Genetics最新文献

Vps13 transporters are large, rod-shaped proteins that mediate the bulk transfer of lipids between intracellular membranes via a hydrophobic channel formed by multiple "repeating beta-groove" (RBG) domains. Gain-of-function mutants in yeast Vps13 bypass the need for phospholipid trafficking by the endoplasmic reticulum-mitochondrion contact site complex ERMES. This work shows these same mutants can partially compensate for defects in lipid transfer at a different membrane contact site, suggesting that these VPS13 alleles encode a protein that is more efficient than wild type Vps13 at lipid transfer. The gain-of-function mutations map to similar positions on different RBG repeats within the predicted Vps13 structure. Computational modeling of the structural dynamics of individual RBG repeats indicates that these mutations are biased to regions that act as hinges within the protein. We propose that lipid transport by Vps13 involves cycling between conformational states and that these mutants increase lipid transport by altering the dynamics of this conformational shift.

The rate and chromosomal positioning of meiotic recombination significantly affects the distribution of the genetic diversity in eukaryotic genomes. Many studies have revealed sex-specific recombination patterns, with male recombination typically biased toward chromosome ends, while female recombination is more evenly distributed along chromosomes. It has been proposed that such a pattern in females may counteract meiotic drive caused by selfish genetic elements associated with centromeres and should not occur in species devoid of clearly defined centromeres, but evidence for this expectation is scarce. Here, we constructed a sex-specific genetic map of a species with holocentric chromosomes, the bulb mite (Rhizoglyphus robini), a model organism for sexual selection studies with heritable alternative male reproductive phenotypes. We found a similar recombination landscape in both males and females, with a consistent pattern of increased rates towards both chromosome ends, and a higher recombination rate in females than in males. The recombination rate was positively correlated with repeat density and negatively correlated with gene density. Our results are consistent with the meiotic drive hypothesis and suggest that the evolution of recombination patterns is closely linked to chromosome features.

Phenotypic variation in species arises from genetic differences and environmental influences on gene expression. Differences in epigenetic modifications, such as histone modifications and DNA methylation, can also contribute to phenotypic variations, even among individuals with identical genetic information. However, the underlying molecular mechanisms are not yet fully understood, particularly in vertebrates. The number of fin rays in teleosts, such as medaka, serves as a useful model for studying this variation. In a previous study, we demonstrated that the teleost Hox code plays a crucial role in determining the anterior-posterior identity necessary for the formation of dorsal and anal fins. In this study, we investigated widefins medaka, a spontaneous mutant displaying phenotypic variation in the number of dorsal and anal fin rays. Long-read whole-genome sequencing revealed that an extremely large transposon, Teratorn, containing a herpesvirus genome, was inserted into the hoxc12a 3'-UTR. This insertion decreased hoxc12a expression and, in some cases, also affected neighboring hox genes, resulting in variations in fin size and the presence or absence of dorsal fins. Additionally, hoxc6a, located 50 kb away from the insertion, was also downregulated in widefins medaka. These findings suggest that this large transposon insertion leads to a reduction in nearby hox gene expression, contributing to the phenotypic variation observed in widefins medaka. These results highlight the role of transposable elements and epigenetic regulation in generating phenotypic diversity in vertebrates.

The Elg1 Replication Factor C-like complex (Elg1-RLC) that functions as a proliferating cell nuclear antigen (PCNA) unloader, is known to be involved in multiple DNA replication/repair-related activities from yeast to humans. By exploiting disassembly prone PCNA mutants, we reveal that Elg1-RLC uses its PCNA unloading activity to counter the DNA-alkylating agent methyl-methanesulfonate (MMS)-mediated slow progression of replication forks (RFs). Despite having a largely functional DNA damage response (DDR), the viability loss of elg1Δ-DDR double mutants, in the presence of MMS, matches that of mec1Δ and rad53Δ cells, deficient for the central checkpoint kinases. This suggests that elg1Δ-DDR double mutants experience RF collapse when exposed to MMS. Indeed, in response to MMS, accumulation of Rad52 foci in the replicative elg1Δ-DDR cells supports this possibility. However, the failure of rescuing elg1Δ-DDR mutants by elevating deoxynucleoside triphosphate (dNTP) levels (by deleting the ribonucleotide reductase SML1) eliminates the possibility of a Rad53-regulated dNTP shortage-mediated fork collapse. Thus, we propose an S-phase checkpoint regulatory role of Elg1-RLC that works through a noncanonical pathway parallel to the canonical one. Collectively, our findings suggest a model in which Elg1-RLC, by timely unloading chromatin-bound PCNA from the damaged/stalled forks, coordinates the DDR pathways to safeguard the integrity of RFs under replication stress.

Genetic variation that influences complex disease susceptibility is introduced into the population by mutation and removed by natural selection and genetic drift. This mutation-selection-drift balance (MSDB) shapes the prevalence of a disease and its genetic architecture. To date, however, MSDB has been modeled only for monogenic (Mendelian) diseases. Here, we develop an MSDB model for complex disease susceptibility: we assume that genotype relates to disease risk according to the canonical liability threshold model and that the selection on variants affecting risk stems from the fitness cost of the disease. We focus on diseases that are highly polygenic, entail a substantial fitness cost, and are neither extremely common in the population nor exceedingly rare. The comparison of model predictions with genome-wide association studies and other observations in humans indicates that common genetic variation affecting complex disease susceptibility is little affected by directional selection and instead shaped by pleiotropic stabilizing selection on other traits. In turn, directional selection may exert a more substantial effect on rare, large-effect variants. Our results also suggest that current estimates of disease heritability are likely biased. The model thus provides a better understanding of the evolutionary processes that shape the architecture and prevalence of complex diseases.

A key challenge in human genetics is the discovery of modifiable causal risk factors for complex traits and diseases. Mendelian randomization (MR) using molecular traits as exposures is a particularly promising approach for identifying such risk factors. Despite early successes with the application of MR to biomarkers such as low-density lipoprotein cholesterol and C-reactive protein, recent studies have revealed a more nuanced picture, with widespread horizontal pleiotropy. Using data from the UK Biobank, we illustrate the issue of horizontal pleiotropy with 2 case studies, one involving glycolysis and the other involving vitamin D synthesis. We demonstrate that, although the measured metabolites (pyruvate or histidine, respectively) do not have a direct causal effect on the outcomes of interest (red blood cell count or vitamin D level), we can still use variant effects on these downstream metabolites to infer how they perturb protein function in different gene regions. This allows us to use variant effects on metabolite levels as proxy exposures in a cis-MR framework, thus rediscovering the causal roles of histidine ammonia lyase (HAL) in vitamin D synthesis and glycolysis pathway in red blood cell survival. We also highlight the assumptions that need to be satisfied for cis-MR with proxy exposures to yield valid inferences and discuss the practical challenges of meeting these assumptions.

Heterotrimeric G proteins transduce signals from G protein-coupled receptors, which mediate key aspects of neuronal development and function. Mutations in the GNAI1 gene, which encodes Gαi1, cause a disorder characterized by developmental delay, intellectual disability, hypotonia, and epilepsy. However, the mechanistic basis for this disorder remains unknown. Here, we show that GNAI1 is required for ciliogenesis in human cells and use Caenorhabditis elegans as a whole-organism model to determine the functional impact of 7 GNAI1-disorder patient variants. Using CRISPR-Cas9 editing in combination with robust cellular (cilia morphology) and behavioral (chemotaxis) assays, we find that T48I, K272R, A328P, and V334E orthologous variants impact both cilia assembly and function in AWC neurons, M88V and I321T have no impact on either phenotype, and D175V exerts neuron-specific effects on cilia-dependent sensory behaviors. Finally, we validate in human ciliated cell lines that D173V, K270R, and A326P GNAI1 variants disrupt ciliary localization of the encoded human Gαi1 proteins similarly to their corresponding orthologous substitutions in the C. elegans  ODR-3 (D175V, K272R, and A328P). Overall, our findings determine the in vivo effects of orthologous GNAI1 variants and contribute to the mechanistic understanding of GNAI1-disorder pathogenesis as well as neuron-specific roles of ODR-3 in sensory biology.