Genetics最新文献_第4页

Chimeric Reference Panels for Genomic Imputation. 基因组代入的嵌合参考板。

IF 5.1 3区生物学

Genetics Pub Date : 2025-10-01 DOI: 10.1093/genetics/iyaf212

Meikun Zhou, Maddie E James, Jan Engelstädter, Daniel Ortiz-Barrientos

{"title":"Chimeric Reference Panels for Genomic Imputation.","authors":"Meikun Zhou, Maddie E James, Jan Engelstädter, Daniel Ortiz-Barrientos","doi":"10.1093/genetics/iyaf212","DOIUrl":"https://doi.org/10.1093/genetics/iyaf212","url":null,"abstract":"Despite transformative advances in genomic technologies, missing data remains a fundamental constraint that limits the full potential of genomic research across biological systems. Genotype imputation offers a remedy by inferring unobserved genotypes from observed data. However, conventional imputation methods typically rely on external reference panels constructed from complete genome sequences of hundreds of individuals, a costly approach largely inaccessible for non-model organisms. Moreover, these methods generally overlook novel genomic positions not captured in existing panels. To overcome these limitations, we developed Retriever, a method for constructing a chimeric reference panel that enables genotype imputation without the need for an external reference panel. Retriever constructs a chimeric reference panel directly from the target samples using a sliding window approach to identify and retrieve genomic partitions with complete data. By exploiting the complementary distribution of missing data across samples, Retriever assembles a panel that preserves local patterns of linkage disequilibrium and captures novel variants. When the Retriever-constructed panels are used with Beagle for genotype imputation, Retriever consistently achieves accuracy exceeding 95% across diverse datasets, including plants, animals, and fungi. By eliminating the need for costly external panels, Retriever provides an accessible and cost-effective solution that broadens the application of genomic analyses across various species.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201436","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}

引用次数: 0

Inferring fungal cis-regulatory networks from genome sequences via unsupervised and interpretable representation learning. 通过无监督和可解释的表征学习从基因组序列推断真菌顺式调控网络。

IF 5.1 3区生物学

Genetics Pub Date : 2025-09-30 DOI: 10.1093/genetics/iyaf209

Alan M Moses, Jason E Stajich, Audrey P Gasch, David A Knowles

{"title":"Inferring fungal cis-regulatory networks from genome sequences via unsupervised and interpretable representation learning.","authors":"Alan M Moses, Jason E Stajich, Audrey P Gasch, David A Knowles","doi":"10.1093/genetics/iyaf209","DOIUrl":"https://doi.org/10.1093/genetics/iyaf209","url":null,"abstract":"Gene expression patterns are determined to a large extent by transcription factor binding to non-coding regulatory regions in the genome. However, gene expression cannot yet be systematically predicted from genome sequences, in part because non-functional matches to the sequence patterns (motifs) recognized by transcription factors (TFs) occur frequently throughout the genome. Large-scale functional genomics data for many TFs has enabled characterization of regulatory networks in experimentally accessible cells such as budding yeast. Beyond yeast, fungi are important industrial organisms and pathogens, but large-scale functional data is only sporadically available. Uncharacterized regulatory networks control key pathways and gene expression programs associated with fungal phenotypes. Here we explore a sequence-only approach to inferring regulatory networks by leveraging the 100s of genomes now available for many clades of fungi. We use gene orthology as the learning signal to infer interpretable, TF motif-based representations of non-coding regulatory regions. Using these representations to identify conserved signals for motifs, comparative genomics can be scaled to evolutionary comparisons where sequence similarity cannot be detected. We show that similarity of these conserved motif signals predicts gene expression and regulation better than using experimental data, and that we can infer known and novel regulatory connections in diverse fungi. Our new predictions include a pathway for recombination in C. albicans and pathways for mating and an RNAi immune response in Neurospora. Taken together, our results indicate that specific hypotheses about transcriptional regulation in fungi can be obtained for many genes from genome sequence analysis alone.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145193670","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}

引用次数: 0

The Fitness Landscape: A Call for Papers. 健身景观：论文征集。

IF 5.1 3区生物学

Genetics Pub Date : 2025-09-29 DOI: 10.1093/genetics/iyaf206

Ruth Isaacson

引用次数: 0

The impact of non-neutral synonymous mutations when inferring selection on non-synonymous mutations. 非中性同义突变对非同义突变选择的影响。

IF 5.1 3区生物学

Genetics Pub Date : 2025-09-27 DOI: 10.1093/genetics/iyaf200

Aina Martinez I Zurita, Christopher C Kyriazis, Kirk E Lohmueller

{"title":"The impact of non-neutral synonymous mutations when inferring selection on non-synonymous mutations.","authors":"Aina Martinez I Zurita, Christopher C Kyriazis, Kirk E Lohmueller","doi":"10.1093/genetics/iyaf200","DOIUrl":"10.1093/genetics/iyaf200","url":null,"abstract":"The distribution of fitness effects (DFE) describes the proportions of new mutations that have different effects on fitness. Accurate measurements of the DFE are important because the DFE is a fundamental parameter in evolutionary genetics and has implications for our understanding of other phenomena like complex disease or inbreeding depression. Current computational methods to infer the DFE for non-synonymous mutations from natural variation first estimate demographic parameters from synonymous variants to control for the effects of demography and background selection. Then, conditional on these parameters, the DFE is then inferred for non-synonymous mutations. This approach relies on the assumption that synonymous variants are neutrally evolving. However, some evidence points toward synonymous mutations having measurable effects on fitness. To test whether selection on synonymous mutations affects inference of the DFE of non-synonymous mutations, we simulated several possible models of selection on synonymous mutations using SLiM and attempted to recover the DFE of non-synonymous mutations using Fit∂a∂i, a common method for DFE inference. Our results show that the presence of selection on synonymous variants leads to incorrect inferences of recent population growth. Furthermore, under certain parameter combinations with pervasive selection on synonymous mutations, the inferred DFEs for non-synonymous mutations show an inflated proportion of highly deleterious and nearly-neutral mutations. However, this bias can be eliminated if the correct demographic parameters are used for DFE inference instead of the biased ones inferred from synonymous variants. Our work demonstrates how unmodeled selection on synonymous mutations may affect downstream inferences of the DFE.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145179709","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}

引用次数: 0

Mendelian randomisation with proxy exposures: challenges and opportunities. 孟德尔随机化与代理暴露：挑战与机遇。

IF 5.1 3区生物学

Genetics Pub Date : 2025-09-26 DOI: 10.1093/genetics/iyaf210

Ida Rahu, Ralf Tambets, Eric B Fauman, Kaur Alasoo

{"title":"Mendelian randomisation with proxy exposures: challenges and opportunities.","authors":"Ida Rahu, Ralf Tambets, Eric B Fauman, Kaur Alasoo","doi":"10.1093/genetics/iyaf210","DOIUrl":"https://doi.org/10.1093/genetics/iyaf210","url":null,"abstract":"A key challenge in human genetics is the discovery of modifiable causal risk factors for complex traits and diseases. Mendelian randomisation (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 two 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.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145179697","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}

引用次数: 0

Craniofacial-specific transcriptomics uncovers novel genes underlying jaw divergence in dietary specialist pupfishes. 颅面特异性转录组学揭示了饮食特殊小鱼下颌分化的新基因。

IF 5.1 3区生物学

Genetics Pub Date : 2025-09-26 DOI: 10.1093/genetics/iyaf207

M Fernanda Palominos, Vanessa Muhl, Christopher H Martin

{"title":"Craniofacial-specific transcriptomics uncovers novel genes underlying jaw divergence in dietary specialist pupfishes.","authors":"M Fernanda Palominos, Vanessa Muhl, Christopher H Martin","doi":"10.1093/genetics/iyaf207","DOIUrl":"https://doi.org/10.1093/genetics/iyaf207","url":null,"abstract":"Changes in gene expression underlie most phenotypic differences among closely related species. While previous studies in model systems have identified conserved genes and pathways involved in craniofacial evolution, less is known about gene expression differences associated with craniofacial divergence in rapidly evolving species. Here, we investigate craniofacial-specific gene expression in a nascent adaptive radiation of Cyprinodon pupfishes endemic to San Salvador Island, Bahamas, which includes three trophic specialists with highly divergent craniofacial morphologies (scale-eaters and a molluscivore) derived from an ancestral Caribbean-wide generalist. We compared gene expression in the most morphologically divergent craniofacial region with the relatively conserved caudal region across five Cyprinodon species and nine populations. We focused on the hatching stage, the earliest developmental stage at which craniofacial differences among species are evident. Our approach revealed a large proportion of differentially expressed genes (DEGs) found exclusively in the craniofacial region of the specialists only. By intersecting these specialist-specific craniofacial-exclusive genes with genomic regions harboring fixed single nucleotide variants under selection in the specialists, we identified fourteen candidate genes. We confirmed novel craniofacial expression for two of these candidates, pycr3 and atp8a1, genes not previously associated with craniofacial development or function, in hatchlings using in-situ mRNA hybridization and observed species-specific differences in the pharyngeal arches and craniofacial muscles, respectively. Our findings demonstrate how an 'evolutionary mutant' model can reveal novel gene expression patterns, highlighting the power of integrating tissue-species transcriptomics with speciation genomics to identify novel regulators of craniofacial evolution.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145151600","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}

引用次数: 0

A replication stress safeguard provided by the Elg1 Replication Factor C-like complex. 由Elg1复制因子c样复合体提供的复制压力保护。

IF 5.1 3区生物学

Genetics Pub Date : 2025-09-23 DOI: 10.1093/genetics/iyaf196

Pallavi Bose, Soumitra Sau

{"title":"A replication stress safeguard provided by the Elg1 Replication Factor C-like complex.","authors":"Pallavi Bose, Soumitra Sau","doi":"10.1093/genetics/iyaf196","DOIUrl":"https://doi.org/10.1093/genetics/iyaf196","url":null,"abstract":"The Elg1 Replication Factor C-like complex (Elg1-RLC) that functions as a 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. 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 replication fork 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 dNTP levels (by deleting the ribonucleotide reductase SML1) eliminates the possibility of a Rad53-regulated dNTP shortage-mediated fork collapse. Thus, we propose a 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 replication forks under replication stress.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126321","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}

引用次数: 0

Unexpected Molecular Mechanism of Orc6-Based Meier-Gorlin Syndrome: Insights from a Humanized Drosophila Model. 基于orc6的Meier-Gorlin综合征意想不到的分子机制：来自人源化果蝇模型的见解。

IF 5.1 3区生物学

Genetics Pub Date : 2025-09-23 DOI: 10.1093/genetics/iyaf203

Maxim Balasov, Katarina Akhmetova, Igor Chesnokov

{"title":"Unexpected Molecular Mechanism of Orc6-Based Meier-Gorlin Syndrome: Insights from a Humanized Drosophila Model.","authors":"Maxim Balasov, Katarina Akhmetova, Igor Chesnokov","doi":"10.1093/genetics/iyaf203","DOIUrl":"https://doi.org/10.1093/genetics/iyaf203","url":null,"abstract":"Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by microtia, primordial dwarfism, and skeletal abnormalities. Patients with MGS often carry mutations in genes encoding the subunits of the Origin Recognition Complex (ORC), components of the pre-replicative complex and replication machinery. ORC6, an essential ORC subunit, plays a critical role in both DNA replication and cytokinesis. Approximately 30% of reported ORC6-related MGS cases exhibit compound heterozygosity for the ORC6 variants c.2T>C (p.Met1Thr) and c.449+5G>A. The c.2T>C mutation disrupts the start ATG codon by changing it to ACG, potentially initiating translation at an alternative downstream in frame Methionine (Met20), while c.449+5G>A results in in-frame exon skipping. Both mutations are predicted to produce significantly truncated ORC6 proteins with impaired functionality. In this study, using a humanized ORC6 based Drosophila model, we demonstrate that these truncated proteins fail to rescue orc6 deletion. Instead, our findings reveal that the strong Kozak sequence, naturally present in human ORC6 mRNA, promotes translation from a non-canonical ACG codon. Rescued flies demonstrated a phenotype that we observed earlier for other MGS mutants in Drosophila. These results provide compelling evidence that MGS patients with c.2T>C/c.449+5G>A mutation rely on full size ORC6 protein initiated from a non-canonical ACG start codon.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145132367","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}

引用次数: 0

A forest is more than its trees: haplotypes and ancestral recombination graphs. 森林不仅仅是树木：单倍型和祖先重组图。

IF 5.1 3区生物学

Genetics Pub Date : 2025-09-23 DOI: 10.1093/genetics/iyaf198

Halley Fritze, Nathaniel Pope, Jerome Kelleher, Peter Ralph

{"title":"A forest is more than its trees: haplotypes and ancestral recombination graphs.","authors":"Halley Fritze, Nathaniel Pope, Jerome Kelleher, Peter Ralph","doi":"10.1093/genetics/iyaf198","DOIUrl":"10.1093/genetics/iyaf198","url":null,"abstract":"Foreshadowing haplotype-based methods of the genomics era, it is an old observation that the ``junction'' between two distinct haplotypes produced by recombination is inherited as a Mendelian marker. In a genealogical context, this recombination-mediated information reflects the persistence of ancestral haplotypes across local genealogical trees in which they do not represent coalescences. We show how these non-coalescing haplotypes (``locally-unary nodes'') may be inserted into ancestral recombination graphs (ARGs), a compact but information-rich data structure describing the genealogical relationships among recombinant sequences. The resulting ARGs are smaller, faster to compute with, and the additional ancestral information that is inserted is nearly always correct where the initial ARG is correct. We provide efficient algorithms to infer locally-unary nodes within existing ARGs, and explore some consequences for ARGs inferred from real data. To do this, we introduce new metrics of agreement and disagreement between ARGs that, unlike previous methods, consider ARGs as describing relationships between haplotypes rather than just a collection of trees.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145132388","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}

引用次数: 0

Mutation ages and population origins inferred from genomes in structured populations. 从结构群体的基因组推断突变年龄和群体起源。

IF 5.1 3区生物学

Genetics Pub Date : 2025-09-23 DOI: 10.1093/genetics/iyaf204

Anna A Nagel, Bruce Rannala

{"title":"Mutation ages and population origins inferred from genomes in structured populations.","authors":"Anna A Nagel, Bruce Rannala","doi":"10.1093/genetics/iyaf204","DOIUrl":"https://doi.org/10.1093/genetics/iyaf204","url":null,"abstract":"Inferring the time of origin (age) of mutations is an old question in population genetics and inferring their population of origin has become of particular interest with the sequencing of the Neanderthal genome. However, existing methods to infer mutation ages and populations of origin do not explicitly consider population structure, migration rates, and divergence times, which may bias estimates, and it is unclear how to even apply single-population estimators to structured populations. We develop a method to jointly estimate the time and population of origin of a mutation (as well as the ancestral and derived states) in a structured population using population genomic data and examine its statistical performance using simulations. Results indicate that mutation age and population of origin can be quite uncertain, even with long sequences or many samples, but this uncertainty is accurately captured using credible intervals/sets. The ancestral nucleotide state is relatively easy to infer. We apply our method to whole genome data from the 1000 Genomes Project, analyzing seven SNP mutations from six genes associated with human skin pigmentation for populations from Great Britain, China, and Kenya. Our results partially support previous conclusions, with the putative ancestral alleles from the literature matching our inferences, while the mutation age estimates only overlap in some cases.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145132380","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}

引用次数: 0