Genetics最新文献

Integrin adhesion complexes (IACs) are a network of proteins that anchor cells to the extracellular matrix. In C. elegans muscle IACs exist at the bases of dense bodies and M-lines, and at the boundaries of adjacent muscle cells (MCBs). Proper assembly of IACs requires the RacGEF PIX-1 and members of the PIX-1 pathway. We report that investigation into the original Million Mutation Project strain that led us to uncover the role of PIX-1 in muscle, revealed a genetic enhancer of the pix-1 phenotype. Genetic mapping shows that the enhancer is a recessive mutation in ipmk-1. ipmk-1 encodes inositol phosphate multikinase and converts PIP2 to PIP3, IP3 to IP4, and IP4 to IP5. pix-1 loss of function mutants show reduced accumulation of IAC proteins at the MCB, and ipmk-1; pix-1 doubles additionally display large gaps between muscle cells. ipmk-1 similarly enhances other members of the PIX pathway including PAK-1, and the RacGAP RRC-1. Lack of ipmk-1 itself shows abnormal clumping of IAC proteins at MCBs and decreased animal locomotion. Muscle activity contributes to formation of the gap, since suppression occurs by paralysis induced by unc-13. The MCB defect of ipmk-1 is not due to decreased IP3 and Ca2+ signaling from analysis of ipmk-1; ipp-5 doubles and GCaMP Ca2+ measurements. PIP3 localizes to the MCB and between dense bodies and is decreased in ipmk-1. Mutants in DAF-18 (PTEN), which converts PIP3 to PIP2, partially suppress the clumping phenotype of ipmk-1, suggesting that the PIP3 to PIP2 ratio is important for IAC organization.

An individual's phenotype reflects a complex interplay of the direct effects of their DNA, epigenetic modifications of their DNA induced by their parents, and indirect effects of their parents' DNA. Here, we derive how the genetic variance within a population is changed under the influence of indirect maternal, paternal and parent-of-origin effects under random mating. We also consider indirect effects of a sibling, in particular how the genetic variance is altered when looking at the phenotypic difference between two siblings. The calculations are then extended to include assortative mating (AM), which alters the variance by inducing increased homozygosity and correlations within and across loci. AM likely leads to covariance of parental genetic effects, a measure of the similarity of parents in the indirect effects they have on their children. We propose that this assortment for parental characteristics, where biological parents create similar environments for their children, can create shared parental effects across traits and the appearance of cross-trait AM. Our theory shows how the resemblance among relatives increases under both AM, indirect and parent-of-origin effects. When our model is used to predict correlations among relatives in human height, we find that explaining the patterns observed in real data requires both indirect genetic effects and assortative mating. The degree to which direct, indirect and epigenetic effects shape the phenotypic variance of complex traits remains an open question that requires large-scale family data to be resolved.

Population genetic studies use genetic data to understand aspects of the evolutionary history of species. Here, we extend the piecewise-homogeneous structured coalescent framework to complex models where the parameters of the model, and thus the state space, change between periods of constant gene flow. To do this, we introduce glue matrices to map one state space to another, hence enabling the computation of the Inverse Instantaneous Coalescence Rate (IICR) using Q-matrices of different dimensions. This approach allows us to study structured models where the number of demes changes forward in time due to extinction or foundation of demes. Our analysis confirms that interpreting IICR curves as indicators of changes in Ne can be misleading and that a robust theoretical framework is required to ensure the correct interpretation of coalescent-based inferential methods. We show that there are cases where new deme foundations can generate an increase in the IICR (forward in time) hence producing an intuitive change where an increase in the IICR follows an increase in the size of the population. However, when we explore the impact of changes in migration rates, timing of deme creation or deletion, and sampling strategies on the IICR, we also identify several counter-intuitive results, where changes in the IICR and the total size of the population appear disconnected. For instance, we find that the IICR starts to decrease several generations before any change in the number of demes, effectively anticipating the upcoming change as if the population 'knew' something was about to happen. By presenting examples of IICRs for various transitions and sampling scenarios, we emphasize the importance of a thorough understanding of the IICR as a foundation for accurate demographic inference.}{nuanced approaches in population genetic studies.

Understanding how genetic variation contributes to organism-wide phenotypes is critical for identifying mechanisms of disease. Here, we present a computational approach to analyze whole-organism comorbidities associated with genes underlying non-obstructive azoospermia (NOA), the most severe form of male infertility. We curated 204 mouse genes with experimentally validated spermatogenic failure and mapped their orthologs and phenotype annotations across humans, M. musculus, D. rerio, D. melanogaster and C. elegans using a unified cross-species phenotype structure. This framework integrates a newly developed reproductive phenotype ontology with standardized whole-body phenotype categories to enable direct cross-species comparisons, using thousands of genotype-phenotype associations stored in model organism databases. Our analysis shows that most NOA genes have conserved orthologs across models, and that perturbation of these genes is frequently associated with non-reproductive phenotypes. In particular, integumentary defects and neoplastic phenotypes recur across species, supporting a shared genetic basis for epidemiological links between male infertility and systemic disease. Gene-level comorbidity patterns are partially predictable from single-cell RNA-seq, whole-body gene expression, and Gene Ontology annotations, suggesting that fundamental biological constraints shape the systemic consequences of reproductive gene dysfunction. Clustering genes by comorbidity profiles further distinguished genes with isolated reproductive effects from those with broad organismal consequences. This work demonstrates the power of ontology-based cross-species analysis for identifying pleiotropic effects of Mendelian disease mutations, and provides a resource, CoMorbidity DataBase Mapper (CoMo DBM), for joint analysis of genotype-phenotype associations in model organism databases.

Precise regulation of chromatin structure is essential for ensuring genome stability and cellular function. In Saccharomyces cerevisiae, the YEATS (Yaf9-ENL-AF9-Taf14-Sas5) domain protein Yaf9 is a shared component of the NuA4 acetyltransferase and the SWR1 chromatin remodelling complexes. We investigated the function of Yaf9 and discovered that it becomes essential for survival when histone H4 acetylation is impaired. The loss of Yaf9 in a strain with impaired H4 acetylation led to cell cycle arrest in the G2/M phase and activation of the homologous recombination pathway. This synthetic lethality was not recapitulated by inactivating the Yaf9 YEATS domain, suggesting that it is independent of Yaf9's ability to recognise acyl-modified lysine residues. We also found that Yaf9 was required in both NuA4 and SWR1 complexes to ensure cell viability in the absence of H4 acetylation. Together, these findings reveal a compensatory relationship between Yaf9 and histone H4 acetylation, suggesting that Yaf9 acts as a functional link between chromatin remodelling and histone modification pathways to maintain genome integrity under conditions of chromatin stress.

Histone H1 and related linker histones play critical roles in chromosome organization in eukaryotic cells. Although histone H1 is essential for compacting nucleosomes into chromatin fibers and is a major structural component of chromosomes, its association with chromatin is highly dynamic. Histone H1 exchange modulates the accessibility of regulatory proteins to DNA and has been implicated in the regulation of gene expression and cellular pluripotency. Relatively little is known, however, about how histone H1 binding, exchange and function is regulated in vivo. In this study, we investigated the regulation of histone H1 function in Drosophila using live analysis and confocal microscopy. A gain-of-function genetic screen identified several factors that affect chromosome structure, histone H1 binding or histone H1 exchange, including the ATP-dependent chromatin-remodeling factor XNP, the hypoxia-induced factor Scylla, the winged helix transcription factor Jumeau and the microRNA bantam. Our findings show that altered expression of single factors can have surprisingly global effects on higher-order chromatin structure and histone H1 binding in vivo, with the potential to trigger large scale changes in genome organization and accessibility.

The optimal choice of parents and crosses and, therefore, the prediction of the segregation variance are of high relevance to maximize genetic gain in breeding programs. Several methods have been developed for the prediction of segregation variance, includingcorrelation with genotypic diversity, progeny simulations, or algebraic derivations in case of a diploid inheritance. To the best of our knowledge, no algebraic derivation using parental genotypic information is available to predict segregation variance for autotetraploid species. The objectives of our study were to (1) derive algebraic derivation based on linkage disequilibrium (LD) between linked loci to predict the segregation variance in autotetraploid species; (2) compare the performance of segregation variance estimated based on simulated progenies and the algebraic derivations; (3) investigate by simulations how experimental parameters affect the accuracy of segregation variance prediction; and (4) compare the segregation variance estimated in empirical data of potato and the one based on the algebraic derivations. The segregation variance estimated by the developed derivations showed very high correlations with the one observed in large simulated progenies, but those were lower when phased parental haplotypes were not available or family size decreased. The correlation between segregation variance estimated by the developed derivation and the empirical data was low. This could be attributed to the small family size used in the study, which we could show to increase LD between unlinked loci. The proposed algebraic derivations promise to be a precise alternative to simulations to help breeders in optimizing their family choices and sizes considering the segregation variance.

Many mutations have detrimental effects. The mutation load in a population depends on the efficacy of purifying selection in removing deleterious genetic variation. Here, we estimated the proportion of deleterious mutations segregating in 24 population samples of 19 bird species. Exploiting the conserved avian karyotype with high variation in recombination rate and GC content, we quantified the joint effects of effective population size (Ne), recombination (r) and GC-biased gene-conversion (gBGC). In agreement with the nearly-neutral theory of molecular evolution, mutation load was substantially higher in populations with small Ne. Purging efficacy increased with recombination rate resulting in more than a two-fold difference of genetic load between large and small chromosomes. GC-biased mutations contributed about one third to the pool of deleterious mutations. Their expected accumulation in regions of high recombination was offset by purging efficacy in large, but not small populations. This study provides insight into how the interaction of evolutionary processes shapes mutation load. It suggests that genetic risk factors in small populations are fueled by gBGC and cluster in regions of low recombination.

The chromatin remodelling factor and histone chaperone Yta7 is a member of the ATAD2 family of AAA+ ATPases from Saccharomyces cerevisiae that has in vivo functions consistent with both nucleosome assembly and disassembly activity. At the centromere, Yta7 is required for proper deposition of the centromeric histone H3 variant CENP-A Cse4. Here, we performed a genetic screen to identify suppressors of the defect of a mutation in CENP-A Cse4 that impairs the interaction with the DNA of the centromeric nucleosome (cse4-S135A). This identified two suppressor alleles of YTA7, yta7-R483S and -D518E, which are in the AAA1 domain of Yta7. Interestingly, Yta7-R483S enhanced the deposition of CENP-A Cse4 at the centromere and showed a ∼40% increased ATPase activity, suggesting that the hyperactivity of the motor domain is responsible for suppression of the cse4-S135A growth defect. In contrast, Yta7-D518E showed reduced ATPase activity, but both Yta7-R483S and -D518E retained the interaction with CENP-A Cse4 and centromeric sequences as well as hexamer formation in vitro. Our analysis of in vivo interactions between Yta7 and CENP-A Cse4 further showed that the two AAA+ domains and the non-canonical bromodomain of Yta7 are necessary and sufficient for interaction with CENP-A Cse4. The genetic screen furthermore revealed a mutation in the chromatin remodeler Fun30 as a suppressor of the centromeric defect of cse4-S135A. Altogether, this work reveals unusual, hypermorphic properties of Yta7 variants and highlights the importance of nucleosome remodelers in establishing centromeric chromatin.

The abnormal oocyte (ao) gene of Drosophila melanogaster is a maternal-effect lethal gene previously identified as encoding a transcriptional regulator of core histones. However, background genetic mutations in existing ao mutant strains could compromise their utility in manipulating histone levels. To distinguish the true ao phenotype from background effects, we created two new ao reagents: a CRISPR/Cas9-mediated knockout of the ao allele for genetic and molecular analyses and an epitope-tagged ao allele for cytological experiments. Using these reagents, we confirm previous findings that loss of ao causes maternal-effect lethality, which can be rescued by either a decrease in the histone gene copy number or by Y chromosome heterochromatin. Our data indicate that ao genetically interacts with the heterochromatin, as previously suggested. However, contrary to a prior study, we detected neither Ao localization to histone genes nor ao repression of core histone transcript levels. Thus, the molecular basis for ao-associated maternal-effect lethality remains unknown.