Genetics最新文献

{"title":"Quantitative Resolution of Cell Fate in the Early Embryogenesis of Caenorhabditis elegans.","authors":"Ruiqi Xiong, Yang Su, Mengchao Yao, Zefei Liu, Jie Lu, Yong-Cong Chen, Ping Ao","doi":"10.1093/genetics/iyaf095","DOIUrl":"https://doi.org/10.1093/genetics/iyaf095","url":null,"abstract":"<p><p>The nematode Caenorhabditis elegans exhibits an invariant cell lineage during its development, where the gene-molecular network that regulates the development is crucial for the biological process. While there are many molecular cell atlases describing the phenomena and key molecules involved in cell transformation, the underlying mechanisms from a systems biology perspective have received less attention. Based on an endogenous molecular-cellular theory that relates the molecular mechanisms to biological phenotypes, we constructed a model of the core endogenous network to describe the early stages of embryonic development of the C. elegans. Different cell types and intermediate cell states during development from zygotes to founder cells correspond to the steady states of the network as a nonlinear stochastic dynamical system. Connections between steady states form a topological landscape that encompasses known developmental lineage trajectories. By regulating the expression of agents in the network, we quantitatively simulated the effects of the Wnt and Notch signaling pathway on cell fate transitions and predicted the possible trajectories of transdifferentiation of the AB cell across the lineage. The success of the current study may help advance our understanding of the fundamental principles of developmental biology and cell fate determination, offering an effective tool for the quantitative analysis of cellular processes.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144111494","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":"More than meets the eye: Mutation of the white gene in Drosophila has broad phenotypic and transcriptomic effects.","authors":"April Rickle, Krittika Sudhakar, Alix Booms, Ellen Stirtz, Adelheid Lempradl","doi":"10.1093/genetics/iyaf097","DOIUrl":"https://doi.org/10.1093/genetics/iyaf097","url":null,"abstract":"<p><p>The white gene, one of the most widely used genetic markers in Drosophila research, serves as a standard background mutation for transgene insertions and genetic manipulations. While its primary function involves eye pigmentation, mutations in white have been associated with diverse phenotypic effects, including those related to metabolism, behavior, and stress responses. However, many of the published studies do not account for differences in genetic background, raising concerns about the interpretation of experimental results. To address this, we generated fly lines through 10 generations of backcrossing that are highly genetically similar except at the white locus, minimizing background variation. Given the likely metabolic consequences of white gene deletion and its role in neurotransmitter production, we focused on behavioral, metabolic, and fitness-related traits and performed transcriptomic analysis on adult fly heads. Our findings both confirm and refine previous observations, revealing that some reported effects of white mutation are robust while others likely reflect underlying genetic background differences. These results emphasize the necessity of genetic background control in Drosophila research and warrant caution when using white mutants as a baseline for comparative studies.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086710","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":"Conflicting kinesin-14s in a single chromosomal drive haplotype.","authors":"Meghan J Brady, Anjali Gupta, Jonathan I Gent, Kyle W Swentowsky, Robert L Unckless, R Kelly Dawe","doi":"10.1093/genetics/iyaf091","DOIUrl":"10.1093/genetics/iyaf091","url":null,"abstract":"<p><p>In maize, there are two meiotic drive systems that target large heterochromatic knobs composed of tandem repeats known as knob180 and TR-1. The first meiotic drive haplotype, Abnormal chromosome 10 (Ab10) confers strong meiotic drive (∼75% transmission as a heterozygote) and encodes two kinesins: KINDR, which associates with knob180 repeats and TRKIN, which associates with TR-1 repeats. Prior data show that meiotic drive is conferred primarily by the KINDR/knob180 system while the TRKIN/TR-1 system seems to have little or no role, making it unclear why Trkin has been maintained in Ab10 haplotypes. The second meiotic drive haplotype, K10L2, confers a low level of meiotic drive (∼51-52%) and only encodes the TRKIN/TR-1 system. Here we used long-read sequencing to assemble the K10L2 haplotype and showed that it has strong homology to an internal portion of the Ab10 haplotype. We also carried out CRISPR mutagenesis to test the role of Trkin on Ab10 and K10L2. The data indicate that the Trkin gene on Ab10 does not improve drive or fitness but instead has a weak deleterious effect when paired with a normal chromosome 10. The deleterious effect is more severe when Ab10 is paired with K10L2: in this context functional Trkin on either chromosome nearly abolishes Ab10 drive. Mathematical modeling based on the empirical data suggest that Trkin is unlikely to persist on Ab10. We conclude that Trkin either confers an advantage to Ab10 in untested circumstances or that it is in the process of being purged from the Ab10 population.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035449","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":"Genetic analysis of stress hormone levels in hair of healthy nursery pigs and their relationships with backtest responses.","authors":"Fazhir Kayondo, Hayder Al-Shanoon, Yolande M Seddon, Dylan Carette, Carmen Cole, David M Janz, Frederic Fortin, John C S Harding, Michael K Dyck, Graham S Plastow, Pig Gen Canada, Jack C M Dekkers","doi":"10.1093/genetics/iyaf092","DOIUrl":"https://doi.org/10.1093/genetics/iyaf092","url":null,"abstract":"<p><p>This study explored the genetics of the levels of stress hormones (cortisol, cortisone, DHEA, and DHEA-S) in hair of 863 clinically healthy Yorkshire x Landrace male pigs at ∼40 days of age and evaluated their potential as biomarkers of innate stress response by estimating genetic correlations with responses to a 30 s backtest performed at ∼27 days of age. Backtest responses included the number and intensity of vocalizations (VN, VI) and struggles (SN, SI). With pigs genotyped using a 50K single nucleotide polymorphism (SNP) panel that was imputed to 650K SNPs, heritability estimates for the levels of cortisol, cortisone, DHEA, and DHEA-S were 0.33, 0.04, 0, and 0.31, respectively, while those for backtest responses ranged from 0.26 to 0.57. Litter effects accounted for 9 to 16% of the phenotypic variance for stress hormone levels and none for backtest responses. Genetic correlation estimates among stress hormone levels were strongest between cortisol and cortisone (0.99±0.12), while those among backtest responses ranged from 0.60 to 0.99. Cortisol was estimated to have moderate genetic correlations with VN (0.24±0.19) and VI (0.50±0.24) but not with SN and SI. Genome-wide association studies identified a major quantitative trait locus (QTL) for hair cortisol levels near the glucocorticoid receptor gene (NR3C1) that explained 45.3% of the genetic variance and that may be different than a causative mutation that was previously identified in this gene for cortisol levels in porcine blood. An extra copy of the minor allele (frequency=9%) at the lead SNP for this QTL, rs341258564 originated from both parental breeds and reduced levels of cortisol by 30±6% and of cortisone by 17±4%, and increased VN by 5±2%. Additional QTL with smaller effects (1.0 to 11.1% of genetic variance) were identified for DHEA-S, cortisol/DHEA-S, cortisone/DHEA-S, VI, and VN. Ranked gene set enrichment analyses of 0.25 Mb windows based on genetic variance explained showed that windows associated with glucocorticoid levels were enriched for biological terms related to energy production and suppression of inflammation. In contrast, those associated with DHEA-S were enriched for biological processes related to immunity activation and gene transcriptional and post-transcriptional regulation. These findings establish the genetic basis of stress response in young and clinically healthy pigs, identify the genomic location of a major QTL for hair cortisol levels, and show that cortisol levels in hair of young and healthy pigs are potential genetic biomarkers for the innate coping response style of pigs to non-infectious stressors. These results open avenues that can facilitate selection of pigs that cope better with non-infectious stressors.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081453","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":"Improvement of polygenic modeling of blood pressure traits using lifestyle information in the UK Biobank.","authors":"Francesco Tiezzi, Khushi Goda, Fabio Morgante","doi":"10.1093/genetics/iyaf089","DOIUrl":"10.1093/genetics/iyaf089","url":null,"abstract":"<p><p>Complex traits are determined by the effects of multiple genetic variants, multiple environmental factors, and potentially their interaction. Predicting complex trait phenotypes from genotypes is a fundamental task in quantitative genetics that was pioneered in agricultural breeding for selection purposes. However, it has recently become important in human genetics. While prediction accuracy for some human complex traits is appreciable, this remains low for most traits. A promising way to improve prediction accuracy is by including not only genetic information but also environmental information in prediction models. However, environmental factors can, in turn, be genetically determined. This phenomenon gives rise to collinearity between the genetic and environmental components of the phenotype, which violates the assumptions of most statistical methods for polygenic modeling (i.e., environmental factors are non-randomized over the genetic factors). This phenomenon is also known as \"reverse causation\", and could lead to biased predictions due to the difficulty in disentangling the genetic and environmental effects. In this work, we investigated the impact of including 27 lifestyle variables as well as genotype information (and their interaction) for predicting diastolic blood pressure, systolic blood pressure, and pulse pressure in older individuals in UK Biobank. The 27 lifestyle variables were included as either raw variables or adjusted for genetic and other non-genetic factors. The results show that proper adjustment of the lifestyle variables allows for improved model performance and reduces the bias generated by reverse causation. Our work confirms the utility of including environmental information in polygenic models of complex traits and highlights the importance of proper handling of the environmental variables.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144043127","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":"Genome-wide analysis reveals genes mediating resistance to paraquat neurodegeneration in Drosophila.","authors":"Stefanny Villalobos-Cantor, Alicia Arreola-Bustos, Ian Martin","doi":"10.1093/genetics/iyaf087","DOIUrl":"https://doi.org/10.1093/genetics/iyaf087","url":null,"abstract":"<p><p>Parkinson's disease (PD) is thought to develop through a complex interplay of genetic and environmental factors. Epidemiological studies have linked exposure to certain pesticides such as paraquat with elevated PD risk, although how a person's genetic makeup influences disease risk upon exposure remains unknown. Here, we used a genome-wide approach to uncover genes that play a role in resistance to paraquat-induced dopaminergic neurodegeneration in Drosophila. We developed a paraquat exposure model displaying delayed-onset dopaminergic (DA) neurodegeneration to recapitulate this aspect of human disease. We reveal that genetic background is a strong determinant of paraquat-induced DA neurodegeneration susceptibility across a series of nearly 200 fly strains called the Drosophila genetic reference panel (DGRP). Through unbiased genome-wide analysis and follow-up validation, we identify two candidate paraquat resistance genes, luna and CG32264. In gene-level studies, decreased expression of luna or CG32264 is associated with paraquat-induced DA neuron loss while overexpression of either gene prevents neurodegeneration in vivo. The mammalian ortholog of CG32264 is Phactr2, which has previously been linked to human idiopathic PD risk in several populations. Hence, our results reveal genes regulating paraquat-induced DA neuron loss that intersect with human PD risk variants, supporting the potential relevance of our findings to PD and underscoring a role for gene-environment interactions in pesticide-related DA neurodegeneration.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988925","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":"Parameters that influence bipartite reporter system expression in Caenorhabditis elegans.","authors":"Emma Knoebel, Anna Brinck, Michael L Nonet","doi":"10.1093/genetics/iyaf076","DOIUrl":"https://doi.org/10.1093/genetics/iyaf076","url":null,"abstract":"<p><p>The development of bipartite reporter systems in Caenorhabditis elegans has lagged by more than a decade behind its adoption in Drosophila, the other invertebrate model commonly used to dissect biological mechanisms. Here, we characterize many parameters that influence expression in recently developed C. elegans bipartite systems. We examine how DNA binding site number and spacing influence expression and characterize how these expression parameters vary in distinct tissue types. Furthermore, we examine how both basal promoters and 3' UTR influence the specificity and level of expression. These studies provide both a framework for the rational design of driver and reporter transgenes and molecular and genetic tools for the creation, characterization, and optimization of bipartite system components for expression in other cell types.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005012","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":"Expanding biobank pharmacogenomics through machine learning calls of structural variation.","authors":"Brett Vanderwerff, Amy L Pasternak, Lars G Fritsche, Emily Bertucci-Richter, Snehal Patil, Michael Boehnke, Xiang Zhou, Sebastian Zöllner, Daniel L Hertz, Matthew Zawistowski","doi":"10.1093/genetics/iyaf088","DOIUrl":"https://doi.org/10.1093/genetics/iyaf088","url":null,"abstract":"<p><p>Biobanks linking genetic data with clinical health records provide exciting opportunities for pharmacogenomic (PGx) research on genetic variation and drug response. Designed as central and multi-use resources, biobanks can facilitate diverse PGx research efforts, including the study of drug efficacy and adverse effects. Specialized PGx alleles and phenotypes are critical for such studies and can be conveniently called from existing array-based genotypes routinely collected in most biobanks. We describe a central callset of PGx alleles and phenotypes in over 80,000 participants of the Michigan Genomics Initiative (MGI) biobank, created using the PyPGx software on TOPMed imputed genotypes. The array-based PGx allele calls demonstrate concordance (>92%) with a set of PCR-validated alleles collected during clinical care, but do not identify PGx alleles dependent on structural variation, including the clinically important CYP2D6*5 deletion. To address this, we developed a support vector machine trained on genotype array SNV probe intensities to classify CYP2D6*5 carriers. This method had >99% accuracy and reclassified ∼7% of African American and ∼4% of White MGI participants to lower activity metabolizer phenotypes, predicting higher risks of adverse drug reactions. We demonstrate that central PGx callsets created with existing tools and genetic data can be augmented by customized calls for challenging alleles based on structural variants to broaden the research potential and clinical utility of biobanks. These PGx callsets can be created in biobanks with existing array-based genotype data and highlight the utility of advanced computational methods in PGx allele identification.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144053560","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":"ASiDentify (ASiD): a machine learning model to predict new autism spectrum disorder risk genes.","authors":"Katherine M Rynard, Kara Han, Michael Wainberg, John A Calarco, Hyun O Lee, Howard D Lipshitz, Craig A Smibert, Shreejoy J Tripathy","doi":"10.1093/genetics/iyaf040","DOIUrl":"10.1093/genetics/iyaf040","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) is a neurodevelopmental disorder that affects nearly 3% of children and has a strong genetic component. While hundreds of ASD risk genes have been identified through sequencing studies, the genetic heterogeneity of ASD makes identifying additional risk genes using these methods challenging. To predict candidate ASD risk genes, we developed a simple machine learning model, ASiDentify (ASiD), using human genomic, RNA- and protein-based features. ASiD identified over 1,300 candidate ASD risk genes, over 300 of which have not been previously predicted. ASiD made accurate predictions of ASD risk genes using 6 features predictive of ASD risk gene status, including mutational constraint, synapse localization and gene expression in neurons, astrocytes and non-brain tissues. Particular functional groups of proteins found to be strongly implicated in ASD include RNA-binding proteins (RBPs) and chromatin regulators. We constructed additional logistic regression models to make predictions and assess informative features specific to RBPs, including mutational constraint, or chromatin regulators, for which both expression level in excitatory neurons and mutational constraint were informative. The fact that RBPs and chromatin regulators had informative features distinct from all protein-coding genes suggests that specific biological pathways connect risk genes with different molecular functions to ASD.</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":"143634903","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":"A model of Hill-Robertson interference caused by purifying selection in a nonrecombining genome.","authors":"Hannes Becher, Brian Charlesworth","doi":"10.1093/genetics/iyaf048","DOIUrl":"10.1093/genetics/iyaf048","url":null,"abstract":"<p><p>A new approach to modeling the effects of Hill-Robertson interference on levels of adaptation and patterns of variability in a nonrecombining genome or genomic region is described. The model assumes a set of L diallelic sites subject to reversible mutations between beneficial and deleterious alleles, with the same selection coefficient at each site. The assumption of reversibility allows the system to reach a stable statistical equilibrium with respect to the frequencies of deleterious mutations, in contrast to many previous models that assume irreversible mutations to deleterious alleles. The model is therefore appropriate for understanding the long-term properties of nonrecombining genomes such as Y chromosomes, and is applicable to haploid genomes or to diploid genomes when there is intermediate dominance with respect to the effects of mutations on fitness. Approximations are derived for the equilibrium frequencies of deleterious mutations, the effective population size that controls the fixation probabilities of mutations at sites under selection, the nucleotide site diversity at neutral sites located within the nonrecombining region, and the site frequency spectrum for segregating neutral variants. The approximations take into account the effects of linkage disequilibrium on the genetic variance at sites under selection. Comparisons with published and new computer simulation results show that the approximations are sufficiently accurate to be useful, and can provide insights into a wider range of parameter sets than is accessible by simulation. The relevance of the findings to data on nonrecombining genome regions is discussed.</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/PMC12059647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694244","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}