxious cues that elicit protective behavioral responses. Nociceptive somatosensory neurons densely innervate and intimately interact with epidermal cells to receive these cues, however the mechanisms by which epidermal interactions shape processing of noxious inputs is still poorly understood. Here, we identify a role for dendrite intercalation between epidermal cells in tuning sensitivity of Drosophila larvae to noxious mechanical stimuli...

Genetic effects can be sex-specific, particularly for traits such as testosterone, a sex hormone. While sex-stratified analysis provides easily interpretable sex-specific effect size estimates, the presence of sex-differences in SNP effect implies a SNP×sex interaction. This suggests the usage of the often overlooked joint test, testing for an SNP's main and SNP×sex interaction effects simultaneously. Notably, even without individual-level data, the joint test statistic can be derived from sex-stratified summary statistics through an omnibus meta-analysis...

Genome-wide association studies (GWAS) have identified many genetic loci associated with complex traits and diseases in the past 20 years. Multiple heritable covariates may be added into GWAS regression models to estimate direct effects of genetic variants on a focal trait, or to improve the power by accounting for environmental effects and other sources of trait variations. When one or more covariates are causally affected by both genetic variants and hidden confounders, adjusting for them in GWAS will produce biased estimation of SNP effects, known as collider bias...

Gene expression can be influenced by genetic variants that are closely linked to the expressed gene (cis eQTLs) and variants in other parts of the genome (trans eQTLs). We created a multiparental mapping population by sampling genotypes from a single natural population of Mimulus guttatus and scored gene expression in the leaves of 1,588 plants. We find that nearly every measured gene exhibits cis regulatory variation (91% have FDR < 0.05). cis eQTLs are usually allelic series with three or more functionally distinct alleles...

Peptidoglycan (PG) is the main component of the bacterial cell wall; it maintains cell shape while protecting the cell from internal osmotic pressure and external environmental challenges. PG synthesis is essential for bacterial growth and survival, and a series of PG modifications are required to allow expansion of the sacculus. Endopeptidases (EPs), for example, cleave the crosslinks between adjacent PG strands to allow the incorporation of newly synthesized PG. EPs are collectively essential for bacterial growth and must likely be carefully regulated to prevent sacculus degradation and cell death...

The laboratory mouse has served as the premier animal model system for both basic and preclinical investigations for over a century. However, laboratory mice capture only a subset of the genetic variation found in wild mouse populations, ultimately limiting the potential of classical inbred strains to uncover phenotype-associated variants and pathways. Wild mouse populations are reservoirs of genetic diversity that could facilitate the discovery of new functional and disease-associated alleles, but the scarcity of commercially available, well-characterized wild mouse strains limits their broader adoption in biomedical research...

Integrons are adaptive devices that capture, stockpile, shuffle and express gene cassettes thereby sampling combinatorial phenotypic diversity. Some integrons called sedentary chromosomal integrons (SCIs) can be massive structures containing hundreds of cassettes. Since most of these cassettes are non-expressed, it is not clear how they remain stable over long evolutionary timescales. Recently, it was found that the experimental inversion of the SCI of Vibrio cholerae led to a dramatic increase of the cassette excision rate associated with a fitness defect...

Symbiomonas scintillans Guillou et Chrétiennot-Dinet, 1999 is a tiny (1.4 μm) heterotrophic microbial eukaryote. The genus was named based on the presence of endosymbiotic bacteria in its endoplasmic reticulum, however, like most such endosymbionts neither the identity nor functional association with its host were known. We generated both amplification-free shotgun metagenomics and whole genome amplification sequencing data from S. scintillans strains RCC257 and RCC24, but were unable to detect any sequences from known lineages of endosymbiotic bacteria...

The HostSeq initiative recruited 10,059 Canadians infected with SARS-CoV-2 between March 2020 and March 2023, obtained clinical information on their disease experience and whole genome sequenced (WGS) their DNA. We analyzed the WGS data for genetic contributors to severe COVID-19 (considering 3,499 hospitalized cases and 4,975 non-hospitalized after quality control). We investigated the evidence for replication of loci reported by the International Host Genetics Initiative (HGI); analyzed the X chromosome; conducted rare variant gene-based analysis and polygenic risk score testing...

Cultural exchange of fermentation techniques has driven the spread of Saccharomyces cerevisiae across the globe, establishing natural populations in many countries. Despite this, Oceania is thought to lack native populations of S. cerevisiae, only being introduced after colonisation. Here we investigate the genomic landscape of 411 S. cerevisiae isolated from spontaneous grape fermentations in Australia across multiple locations, years, and grape cultivars. Spontaneous fermentations contained highly recombined mosaic strains that exhibited high levels of genome instability...

Tissues are subject to multiple mechanical inputs at the cellular level that influence their overall shape and function. In the small intestine, actomyosin contractility can be induced by many physiological and pathological inputs. However, we have little understanding of how contractility impacts the intestinal epithelium on a cellular and tissue level. In this study, we probed the cell and tissue-level effects of contractility by using mouse models to genetically increase the level of myosin activity in the two distinct morphologic compartments of the intestinal epithelium, the crypts and villi...

Enterococci are commensal members of the gastrointestinal tract and also major nosocomial pathogens. They possess both intrinsic and acquired resistance to many antibiotics, including intrinsic resistance to cephalosporins that target bacterial cell wall synthesis. These antimicrobial resistance traits make enterococcal infections challenging to treat. Moreover, prior therapy with antibiotics, including broad-spectrum cephalosporins, promotes enterococcal proliferation in the gut, resulting in dissemination to other sites of the body and subsequent infection...

Fibrolamellar carcinoma (FLC) is a rare liver cancer that disproportionately affects adolescents and young adults. Currently, no standard of care is available and there remains a dire need for new therapeutics. Most patients harbor the fusion oncogene DNAJB1-PRKACA (DP fusion), but clinical inhibitors are not yet developed and it is critical to identify downstream mediators of FLC pathogenesis. Here, we identify long noncoding RNA LINC00473 among the most highly upregulated genes in FLC tumors and determine that it is strongly suppressed by RNAi-mediated inhibition of the DP fusion in FLC tumor epithelial cells...

Across the human genome, there are large-scale fluctuations in genetic diversity caused by the indirect effects of selection. This "linked selection signal" reflects the impact of selection according to the physical placement of functional regions and recombination rates along chromosomes. Previous work has shown that purifying selection acting against the steady influx of new deleterious mutations at functional portions of the genome shapes patterns of genomic variation. To date, statistical efforts to estimate purifying selection parameters from linked selection models have relied on classic Background Selection theory, which is only applicable when new mutations are so deleterious that they cannot fix in the population...

Age-related hearing loss (ARHL) is a common sensory impairment with complex underlying mechanisms. In our previous study, we performed a meta-analysis of genome-wide association studies (GWAS) in mice and identified a novel locus on chromosome 18 associated with ARHL specifically linked to a 32 kHz tone burst stimulus. Consequently, we investigated the role of Formin Homology 2 Domain Containing 3 (Fhod3), a newly discovered candidate gene for ARHL based on the GWAS results. We observed Fhod3 expression in auditory hair cells (HCs) primarily localized at the cuticular plate (CP)...

Permanent heterozygous loci, such as sex- or mating-compatibility regions, often display suppression of recombination and signals of genomic degeneration. In Basidiomycota, two distinct loci confer mating compatibility. These loci encode homeodomain (HD) transcription factors and pheromone receptor (Pra)-ligand allele pairs. To date, an analysis of genome level mating-type (MAT) loci is lacking for obligate biotrophic basidiomycetes in the Pucciniales, an order containing serious agricultural plant pathogens...