Genetics最新文献

{"title":"909 Haplotype-specific chromatin looping reveals genetic interactions of regulatory regions modulating gene expression at the SLE susceptibility locusFAM167A-BLK","authors":"Mariana Saint Just Ribeiro, P. Tripathi, B. Namjou, J. Harley, I. Chepelev","doi":"10.1136/lupus-2022-lupus21century.60","DOIUrl":"https://doi.org/10.1136/lupus-2022-lupus21century.60","url":null,"abstract":"","PeriodicalId":12706,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45058894","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":"1001 A new model of spontaneous anti-phospholipid antibody induced pregnancy loss in mice over-expressing human TLR8","authors":"N. Maria, Shani Martinez, Chirag Raparia, Z. Yi, H. Tao, Ke Lin, Weijia Zhang, A. Davidson","doi":"10.1136/lupus-2022-lupus21century.61","DOIUrl":"https://doi.org/10.1136/lupus-2022-lupus21century.61","url":null,"abstract":"","PeriodicalId":12706,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47077570","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":"Driving lessons: a brief (personal) history of centromere drive.","authors":"Harmit S Malik","doi":"10.1093/genetics/iyac155","DOIUrl":"10.1093/genetics/iyac155","url":null,"abstract":"","PeriodicalId":12706,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2022-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9713404/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42708410","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":"Science from the soul: original research by middle and high school students addresses community health needs and increases representation in science.","authors":"Dara M Ruiz-Whalen, Alana M O'Reilly","doi":"10.1093/genetics/iyac156","DOIUrl":"10.1093/genetics/iyac156","url":null,"abstract":"","PeriodicalId":12706,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2022-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9713453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46458099","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":"Complex genetics cause and constrain fungal persistence in different parts of the mammalian body.","authors":"Martin N Mullis, Caleb Ghione, Michael Lough-Stevens, Ilan Goldstein, Takeshi Matsui, Sasha F Levy, Matthew D Dean, Ian M Ehrenreich","doi":"10.1093/genetics/iyac138","DOIUrl":"10.1093/genetics/iyac138","url":null,"abstract":"<p><p>Determining how genetic polymorphisms enable certain fungi to persist in mammalian hosts can improve understanding of opportunistic fungal pathogenesis, a source of substantial human morbidity and mortality. We examined the genetic basis of fungal persistence in mice using a cross between a clinical isolate and the lab reference strain of the budding yeast Saccharomyces cerevisiae. Employing chromosomally encoded DNA barcodes, we tracked the relative abundances of 822 genotyped, haploid segregants in multiple organs over time and performed linkage mapping of their persistence in hosts. Detected loci showed a mix of general and antagonistically pleiotropic effects across organs. General loci showed similar effects across all organs, while antagonistically pleiotropic loci showed contrasting effects in the brain vs the kidneys, liver, and spleen. Persistence in an organ required both generally beneficial alleles and organ-appropriate pleiotropic alleles. This genetic architecture resulted in many segregants persisting in the brain or in nonbrain organs, but few segregants persisting in all organs. These results show complex combinations of genetic polymorphisms collectively cause and constrain fungal persistence in different parts of the mammalian body.</p>","PeriodicalId":12706,"journal":{"name":"Genetics","volume":"222 3","pages":""},"PeriodicalIF":5.1,"publicationDate":"2022-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9630980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40357752","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":"Fine-tuning acetyl-CoA carboxylase 1 activity through localization: functional genomics reveals a role for the lysine acetyltransferase NuA4 and sphingolipid metabolism in regulating Acc1 activity and localization.","authors":"Trang Pham, Elizabeth Walden, Sylvain Huard, John Pezacki, Morgan D Fullerton, Kristin Baetz","doi":"10.1093/genetics/iyac086","DOIUrl":"10.1093/genetics/iyac086","url":null,"abstract":"<p><p>Acetyl-CoA Carboxylase 1 catalyzes the conversion of acetyl-CoA to malonyl-CoA, the committed step of de novo fatty acid synthesis. As a master regulator of lipid synthesis, acetyl-CoA carboxylase 1 has been proposed to be a therapeutic target for numerous metabolic diseases. We have shown that acetyl-CoA carboxylase 1 activity is reduced in the absence of the lysine acetyltransferase NuA4 in Saccharomyces cerevisiae. This change in acetyl-CoA carboxylase 1 activity is correlated with a change in localization. In wild-type cells, acetyl-CoA carboxylase 1 is localized throughout the cytoplasm in small punctate and rod-like structures. However, in NuA4 mutants, acetyl-CoA carboxylase 1 localization becomes diffuse. To uncover mechanisms regulating acetyl-CoA carboxylase 1 localization, we performed a microscopy screen to identify other deletion mutants that impact acetyl-CoA carboxylase 1 localization and then measured acetyl-CoA carboxylase 1 activity in these mutants through chemical genetics and biochemical assays. Three phenotypes were identified. Mutants with hyper-active acetyl-CoA carboxylase 1 form 1 or 2 rod-like structures centrally within the cytoplasm, mutants with mid-low acetyl-CoA carboxylase 1 activity displayed diffuse acetyl-CoA carboxylase 1, while the mutants with the lowest acetyl-CoA carboxylase 1 activity (hypomorphs) formed thick rod-like acetyl-CoA carboxylase 1 structures at the periphery of the cell. All the acetyl-CoA carboxylase 1 hypomorphic mutants were implicated in sphingolipid metabolism or very long-chain fatty acid elongation and in common, their deletion causes an accumulation of palmitoyl-CoA. Through exogenous lipid treatments, enzyme inhibitors, and genetics, we determined that increasing palmitoyl-CoA levels inhibits acetyl-CoA carboxylase 1 activity and remodels acetyl-CoA carboxylase 1 localization. Together this study suggests yeast cells have developed a dynamic feed-back mechanism in which downstream products of acetyl-CoA carboxylase 1 can fine-tune the rate of fatty acid synthesis.</p>","PeriodicalId":12706,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":5.1,"publicationDate":"2022-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9339284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46762057","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":"FMRP-dependent production of large dosage-sensitive proteins is highly conserved.","authors":"Keegan Flanagan,&nbsp;Alireza Baradaran-Heravi,&nbsp;Qi Yin,&nbsp;Khanh Dao Duc,&nbsp;Allan C Spradling,&nbsp;Ethan J Greenblatt","doi":"10.1093/genetics/iyac094","DOIUrl":"https://doi.org/10.1093/genetics/iyac094","url":null,"abstract":"<p><p>Mutations in FMR1 are the most common heritable cause of autism spectrum disorder. FMR1 encodes an RNA-binding protein, FMRP, which binds to long, autism-relevant transcripts and is essential for normal neuronal and ovarian development. In contrast to the prevailing model that FMRP acts to block translation elongation, we previously found that FMRP activates the translation initiation of large proteins in Drosophila oocytes. We now provide evidence that FMRP-dependent translation is conserved and occurs in the mammalian brain. Our comparisons of the mammalian cortex and Drosophila oocyte ribosome profiling data show that translation of FMRP-bound mRNAs decreases to a similar magnitude in FMRP-deficient tissues from both species. The steady-state levels of several FMRP targets were reduced in the Fmr1 KO mouse cortex, including a ∼50% reduction of Auts2, a gene implicated in an autosomal dominant autism spectrum disorder. To distinguish between effects on elongation and initiation, we used a novel metric to detect the rate-limiting ribosome stalling. We found no evidence that FMRP target protein production is governed by translation elongation rates. FMRP translational activation of large proteins may be critical for normal human development, as more than 20 FMRP targets including Auts2 are dosage sensitive and are associated with neurodevelopmental disorders caused by haploinsufficiency.</p>","PeriodicalId":12706,"journal":{"name":"Genetics","volume":"221 4","pages":""},"PeriodicalIF":3.3,"publicationDate":"2022-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9339308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40178133","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":"SUMOylation of Dorsal attenuates Toll/NF-κB signaling.","authors":"Sushmitha Hegde, Ashley Sreejan, Chetan J Gadgil, Girish S Ratnaparkhi","doi":"10.1093/genetics/iyac081","DOIUrl":"10.1093/genetics/iyac081","url":null,"abstract":"<p><p>In Drosophila, Toll/NF-κB signaling plays key roles in both animal development and in host defense. The activation, intensity, and kinetics of Toll signaling are regulated by posttranslational modifications such as phosphorylation, SUMOylation, or ubiquitination that target multiple proteins in the Toll/NF-κB cascade. Here, we have generated a CRISPR-Cas9 edited Dorsal (DL) variant that is SUMO conjugation resistant. Intriguingly, embryos laid by dlSCR mothers overcome dl haploinsufficiency and complete the developmental program. This ability appears to be a result of higher transcriptional activation by DLSCR. In contrast, SUMOylation dampens DL transcriptional activation, ultimately conferring robustness to the dorso-ventral program. In the larval immune response, dlSCR animals show an increase in crystal cell numbers, stronger activation of humoral defense genes, and high cactus levels. A mathematical model that evaluates the contribution of the small fraction of SUMOylated DL (1-5%) suggests that it acts to block transcriptional activation, which is driven primarily by DL that is not SUMO conjugated. Our findings define SUMO conjugation as an important regulator of the Toll signaling cascade, in both development and host defense. Our results broadly suggest that SUMO attenuates DL at the level of transcriptional activation. Furthermore, we hypothesize that SUMO conjugation of DL may be part of a Ubc9-dependent mechanism that restrains Toll/NF-κB signaling.</p>","PeriodicalId":12706,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2022-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9252280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44998648","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":"Ongoing transposition in cell culture reveals the phylogeny of diverse Drosophila S2 sublines.","authors":"Shunhua Han, Guilherme B Dias, Preston J Basting, Michael G Nelson, Sanjai Patel, Mar Marzo, Casey M Bergman","doi":"10.1093/genetics/iyac077","DOIUrl":"10.1093/genetics/iyac077","url":null,"abstract":"<p><p>Cultured cells are widely used in molecular biology despite poor understanding of how cell line genomes change in vitro over time. Previous work has shown that Drosophila cultured cells have a higher transposable element content than whole flies, but whether this increase in transposable element content resulted from an initial burst of transposition during cell line establishment or ongoing transposition in cell culture remains unclear. Here, we sequenced the genomes of 25 sublines of Drosophila S2 cells and show that transposable element insertions provide abundant markers for the phylogenetic reconstruction of diverse sublines in a model animal cell culture system. DNA copy number evolution across S2 sublines revealed dramatically different patterns of genome organization that support the overall evolutionary history reconstructed using transposable element insertions. Analysis of transposable element insertion site occupancy and ancestral states support a model of ongoing transposition dominated by episodic activity of a small number of retrotransposon families. Our work demonstrates that substantial genome evolution occurs during long-term Drosophila cell culture, which may impact the reproducibility of experiments that do not control for subline identity.</p>","PeriodicalId":12706,"journal":{"name":"Genetics","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2022-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9252272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47594126","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":"Are asymmetric inheritance systems an evolutionary trap? Transitions in the mechanism of paternal genome loss in the scale insect family Eriococcidae","authors":"C. N. Hodson, A. Toon, L. Cook, L. Ross","doi":"10.1101/2022.06.23.497384","DOIUrl":"https://doi.org/10.1101/2022.06.23.497384","url":null,"abstract":"Haplodiploidy and paternal genome elimination (PGE) are examples of asymmetric inheritance, where males transmit only maternally inherited chromosomes to their offspring. Under haplodiploidy this results from males being haploid, whereas under PGE males inherit but subsequently eliminate paternally inherited chromosomes during meiosis. Their evolution involves changes in the mechanisms of meiosis and sex determination, and sometimes also dosage compensation. As a result, these systems are thought to be an evolutionary trap, meaning that once asymmetric chromosome transmission evolves, it is difficult to transition back to typical Mendelian transmission. We assess whether there is evidence for this idea in the scale insect family Eriococcidae, a lineage with PGE and the only clade with a suggestion that asymmetric inheritance has transitioned back to Mendelian inheritance. We conduct a cytological survey of 13 eriococcid species, and a cytological, genetic, and gene expression analysis of species in the genus Cystococcus, to investigate whether there is evidence for species in this clade evolving Mendelian chromosome transmission. Although we find that all species we examined exhibit PGE, the mechanism is extremely variable within Eriococcidae. Within Cystococcus, in fact, we uncover a previously undiscovered type of PGE in scale insects, where in males paternally inherited chromosomes are present, uncondensed, and expressed in somatic cells, but are eliminated prior to meiosis. Broadly, we fail to find evidence for a reversion from PGE to Mendelian inheritance in Eriococcidae, supporting the idea that asymmetric inheritance systems such as PGE may be an evolutionary trap.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":"224 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2022-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43407585","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}