Genetics最新文献_第2页

Global epistasis in budding yeast driven by many natural variants whose effects scale with fitness. 芽殖酵母的全局上位是由许多自然变异驱动的，其影响与适应度有关。

IF 5.1 3区生物学

Genetics Pub Date : 2025-10-08 DOI: 10.1093/genetics/iyaf136

Ilan Goldstein, Joseph J Hale, Ian M Ehrenreich

{"title":"Global epistasis in budding yeast driven by many natural variants whose effects scale with fitness.","authors":"Ilan Goldstein, Joseph J Hale, Ian M Ehrenreich","doi":"10.1093/genetics/iyaf136","DOIUrl":"10.1093/genetics/iyaf136","url":null,"abstract":"Global epistasis is a phenomenon in which the effects of genetic perturbations depend on the fitness of the individuals in which they occur. In populations with natural genetic variation, global epistasis arises from interactions between perturbations and polymorphic loci that are mediated by fitness. To investigate the prevalence and characteristics of loci involved in these interactions in the budding yeast Saccharomyces cerevisiae, we used combinatorial DNA barcode sequencing to measure the fitness of 169 cross progeny (segregants) subjected to 8,126 CRISPRi perturbations across 2 environments. Global epistasis was evident in these data, with more fit segregants within each environment exhibiting greater sensitivity to genetic perturbations than less fit segregants. We dissected the genetic basis of this global epistasis by scanning the genome for loci whose effects covary with CRISPRi-induced reductions in population fitness. This approach identified 58 loci that interact with fitness, most of which exhibited larger effects in the absence of genetic perturbations. In aggregate, these loci explained the observed global epistasis in each environment and demonstrated that the loci contributing to global epistasis largely overlap with those influencing fitness in unperturbed conditions.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144660859","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}

引用次数: 0

Alternative splicing repurposes the Drosophila mitotic regulator Mud for meiotic functions. 选择性剪接将果蝇有丝分裂调节因子Mud用于减数分裂功能。

IF 5.1 3区生物学

Genetics Pub Date : 2025-10-08 DOI: 10.1093/genetics/iyaf145

Tara M Finegan, Kevin Deem, Ruiyue Tan, Nicholas Lowe, Nicholas Weeks, Michael W Linhoff, Xuke Wang, Isabel López-Molini, Anne Benraiss, Dan T Bergstralh

{"title":"Alternative splicing repurposes the Drosophila mitotic regulator Mud for meiotic functions.","authors":"Tara M Finegan, Kevin Deem, Ruiyue Tan, Nicholas Lowe, Nicholas Weeks, Michael W Linhoff, Xuke Wang, Isabel López-Molini, Anne Benraiss, Dan T Bergstralh","doi":"10.1093/genetics/iyaf145","DOIUrl":"10.1093/genetics/iyaf145","url":null,"abstract":"Mud/NuMA/LIN-5 (in flies, vertebrates, and worms) is an evolutionarily conserved protein that regulates the shape and orientation of the mitotic spindle. In vertebrate cells, these functions depend on a C-terminal region called the NuMA-Tip, which (i) mediates interaction with the conserved partner protein LGN (called Pins in flies), (ii) contains a highly conserved subsequence called the NLM, and (ii) binds directly to microtubule ends. Although Mud plays a vital role in Drosophila mitosis, less is known about its structure, particularly at the C-terminus. Through sequence analysis and functional studies, we identify the Mud-Tip region and show that it is encoded by 3 consecutive exons. These exons are spliced out of several Mud isoforms, creating functionally distinct \"Tipless\" variants. We find that Tipless isoforms are specifically expressed in male and female gametes, where they localize to the nuclear envelope. Although Mud is known to be essential for female fertility, we demonstrate that this function does not require an intact Tip region. We also find that Mud antagonizes the localization of Lamin, a nucleoskeletal protein, in the testis, and uncover an unexpected role for Tipless Mud in promoting male fertility. Our work reveals that while the Mud-Tip is important for Mud function at mitosis, alternative splicing ensures this region is absent from Mud isoforms that perform a moonlighting role during meiosis.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144754905","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}

引用次数: 0

Activation of a Src-JNK pathway in unscheduled endocycling cells of the Drosophila wing disc induces a chronic wounding response. 果蝇翅盘非预定内环细胞中Src-JNK通路的激活可诱导慢性损伤反应。

IF 5.1 3区生物学

Genetics Pub Date : 2025-10-08 DOI: 10.1093/genetics/iyaf147

Yi-Ting Huang, Brian R Calvi

{"title":"Activation of a Src-JNK pathway in unscheduled endocycling cells of the Drosophila wing disc induces a chronic wounding response.","authors":"Yi-Ting Huang, Brian R Calvi","doi":"10.1093/genetics/iyaf147","DOIUrl":"10.1093/genetics/iyaf147","url":null,"abstract":"The endocycle is a specialized cell cycle during which cells undergo repeated G/S phases to replicate DNA without division, leading to large polyploid cells. The transition from a mitotic cycle to an endocycle can be triggered by various stresses, which results in unscheduled or induced endocycling cells (iECs). While iECs can be beneficial for wound healing, they can also be detrimental by impairing tissue growth or promoting cancer. However, the regulation of endocycling and its role in tissue growth remain poorly understood. Using the Drosophila wing disc as a model, we previously demonstrated that iEC growth is arrested through a Jun N-Terminal Kinase (JNK)-dependent, reversible senescence-like response. However, it remains unclear how JNK is activated in iECs and how iECs impact the overall tissue structure. In this study, we performed a genetic screen and identified the Src42A-Shark-Slpr pathway as an upstream regulator of JNK in iECs, leading to their senescence-like arrest. We found that tissues recognize iECs as wounds, releasing wound-related signals that induce a JNK-dependent developmental delay. Similar to wound closure, this response triggers Src-JNK-mediated actomyosin remodeling and focal adhesion formation, yet iECs persist rather than being eliminated. Our findings suggest that the tissue response to iECs shares key signaling and cytoskeletal regulatory mechanisms with wound healing and dorsal closure, a developmental process during Drosophila embryogenesis. However, because iECs are retained within the tissue, they create a unique system that may serve as a model for studying chronic wounds and tumor progression.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505303/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762060","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}

引用次数: 0

Mediated pleiotropy drives the negative correlation of total carotenoid and dry matter contents in cassava (Manihot esculenta). 介导的多效性驱动木薯总类胡萝卜素和干物质含量的负相关。

IF 5.1 3区生物学

Genetics Pub Date : 2025-10-08 DOI: 10.1093/genetics/iyaf162

Seren S Villwock, Elizabeth Y Parkes, Edwige Gaby Nkouaya Mbanjo, Ismail Y Rabbi, Jean-Luc Jannink

{"title":"Mediated pleiotropy drives the negative correlation of total carotenoid and dry matter contents in cassava (Manihot esculenta).","authors":"Seren S Villwock, Elizabeth Y Parkes, Edwige Gaby Nkouaya Mbanjo, Ismail Y Rabbi, Jean-Luc Jannink","doi":"10.1093/genetics/iyaf162","DOIUrl":"10.1093/genetics/iyaf162","url":null,"abstract":"Plant breeders aim to increase provitamin A carotenoids in cassava (Manihot esculenta) storage roots to help combat vitamin A deficiency in sub-Saharan Africa, but a negative genetic correlation between total carotenoid and dry matter contents hinders progress. While genetic linkage between a major-effect variant in the phytoene synthase 2 (PSY2) gene and nearby candidate gene(s) has been thought to drive this correlation, molecular evidence suggests there may be a metabolic relationship between total carotenoid and dry matter, implying genome-wide pleiotropic effects. Bivariate genome-wide associations were used to examine the genetic architecture of the negative covariance between traits and test for pleiotropy. A population of 378 accessions in the yellow-fleshed cassava breeding program at the International Institute of Tropical Agriculture (IITA) in Ibadan, Nigeria was genotyped with DArTseqLD and phenotyped in field trials over 10 yr across three locations in Nigeria. Mixed linear models controlling for the previously identified PSY2 causal variant were used to identify multiple new pleiotropic loci. Among 17 jointly associated loci at a relaxed significance threshold, most (11 of 17) affected total carotenoid and dry matter in opposite directions, although this pattern did not reach statistical significance in a binomial test. Even after accounting for these 17 loci as covariates, significantly negative polygenic covariance between total carotenoid and dry matter remained. These findings support the hypothesis that widespread mediated pleiotropy rather than genetic linkage drives the negative genetic correlation between total carotenoid and dry matter in cassava and demonstrate a new application of multivariate genome-wide association study for interrogating the genetic architecture of correlated traits.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144838352","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}

引用次数: 0

Approximate Bayesian computation supports a high incidence of chromosomal mosaicism in blastocyst-stage human embryos. 近似贝叶斯计算支持在囊胚期人类胚胎中染色体嵌合的高发生率。

IF 5.1 3区生物学

Genetics Pub Date : 2025-10-08 DOI: 10.1093/genetics/iyaf149

Qingya Yang, Sara A Carioscia, Matthew Isada, Rajiv C McCoy

{"title":"Approximate Bayesian computation supports a high incidence of chromosomal mosaicism in blastocyst-stage human embryos.","authors":"Qingya Yang, Sara A Carioscia, Matthew Isada, Rajiv C McCoy","doi":"10.1093/genetics/iyaf149","DOIUrl":"10.1093/genetics/iyaf149","url":null,"abstract":"Chromosome mis-segregation is common in human meiosis and mitosis, and the resulting aneuploidies are the leading cause of pregnancy loss. Preimplantation genetic testing for aneuploidy (PGT-A) prioritizes chromosomally normal embryos for transfer based on analysis of a biopsy of ∼5 trophectoderm cells from blastocyst-stage in vitro fertilized embryos. While modern PGT-A platforms classify these biopsies as aneuploid, euploid, or mosaic (a mixture of normal and aneuploid cells), the underlying incidences of aneuploid, euploid, and mosaic embryos and the rates of meiotic and mitotic error that produced them remain largely unknown. To address this knowledge gap, we paired a method for embryo simulation with approximate Bayesian computation to infer rates of meiotic and mitotic error that explain published PGT-A data. Using simulation, we also evaluated the chromosomal status of entire embryos. For a published clinical sample, we estimated a 40% to 58% probability of meiotic error per meiosis and a 1.5% to 6.3% probability of mitotic error per mitosis, depending on assumptions about spatial organization. In addition, our analyses suggest that <1% of blastocysts are fully euploid and that many embryos possess low-level mosaic clones that are not captured during biopsy. These conclusions were relatively insensitive to misclassification of mosaic biopsies. Together, our findings imply that low-level mosaicism is a normal feature of embryogenesis and are consistent with clinical data demonstrating the developmental potential of mosaic-testing embryos. More broadly, our work helps overcome the limitations of embryo biopsies to estimate fundamental rates of chromosome mis-segregation in human development.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762061","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}

引用次数: 0

Synaptic vesicle glycoprotein 2 enables viable aneuploidy following centrosome amplification. 突触囊泡糖蛋白2使中心体扩增后的非整倍体存活。

IF 5.1 3区生物学

Genetics Pub Date : 2025-10-08 DOI: 10.1093/genetics/iyaf148

Jane E Blackmer, Erin A Jezuit, Archan Chakraborty, Satya N Yalamanchi, Ruth A Montague, Erin E Dickert, Nora G Peterson, William Outlaw, Donald T Fox

{"title":"Synaptic vesicle glycoprotein 2 enables viable aneuploidy following centrosome amplification.","authors":"Jane E Blackmer, Erin A Jezuit, Archan Chakraborty, Satya N Yalamanchi, Ruth A Montague, Erin E Dickert, Nora G Peterson, William Outlaw, Donald T Fox","doi":"10.1093/genetics/iyaf148","DOIUrl":"10.1093/genetics/iyaf148","url":null,"abstract":"Amplified centrosome number causes genomic instability, most severely through division into >2 aneuploid daughter cells (multipolar mitosis). Several mechanisms that suppress multipolar division have been uncovered, yet mechanisms that favor viable multipolar division are poorly understood. To uncover factors that promote viability in cells with frequent centrosome amplification and multipolar division, we conducted an unbiased Drosophila genetic screen. In 642 mutagenized lines, we exploited the ability of intestinal papillar cells to form and function despite multipolar divisions. Our top hit is an unnamed gene, CG3168. We name this gene synaptic vesicle glycoprotein 2, reflecting homology to human Synaptic Vesicle Glycoprotein 2 (SV2) proteins. GFP-tagged SV2 localizes to the plasma membrane. In cells with amplified centrosomes, SV2 positions membrane-adjacent centrosomes, which prevents severe errors in chromosome alignment and segregation. Our results uncover membrane-based multipolar division regulation and reveal a novel vulnerability in cells with common cancer properties.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505302/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144762063","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}

引用次数: 0

Residues neighboring an SH3-binding motif participate in the interaction in vivo. 邻近sh3结合基序的残基参与体内相互作用。

IF 5.1 3区生物学

Genetics Pub Date : 2025-10-08 DOI: 10.1093/genetics/iyaf153

David F Jordan, Alexandre K Dubé, Ugo Dionne, David Bradley, Christian R Landry

{"title":"Residues neighboring an SH3-binding motif participate in the interaction in vivo.","authors":"David F Jordan, Alexandre K Dubé, Ugo Dionne, David Bradley, Christian R Landry","doi":"10.1093/genetics/iyaf153","DOIUrl":"10.1093/genetics/iyaf153","url":null,"abstract":"In signaling networks, protein-protein interactions are often mediated by modular domains that bind short linear motifs. The motifs' sequences affect many factors, among them affinity and specificity, or the ability to bind strongly and to the appropriate partners. Using Deep Mutational Scanning to create a mutant library, and protein complementation assays to measure protein-protein interactions, we determined the in vivo binding strength of a library of mutants of a binding motif on the MAP kinase kinase Pbs2, which binds the SH3 domain of the osmosensor protein Sho1 in Saccharomyces cerevisiae. These measurements were made using the full-length endogenous proteins in their native cellular environment. We find that, along with residues within the canonical motif, many mutations in the residues neighboring the motif also modulate binding strength. Interestingly, all Pbs2 mutations that increase binding are situated outside of the Pbs2 region that interacts with the canonical SH3-binding pocket, suggesting that other surfaces on Sho1 contribute to binding. We use predicted structures and mutations to propose a model of binding that involves residues neighboring the canonical Pbs2 motif binding outside of the canonical SH3 binding pocket. We compared this predicted structure with known structures of SH3 domains binding peptides through residues outside of the motif, and put forth possible mechanisms through which Pbs2 can bind specifically to Sho1. We propose that for certain SH3 domain-motif pairs, affinity and specificity are determined by a broader range of sequences than what has previously been considered, potentially allowing easier differentiation between otherwise similar partners.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505296/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144785737","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}

引用次数: 0

Multiple autism genes influence GABA neuron remodeling via distinct developmental trajectories. 多个自闭症基因通过不同的发育轨迹影响GABA神经元重塑。

IF 5.1 3区生物学

Genetics Pub Date : 2025-10-08 DOI: 10.1093/genetics/iyaf156

Kristi Zoga, Sophia Villiere, Vina Tikiyani, Andrea F Edwards-Cintron, Pranav Thokachichu, Patrick Nicodemus, Pablo G Camara, Michael P Hart

{"title":"Multiple autism genes influence GABA neuron remodeling via distinct developmental trajectories.","authors":"Kristi Zoga, Sophia Villiere, Vina Tikiyani, Andrea F Edwards-Cintron, Pranav Thokachichu, Patrick Nicodemus, Pablo G Camara, Michael P Hart","doi":"10.1093/genetics/iyaf156","DOIUrl":"10.1093/genetics/iyaf156","url":null,"abstract":"Variation in over 100 genes is now associated with increased risk for autism and related neurodevelopmental conditions, but how this variation results in distinct and overlapping behavioral changes is still not well understood. Recent efforts have focused on screening many autism genes at once for functional and phenotypic convergence, and identified subsets that are crucial for many early steps of neurodevelopment. Few studies have screened later steps of neurodevelopment, circuit function, circuit plasticity, or behaviors. We screened 20 conserved autism-associated genes for impact on experience-dependent neuron remodeling in Caenorhabditis elegans. Loss of unc-44/ANK2, set-4/KMT5B, daf-18/PTEN, gap-2/SYNGAP1, and chd-1/CHD2/8 increased, while unc-36/CACNA2D3 decreased, neurite outgrowth of the GABAergic DVB neuron in adults. Although daf-18/PTEN, set-4/KMT5B, and unc-44/ANK2 had convergent phenotypes, they arise from distinct temporal trajectories with differential impact on DVB presynaptic morphology. Screening for the DVB regulated spicule protraction behavior identified multiple autism genes involved, but only unc-44/ANK2 and unc-36/CACNA2D3 were shared between screens. Application of a metric geometry computational framework (CAJAL) to the DVB morphology dataset identified 5 additional genes that impact DVB morphology, including unc-2/CACNA1A and unc-10/RIMS1, which also significantly impacted behavior. This work defines new regulators and molecular mechanisms of experience-dependent neuron remodeling and circuit plasticity, and further links these processes with conserved autism genes. It also demonstrates the utility of using intact, behavior generating circuits in C. elegans, to screen for novel roles for conserved autism genes.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144838353","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}

引用次数: 0

Transcriptional control of C. elegans male tail tip morphogenesis by DMD-3. DMD-3对线虫雄性尾尖形态发生的转录调控。

IF 5.1 3区生物学

Genetics Pub Date : 2025-10-08 DOI: 10.1093/genetics/iyaf161

Porfirio Fernandez, Sevinç Ercan, Karin C Kiontke, David H A Fitch

{"title":"Transcriptional control of C. elegans male tail tip morphogenesis by DMD-3.","authors":"Porfirio Fernandez, Sevinç Ercan, Karin C Kiontke, David H A Fitch","doi":"10.1093/genetics/iyaf161","DOIUrl":"10.1093/genetics/iyaf161","url":null,"abstract":"Sexually dimorphic morphogenesis is governed by DM-domain transcription factors (TFs) in many animals, but how this transcriptional control links to the morphogenetic mechanisms is insufficiently known. The DM-domain TF DMD-3 in Caenorhabditis elegans is the master regulator of a male-specific morphogenetic event that changes the shape of the tail tip from long and pointed in larvae to short and round in adults. This tail tip morphogenesis (TTM) involves cell-shape changes, cell migration, and fusion. To understand how transcriptional regulation by DMD-3 governs TTM, we used male-specific ChIP-seq to identify its direct targets. We found 1,755 DMD-3-bound sites. We identify a DMD-3-associated binding motif and validate its function in TTM. This motif is similar to the binding motif of EOR-1, and eor-1 mutations affect TTM at a penetrance of 13%. This suggests that DMD-3 may act cooperatively with EOR-1 and possibly other TFs. DMD-3 targets 273 genes that play a role in TTM. These genes include other TFs as well as effectors and components of morphogenetic mechanisms. By deleting DMD-3-bound sites endogenously and observing changes in reporter expression and tail tip phenotypes, we identify tissue-specific enhancers in the cis-regulatory regions of fos-1, pan-1, nmy-2, and hmr-1 that play a role in TTM. For fos-1, we propose that a feed-forward loop is responsible for the tail-tip-specific increase in gene expression. Our study suggests that the gene regulatory network for TTM downstream of DMD-3 involves an unexpectedly large hierarchical cascade of TFs, but DMD-3 directly targets some non-TF genes as well.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144838357","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}

引用次数: 0

Nonequivalence of Zfp423 premature termination codons in mice. 小鼠Zfp423过早终止密码子的不等效性。

IF 5.1 3区生物学

Genetics Pub Date : 2025-10-08 DOI: 10.1093/genetics/iyaf164

Dorothy Concepcion, Catherine Liang, Daniel Kim, Bruce A Hamilton

{"title":"Nonequivalence of Zfp423 premature termination codons in mice.","authors":"Dorothy Concepcion, Catherine Liang, Daniel Kim, Bruce A Hamilton","doi":"10.1093/genetics/iyaf164","DOIUrl":"10.1093/genetics/iyaf164","url":null,"abstract":"Genetic variants that introduce a premature termination codon (PTC) are often assumed equivalent and functionally null. Exceptions depend on the specific architectures of the affected mRNA and protein. Here we address phenotypic differences among early truncating variants of mouse Zfp423, whose phenotypes resemble Joubert Syndrome and Related Disorders. We replicate quantitative differences previously seen between presumptive null PTC variants based on their position in the coding sequence. We show with reciprocal congenic strains that large phenotype differences between two PTC variants with the same predicted stop and reinitiation codons are due to the specific allele rather than different strain backgrounds, with no evidence for induced exon skipping. Differences in RNA structure, however, could influence translation rate across the affected exon. Using a reporter assay, we find differences in translational reinitiation between 2 deletion variants that correlate with predicted RNA structure rather than distance from the canonical initiation codon. These results confirm and extend earlier evidence for differences among Zfp423 PTC variants, identify parameters for translational reinitiation after an early termination codon, and reinforce caution in the null interpretation of early PTC variants.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12505304/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144876357","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}

引用次数: 0