Genetics最新文献

{"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}

{"title":"Diverse modes of gene action contribute to heterosis for quantitative disease resistance in maize.","authors":"Asher I Hudson, Maggie R Wagner, Shannon Sermons, Peter J Balint-Kurti","doi":"10.1093/genetics/iyaf049","DOIUrl":"10.1093/genetics/iyaf049","url":null,"abstract":"<p><p>Disease resistance in plants can be conferred by single genes of large effect or by multiple genes each conferring incomplete resistance. The latter case, termed quantitative resistance, may be difficult for pathogens to overcome through evolution due to the low selection pressures exerted by the actions of any single gene and, for some diseases, is the only identified source of genetic resistance. We evaluated quantitative resistance to 2 diseases of maize in a biparental mapping population as well as backcrosses to both parents. Quantitative trait locus analysis shows that the genetic architecture of resistance to these diseases is characterized by several modes of gene action including additivity as well as dominance, overdominance, and epistasis. Heterosis or hybrid vigor, the improved performance of a hybrid compared with its parents, can be caused by nonadditive gene action and is fundamental to the breeding of several crops including maize. In the backcross populations and a diverse set of maize hybrids, we find heterosis for resistance in many cases and that the degree of heterosis appears to be dependent on both hybrid genotype and disease.</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":"143701845","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":"Molecular evolution of a reproductive barrier in maize and related species.","authors":"Elli Cryan, Garnet Phinney, Arun S Seetharam, Matthew M S Evans, Elizabeth A Kellogg, Junpeng Zhan, Blake C Meyers, Daniel J Kliebenstein, Jeffrey Ross-Ibarra","doi":"10.1093/genetics/iyaf085","DOIUrl":"https://doi.org/10.1093/genetics/iyaf085","url":null,"abstract":"<p><p>Three cross-incompatibility loci each control a distinct reproductive barrier in both domesticated maize (Zea mays ssp. mays) and its wild teosinte relatives. These three loci, Teosinte crossing barrier1 (Tcb1), Gametophytic factor1 (Ga1), and Ga2, each play a key role in preventing hybridization between incompatible populations and are proposed to maintain the barrier between domesticated and wild subspecies. Each locus encodes both a silk-active and a matching pollen-active pectin methylesterase (PMEs). To investigate the diversity and molecular evolution of these gametophytic factor loci, we identified existing and improved models of the responsible genes in a new genome assembly of maize line P8860 that contains active versions of all three loci. We then examined fifty-two assembled genomes from seventeen species to classify haplotype diversity and identify sites under diversifying selection during the evolution of these genes. We show that Ga2, the oldest of these three loci, was duplicated to form Ga1 at least 12 million years ago. Tcb1, the youngest locus, arose as a duplicate of Ga1 before or around the time of diversification of the Zea genus. We find evidence of positive selection during evolution of the functional genes at an active site in the pollen-expressed PME and predicted surface sites in both the silk- and pollen-expressed PMEs. The most common allele at the Ga1 locus is a conserved ga1 allele (ga1-Off), which is specific haplotype containing three full-length PME gene copies, all of which are non-coding due to conserved stop codons and are between 610 thousand and 1.5 million years old. We show that the ga1-Off allele is associated with and likely generates 24-nt siRNAs in developing pollen-producing tissue, and these siRNAs map to functional Ga1 alleles. In previously-published crosses, the ga1-Off allele was associated with reduced function of the typically dominant functional alleles for the Ga1 and Tcb1 barriers. Taken together, this seems to be an example of an allele at a reproductive barrier locus being associated with an as yet undetermined mechanism capable of silencing the reproductive barrier.</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":"144065159","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":"Dynamic regulation of murine RNA polymerase III transcription during heat shock stress.","authors":"Thomas F Nguyen, James Z J Kwan, Jennifer E Mitchell, Jieying H Cui, Sheila S Teves","doi":"10.1093/genetics/iyaf042","DOIUrl":"10.1093/genetics/iyaf042","url":null,"abstract":"<p><p>Cells respond to many different types of stresses by overhauling gene expression patterns, both at the transcriptional and translational levels. Under heat stress, global transcription and translation are inhibited, while the expression of chaperone proteins is preferentially favored. As the direct link between mRNA transcription and protein translation, transfer RNA (tRNA) expression is intricately regulated during the stress response. Despite extensive research into the heat shock response (HSR), the regulation of tRNA expression by RNA polymerase III (Pol III) transcription has yet to be fully elucidated in mammalian cells. Here, we examine the regulation of Pol III transcription during different stages of heat shock stress in mouse embryonic stem cells. We observe that Pol III transcription is downregulated after 30 min of heat shock, followed by an overall increase in transcription after 60 min of heat shock. This effect is more evident in tRNAs, although other Pol III gene targets are also similarly affected. Notably, we show that the downregulation at 30 min of heat shock is independent of HSF1, the master transcription factor of the HSR, but that the subsequent increase in expression at 60 min requires HSF1. Taken together, these results demonstrate an adaptive RNA Pol III response to heat stress and an intricate relationship between the canonical HSR and tRNA expression.</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/PMC12059648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659381","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":"Yeast molecular genetic tricks to study gene regulation.","authors":"Kevin Struhl","doi":"10.1093/genetics/iyaf041","DOIUrl":"10.1093/genetics/iyaf041","url":null,"abstract":"<p><p>The Genetics Society of America's (GSA) Edward Novitski Prize is awarded to researchers for extraordinary creativity and intellectual ingenuity in genetics research. Struhl is being recognized for his pioneering work cloning a functional eukaryotic gene in E. coli, defining its promoter and regulatory region, and using random DNA and amino acid sequences to define determinants of specificity. The award also recognizes other key scientific contributions including Struhl's discovery of the sequences and protein interactions required for transcriptional activation and repression and demonstrating the importance of nucleosome-free regions for transcription initiation, among others.</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":"143732682","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":"GWAS significance thresholds in large cohorts of European ancestry.","authors":"Evans K Cheruiyot, Tingyan Yang, Allan F McRae","doi":"10.1093/genetics/iyaf056","DOIUrl":"10.1093/genetics/iyaf056","url":null,"abstract":"<p><p>While the P-value threshold of 5.0×10-8 remains the standard for genome-wide association studies (GWAS) in humans and other species, it still needs to be updated to reflect the current era of large-scale GWAS, where tens of thousands of sample sizes are used to discover genetic associations at loci with smaller minor allele frequencies. In this study, we used a dataset of 348,501 individuals of European ancestry from the UK Biobank to determine the GWAS thresholds required for multiple testing corrections when considering rare and common variants in additive and dominant GWAS models. Additionally, we employed conditional and joint analysis to quantify the proportion of false significant hits in the GWAS results for 72 traits in the UK Biobank when applying the traditional GWAS cutoff vs our newly proposed P-value thresholds. Overall, the results indicate that the conventional GWAS significance threshold of 5.0×10-8 yields a false-positive rate of between 20% and 30% in GWAS studies that utilize large sample sizes and less common variants. Instead, a more stringent GWAS P-value threshold of 5.0×10-9 is needed when rare variants (with minor allele frequency > 0.1%) are included in the association test for both additive and dominance models within the European ancestry population. However, further validation across diverse datasets and study designs, is needed to evaluate the broader applicability of this proposed threshold.</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/PMC12059634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143721916","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":"A fission yeast CENP-B homolog Abp1 prevents RNAi-mediated heterochromatin formation at ribosomal DNA repeats.","authors":"Satoru Tsunemine, Miyuki Mori, Yota Murakami","doi":"10.1093/genetics/iyaf050","DOIUrl":"10.1093/genetics/iyaf050","url":null,"abstract":"<p><p>In response to nutritional starvation, living cells sensitively regulate the production rates of molecules required for survival. Under glucose starvation, a facultative heterochromatinization of ribosomal DNA is considered to regulate ribosomal RNA production. However, the molecular mechanism is still unclear. Here, we report a novel function of CENP-B homolog Abp1 in forming facultative heterochromatin at ribosomal DNA repeats. We find that the loss of Abp1 induces an ectopic nucleosome assembly at rDNA repeats. Interestingly, the loss of Abp1 induces two mutually exclusive changes at ribosomal DNA repeats: an excess accumulation of methylation of histone H3 at lysine 9, a hallmark of heterochromatin, and an active RNA polymerase II transcription. This excess heterochromatin represses ribosomal RNA expression and requires RNA interference machinery for its formation. Furthermore, we show that the excess heterochromatin does not affect cellular viability under glucose starvation but prevents the return to the proliferation cycle in recovering glucose-rich conditions. Since glucose starvation rapidly induces partial Abp1 disassociation from ribosomal DNA repeats, we propose that Abp1 regulates activity of RNA polymerase II transcription that is paradoxically required for RNA interference-mediated heterochromatin formation and controls an appropriate level of heterochromatinization at ribosomal DNA repeats under glucose starvation.</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":"143711822","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":"Mediator-29 limits Caenorhabditis elegans fecundity.","authors":"Qi Fan, Christopher Tran, Wei Cao, Roger Pocock","doi":"10.1093/genetics/iyaf051","DOIUrl":"10.1093/genetics/iyaf051","url":null,"abstract":"<p><p>Mediator is an evolutionarily conserved multiprotein complex that acts as a critical coregulator of RNA polymerase II-mediated transcription. While core Mediator components are broadly required for transcription, others govern specific regulatory modules and signaling pathways. Here, we investigated the function of MDT-29/MED29 in the Caenorhabditis elegans germ line. We found that endogenously tagged MDT-29 is ubiquitously expressed and concentrated in discrete foci within germ cell nuclei. Functionally, depleting MDT-29 in the germ line during larval development boosted fecundity. We determined that the increase in progeny production was likely caused by a combination of an expanded germline stem cell pool and decreased germ cell apoptosis. Thus, MDT-29 may act to optimize specific gene expression programs to control distinct germ cell behaviors, providing flexibility to progeny production in certain environments.</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/PMC12059642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694245","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}