Genetics最新文献

{"title":"New perspectives on Drosophila melanogaster de novo gene origination revealed by investigation of ancient African genetic variation.","authors":"Julie M Cridland, Elizabeth S Polston, David J Begun","doi":"10.1093/genetics/iyaf044","DOIUrl":"10.1093/genetics/iyaf044","url":null,"abstract":"<p><p>De novo genes can be defined as sequences producing evolutionarily derived transcripts that are not homologous to transcripts produced in an ancestor. While they appear to be taxonomically widespread, there is little agreement regarding their abundance, their persistence times in genomes, the population genetic processes responsible for their spread or loss, or their possible functions. In Drosophila melanogaster, 2 approaches have been used to discover these genes and investigate their properties. One uses traditional comparative approaches and existing genomic resources and annotations. A second approach uses raw transcriptome data to discover unannotated genes for which there is no evidence of presence in related species. Investigations using the second approach have focused on D. melanogaster genotypes from recently established cosmopolitan populations. However, most of the genetic variation in the species is found in African populations, suggesting the possibility that fuller understanding of genetic novelties in the species may follow from studies of these populations. Here, we investigate de novo gene candidates expressed in testis and accessory glands in a sample of flies from Zambia and compare them with candidate de novo genes expressed in North American populations. We report a large number of previously undiscovered de novo gene candidates, most of which are expressed polymorphically. Many are predicted to code for secreted proteins. In spite of much different levels of genomic variation in Zambian and North American populations, they express similar numbers of candidate de novo genes. We find evidence from genetic analysis of Raleigh inbred lines that a fraction of rarely expressed gene candidates in this population represent deleterious transcription promoted by inbreeding depression. Many de novo gene candidates are expressed in multiple tissues and both sexes, raising questions about how they may interact with natural selection. The relative importance of positive and negative selection, however, remains unclear.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12059636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Performance of qpAdm-based screens for genetic admixture on graph-shaped histories and stepping stone landscapes.","authors":"Olga Flegontova, Ulaş Işıldak, Eren Yüncü, Matthew P Williams, Christian D Huber, Jan Kočí, Leonid A Vyazov, Piya Changmai, Pavel Flegontov","doi":"10.1093/genetics/iyaf047","DOIUrl":"10.1093/genetics/iyaf047","url":null,"abstract":"<p><p>qpAdm is a statistical tool that is often used for testing large sets of alternative admixture models for a target population. Despite its popularity, qpAdm remains untested on 2D stepping stone landscapes and in situations with low prestudy odds (low ratio of true to false models). We tested high-throughput qpAdm protocols with typical properties such as number of source combinations per target, model complexity, model feasibility criteria, etc. Those protocols were applied to admixture graph-shaped and stepping stone simulated histories sampled randomly or systematically. We demonstrate that false discovery rates of high-throughput qpAdm protocols exceed 50% for many parameter combinations since: (1) prestudy odds are low and fall rapidly with increasing model complexity; (2) complex migration networks violate the assumptions of the method; hence, there is poor correlation between qpAdm P-values and model optimality, contributing to low but nonzero false-positive rate and low power; and (3) although admixture fraction estimates between 0 and 1 are largely restricted to symmetric configurations of sources around a target, a small fraction of asymmetric highly nonoptimal models have estimates in the same interval, contributing to the false-positive rate. We also reinterpret large sets of qpAdm models from 2 studies in terms of source-target distance and symmetry and suggest improvements to qpAdm protocols: (1) temporal stratification of targets and proxy sources in the case of admixture graph-shaped histories, (2) focused exploration of few models for increasing prestudy odds; and (3) dense landscape sampling for increasing power and stringent conditions on estimated admixture fractions for decreasing the false-positive rate.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12118350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143765535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nuclear deformability depends on H3K9-methylated heterochromatin anchorage to the nuclear periphery in Caenorhabditis elegans.","authors":"Ellen F Gregory, G W Gant Luxton, Daniel A Starr","doi":"10.1093/genetics/iyaf086","DOIUrl":"https://doi.org/10.1093/genetics/iyaf086","url":null,"abstract":"<p><p>Nuclei adjust their deformability while migrating through constrictions to enable structural changes and maintain nuclear integrity. The effect of heterochromatin anchored at the nucleoplasmic face of the inner nuclear membrane on nuclear morphology and deformability during in vivo nuclear migration through constricted spaces remains unclear. Here, we show that abolishing peripheral heterochromatin anchorage by eliminating CEC-4, a chromodomain protein that tethers H3K9-methylated chromatin to the nuclear periphery, disrupts constrained P-cell nuclear migration in Caenorhabditis elegans larvae in the absence of the established LINC complex-dependent pathway. This effect was suppressed by mutations that stabilize the lamin LMN-1. CEC-4 acts in parallel to an actin and CDC-42-based pathway. We also demonstrate the necessity for the chromatin methyltransferase MET-2 and the demethylase JMJD-1.2 during P-cell nuclear migration in the absence of functional LINC complexes. We conclude that H3K9-methylated chromatin needs to be anchored to the nucleoplasmic face of the inner nuclear membrane to help facilitate nuclear migration through constricted spaces in vivo.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144021846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of lifespan across Diversity Outbred mouse studies identifies multiple longevity-associated loci.","authors":"Martin N Mullis, Kevin M Wright, Anil Raj, Daniel M Gatti, Peter C Reifsnyder, Kevin Flurkey, Jonathan R Archer, Laura Robinson, Andrea Di Francesco, Karen L Svenson, Ron Korstanje, David E Harrison, J Graham Ruby, Gary A Churchill","doi":"10.1093/genetics/iyaf081","DOIUrl":"https://doi.org/10.1093/genetics/iyaf081","url":null,"abstract":"<p><p>Lifespan is an integrative phenotype whose genetic architecture is likely to highlight multiple processes with high impact on health and aging. Here, we conducted a genetic mega-analysis of longevity in Diversity Outbred (DO) mice that included 2,444 animals from three independently conducted lifespan studies. We identified eight loci that contributed significantly to lifespan independently of diet and drug treatment in at least one study. One of these loci also influenced lifespan in a sex-dependent manner, and we detected an additional locus with a diet-specific effect on lifespan. Collectively, these loci explained over half of the estimated heritable variation in lifespan across these studies and provided insight into the genetic architecture of lifespan in DO mice.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potassium-selective channelrhodopsins can exert hyper- or depolarizing effects in excitable cells of Caenorhabditis elegans, depending on experimental conditions.","authors":"Christiane Ruse, Jana Liewald, Marius Seidenthal, Linda Tillert, Johannes Vierock, Alexander Gottschalk","doi":"10.1093/genetics/iyaf083","DOIUrl":"https://doi.org/10.1093/genetics/iyaf083","url":null,"abstract":"<p><p>Among the most frequent applications of optogenetic tools are those for depolarization of excitable cells such as neurons and muscles. Equally important are inhibitory tools that act through cellular hyperpolarization, which often rely on chloride conductance. Yet, in vivo, re- and hyperpolarization is typically mediated by potassium. Recently, light-gated ion channels with potassium selectivity were identified (Kalium channelrhodopsins, KCRs), and their use described in different organisms. Here, we characterized HcKCR1 and WiChR in cholinergic neurons and muscles of the nematode Caenorhabditis elegans. Hyperpolarization of both cell types induces muscle relaxation and elongation of the animals. We analyzed body length changes during illumination, to benchmark stimulation parameters like light intensity and duration. For HcKCR1 in cholinergic neurons, continuous illumination at high light intensities (1-4.5 mW/mm²) evoked only a transient elongation, while stimulation at 0.1 mW/mm² maintained inhibition for the duration of the stimulus in some transgenic strains. Electrophysiological characterization verified that initial hyperpolarization quickly changed to depolarization, and current-voltage relationships indicate that the initial channel selectivity for potassium became progressively tolerant for sodium during the light pulse, scaling with on light intensity. For animals expressing WiChR, we again observed brief hyperpolarization during continuous illumination, however, still during the stimulus, this changed to depolarization. This effect was long lasting, requiring dozens of seconds for reversion, but could be reduced by pulsed illumination and fully avoided by less efficient channel activation using green or orange light. Hence, KCRs can be applied to hyperpolarize C. elegans cells, but require optimized expression and illumination parameters.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144054968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"rDNA copy number variation affects yeast fitness in response to different environments.","authors":"Kevin Thornton, Elizabeth X Kwan, Kerry Bubb, Luana Paleologu, M K Raghuraman, Bonita J Brewer, Josh T Cuperus, Christine Queitsch","doi":"10.1093/genetics/iyaf075","DOIUrl":"https://doi.org/10.1093/genetics/iyaf075","url":null,"abstract":"<p><p>Ribosomal DNA (rDNA) in eukaryotes is maintained in hundreds of copies with rDNA copy number varying greatly among individuals within a species. In the budding yeast Saccharomyces cerevisiae, the rDNA copy number across wild isolates ranges from 90 to 300 copies. Previous studies showed that 35 rDNA copies are sufficient for ribosome biogenesis in this yeast and enable wild-type-like growth in standard laboratory growth conditions. We addressed two major questions concerning rDNA copy number variation in this yeast: (1) What are the fitness consequences of rDNA copy number variation outside and within the natural range in standard laboratory growth conditions? (2) Do these fitness effects change in different growth conditions? We used growth competitions to compare the fitness effects of rDNA copy number variation in otherwise isogenic strains whose rDNA copy number ranged from 35 to 200. In standard growth conditions, we found that fitness gradually increases from 35 rDNA copies until reaching a plateau that spans from 98 to 160 rDNA copies, well within the natural range. However, rDNA copy number-dependent fitness differed across environments. The gradual fitness increase with increasing rDNA copy number in standard growth conditions gave way to a markedly lower fitness of strains with copy numbers below the natural range in these two stress conditions. These results suggest that selective pressures drive rDNA copy number in this yeast to at least ∼100 copies and that a higher number of copies might buffer against environmental stress. The similarity of the S. cerevisiae rDNA copy number range to the ranges reported in C. elegans, D. melanogaster, and humans points to conserved selective pressures maintaining the range of natural rDNA copy number in these highly diverse species.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TF2TG: an online resource mining the potential gene targets of transcription factors in Drosophila.","authors":"Yanhui Hu, Jonathan Rodiger, Yifang Liu, Chenxi Gao, Ying Liu, Mujeeb Qadiri, Austin Veal, Martha L Bulyk, Norbert Perrimon","doi":"10.1093/genetics/iyaf082","DOIUrl":"https://doi.org/10.1093/genetics/iyaf082","url":null,"abstract":"<p><p>Sequence-specific transcription factors (TFs) are key regulators of many biological processes, controlling the expression of their target genes through binding to the cis- regulatory regions such as promoters and enhancers. Each TF has unique DNA binding site motifs, and large-scale experiments have been conducted to characterize TF-DNA binding preferences. However, no comprehensive resource currently integrates these datasets for Drosophila. To address this need, we developed TF2TG (\"transcription factor\" to \"target gene\"), a comprehensive resource that combines both in vitro and in vivo datasets to link transcription factors (TFs) to their target genes based on TF-DNA binding preferences along with the protein-protein interaction data, tissue-specific transcriptomic data, and chromatin accessibility data. Although the genome offers numerous potential binding sites for each TF, only a subset is actually bound in vivo, and of these, only a fraction is functionally relevant. For instance, some TFs bind to their specific sites due to synergistic interactions with other factors nearby. This integration provides users with a comprehensive list of potential candidates as well as aids users in ranking candidate genes and determining condition-specific TF binding for studying transcriptional regulation in Drosophila.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144026596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing selection on complex traits through conditional frequency spectra.","authors":"Roshni A Patel, Clemens L Weiß, Huisheng Zhu, Hakhamanesh Mostafavi, Yuval B Simons, Jeffrey P Spence, Jonathan K Pritchard","doi":"10.1093/genetics/iyae210","DOIUrl":"10.1093/genetics/iyae210","url":null,"abstract":"<p><p>Natural selection on complex traits is difficult to study in part due to the ascertainment inherent to genome-wide association studies (GWAS). The power to detect a trait-associated variant in GWAS is a function of its frequency and effect size - but for traits under selection, the effect size of a variant determines the strength of selection against it, constraining its frequency. Recognizing the biases inherent to GWAS ascertainment, we propose studying the joint distribution of allele frequencies across populations, conditional on the frequencies in the GWAS cohort. Before considering these conditional frequency spectra, we first characterized the impact of selection and non-equilibrium demography on allele frequency dynamics forwards and backwards in time. We then used these results to understand conditional frequency spectra under realistic human demography. Finally, we investigated empirical conditional frequency spectra for GWAS variants associated with 106 complex traits, finding compelling evidence for either stabilizing or purifying selection. Our results provide insights into polygenic score portability and other properties of variants ascertained with GWAS, highlighting the utility of conditional frequency spectra.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12005249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142847951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The divergence of mean phenotypes under persistent Gaussian selection.","authors":"Michael Lynch, Scott Menor","doi":"10.1093/genetics/iyaf031","DOIUrl":"10.1093/genetics/iyaf031","url":null,"abstract":"<p><p>Although multigenic traits are often assumed to be under some form of stabilizing selection, numerous aspects of the population-genetic environment can cause mean phenotypes to deviate from presumed optima, often in ways that effectively transform the fitness landscape to one of directional selection. Focusing on an asexual population, we consider the ways in which such deviations scale with the relative power of selection and genetic drift, the number of linked genomic sites, the magnitude of mutation bias, and the location of optima with respect to possible genotypic space. Even in the absence of mutation bias, mutation will influence evolved mean phenotypes unless the optimum happens to coincide exactly with the mean expected under neutrality. In the case of directional mutation bias and large numbers of selected sites, effective population sizes (Ne) can be dramatically reduced by selective interference effects, leading to further mismatches between phenotypic means and optima. Situations in which the optimum is outside or near the limits of possible genotypic space (e.g. a half-Gaussian fitness function) can lead to particularly pronounced gradients of phenotypic means with respect to Ne, but such gradients can also occur when optima are well within the bounds of attainable phenotypes. These results help clarify the degree to which mean phenotypes can vary among populations experiencing identical mutation and selection pressures but differing in Ne, and yield insight into how the expected scaling relationships depend on the underlying features of the genetic system.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12005259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143505254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Megavariate methods capture complex genotype-by-environment interactions.","authors":"Alencar Xavier, Daniel Runcie, David Habier","doi":"10.1093/genetics/iyae179","DOIUrl":"10.1093/genetics/iyae179","url":null,"abstract":"<p><p>Genomic prediction models that capture genotype-by-environment (GxE) interaction are useful for predicting site-specific performance by leveraging information among related individuals and correlated environments, but implementing such models is computationally challenging. This study describes the algorithm of these scalable approaches, including 2 models with latent representations of GxE interactions, namely MegaLMM and MegaSEM, and an efficient multivariate mixed-model solver, namely Pseudo-expectation Gauss-Seidel (PEGS), fitting different covariance structures [unstructured, extended factor analytic (XFA), Heteroskedastic compound symmetry (HCS)]. Accuracy and runtime are benchmarked on simulated scenarios with varying numbers of genotypes and environments. MegaLMM and PEGS-based XFA and HCS models provided the highest accuracy under sparse testing with 100 testing environments. PEGS-based unstructured model was orders of magnitude faster than restricted maximum likelihood (REML) based multivariate genomic best linear unbiased predictions (GBLUP) while providing the same accuracy. MegaSEM provided the lowest runtime, fitting a model with 200 traits and 20,000 individuals in ∼5 min, and a model with 2,000 traits and 2,000 individuals in less than 3 min. With the genomes-to-fields data, the most accurate predictions were attained with the univariate model fitted across environments and by averaging environment-level genomic estimated breeding values (GEBVs) from models with HCS and XFA covariance structures.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12005252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}