bioRxiv - Genetics最新文献

{"title":"New loci and candidate genes in spring two-rowed barley detected through meta-analysis of a field trial European network","authors":"Francesc Montardit-Tarda, Ana M Casas, William Thomas, Florian Schnaithmann, Rajiv Sharma, Salar Shaaf, Chiara Campoli, Joanne Russell, Luke Ramsay, Stefano Delbono, Marko Jääskeläinen, Maitry Paul, Fred Stoddard, Andrea Visioni, Andrew J Flavell, Klaus Pillen, Benjamin Kilian, A Graner, Laura Rossini, Robbie Waugh, Luigi Cattivelli, Alan H Schulman, Alessandro Tondelli, Ernesto Igartua","doi":"10.1101/2024.09.04.611234","DOIUrl":"https://doi.org/10.1101/2024.09.04.611234","url":null,"abstract":"This study contributes new knowledge on quantitative trait loci (QTLs) and candidate genes for adaptive traits and yield in two-rowed spring barley. A meta-analysis of a network of field trials, varying in latitude and sowing date, with 151 cultivars across several European countries, increased QTL detection power compared to single-trial analyses. The traits analysed were heading date (HD), plant height (PH), thousand-grain weight (TGW), and grain yield (GY). Breaking down the analysis by the main genotype-by-environment trends revealed QTLs and candidate genes specific to conditions like sowing date and latitude. A historical look on the evolution of QTL frequencies revealed that early selection focused on PH and TGW, likely due to their high heritability. GY selection occurred later, facilitated by reduced variance in other traits. The study observed that favourable alleles for plant height were often fixed before those for grain yield and TGW. Some regions showed linkage in repulsion, suggesting targets for future breeding. Several candidate genes were identified, including known genes and new candidates based on orthology with rice. Remarkably, the <em>deficiens</em> allele of gene <em>Vrs1</em>, appears associated to higher GY. These findings provide valuable insights for barley breeders aiming to improve yield, and other agronomic traits.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering Asian elephant TP53: TP53 retrogene knockouts activate common and unique cancer-relevant pathways","authors":"Emil Karpinski, Nikil Badey, Esther Mintzer, Asaf Ashkenazy-Titelman, George M Church","doi":"10.1101/2024.09.07.611789","DOIUrl":"https://doi.org/10.1101/2024.09.07.611789","url":null,"abstract":"TP53 functions as a central regulator in response to DNA damage and other cell stressors by inducing the expression of many protective pathways such as cell cycle arrest and apoptosis. Consequently, this gene is often found disrupted in human cancers. Elephants are a particularly interesting species for the study of cancer, by virtue of their large number of cell divisions and long lives yet low incidence of cancer. Elephants also possess multiple retrogene copies of TP53, which have previously been shown to induce strong cellular responses to DNA damage. However, most previous studies have largely focused only on African elephant TP53 retrogenes and often in non-native backgrounds. Here we generated CRISPR-Cas9 knockouts of TP53, all 29 TP53 retrogenes, or both in combination in Asian elephant fibroblasts. We find that while there is considerable overlap in the DNA damage responses of the TP53 and retrogene knockouts, there are also many unique pathways enriched in both. In particular, the retrogene knockouts exhibit strong enrichment of many extracellular pathways suggesting they may play a large role in the tumor microenvironment and mitigating metastatic growth. We also find that only a small fraction of these 29 retrogenes appear to be expressed across a variety of tissues and identify three loci that are likely driving this response. This work shows for the first time the transcriptomic effect of these retrogenes within their native background and establishes a foundation for future research into the relative contributions of these genes.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nebulized and intravenous enzyme replacement therapy in mice with mucopolysaccharidosis type II","authors":"Alex J. Shamoun, Gisienne Reis, Malaica Ashley, Anatalia Labilloy, Leonardo F. Ferreira","doi":"10.1101/2024.09.03.611097","DOIUrl":"https://doi.org/10.1101/2024.09.03.611097","url":null,"abstract":"Mucopolysaccharidosis Type II is a hereditary lysosomal storage disease characterized by deficiency in the enzyme iduronate 2-sulfatase (IDS). IDS is critical in the breakdown of sulfated glycosaminoglycans and its deficiency leads to an accumulation of these compounds across various tissue types resulting in multisystemic dysfunction. Intravenous administration of recombinant IDS (idursulfase) substantially improves patients’ quality and length of life. However, recombinant IDS delivered intravenously is sequestered in the liver and respiratory failure remains as the leading cause of death for patients independent of idursulfase treatment, which suggests insufficient delivery to the lungs. This study aimed to assess a novel method of idursulfase administration using a nebulizer in combination with intravenous treatment and determine if this combination may improve lung delivery of idursulfase and overall pathology. Whole body IDS knockout mice underwent twelve weeks of intravenous, combination treatment, or vehicle injection and we harvested liver and lungs seven days after the last treatment for assessment of IDS activity, histological markers, and global proteomics for comparison with wild-type mice. Combination treatment increased IDS enzyme activity in the liver but not lungs Proteomics data demonstrated attenuation of key features of the disease in liver (metabolic pathways) and lungs (glycosaminoglycan pathways) with both treatments. Overall, adding nebulized administration of IDS did not lead to sustained increase in enzyme activity in the lungs but caused persistent modifications in glycosaminoglycan degradation pathway suggesting additional benefits to intravenous administration alone.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Genotype and Age on a Defined Microbiota in Gnotobiotic SCID Piglets","authors":"Katherine M Widmer, Faith Rahic-Seggerman, Ahlea Forster, Amanda Ahrens-Kress, Mary Sauer, Shankumar Mooyottu, Akhil Vinithakumari, Aaron Dunkerson-Kurzhumov, Brett Sponseller, Matti Kiupel, Stephan Schmitz-Esser, Christopher K Tuggle","doi":"10.1101/2024.09.03.611011","DOIUrl":"https://doi.org/10.1101/2024.09.03.611011","url":null,"abstract":"Severe combined immunodeficient (SCID) individuals lack functional T and B lymphocytes, leading to a deficient adaptive immune system. SCID pigs are a unique large animal biomedical model as they possess many similarities to humans, allowing for the collection of translatable data in regenerative medicine, cancer, and other biomedical research topics. While many studies suggest early gut microbiota development is necessary for developing the intestinal barrier and immune system, these animals are often cesarian section derived, leaving them uncolonized for normal intestinal microflora. The hypothesis was that an increase in complexity of microbiota inoculum will allow for more stability in the composition of the gut microbiota of SCID piglets. This was tested across multiple litters of SCID piglets with three different defined microbiota consortium (2-strain, 6-strain, 7-strain). All piglets received their designated defined microbiota by oral gavage immediately after birth and again 24 hours later. There was no effect of SCID genotype on the composition of the gut microbiota, but there was a significant effect due to piglet age. Additionally, all three defined microbiota consortia were deemed safe to use in SCID piglets, and the 7-strain microbiota was the most stable over time. Based on these results, the 7-strain defined microbiota will be added to the SCID pig husbandry protocol, allowing for a more reproducible model.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unique Signatures of Highly Constrained Genes Across Publicly Available Genomic Databases","authors":"Pankaj Agrawal, Klaus E Schmitz-Abe, Qifei Li, Sunny Greene, Michela Borrelli, Shiyu Luo, Madesh Ramesh","doi":"10.1101/2024.09.05.611529","DOIUrl":"https://doi.org/10.1101/2024.09.05.611529","url":null,"abstract":"Publicly available genomic databases and genetic constraint scores are crucial in understanding human population variation and the identification of variants that are likely to have a deleterious impact causing human disease. We utilized the one of largest publicly available databases, gnomAD, to determine genes that are highly constrained for only LoF, only missense, and both LoF/missense variants, identified their unique signatures, and explored their causal relationship with human conditions. Those genes were evaluated for unique patterns including their chromosomal location, tissue level expression, gene ontology analysis, and gene family categorization using multiple publicly available databases. Those highly constrained genes associated with human disease, we identified unique patterns of inheritance, protein size, and enrichment in distinct molecular pathways. In addition, we identified a cohort of highly constrained genes that are currently not known to cause human disease, that we suggest will be candidates to pursue as novel disease-associated genes. In summary, these insights not only elucidate biological pathways of highly constrained genes that expand our understanding of critical cellular proteins but also advance research in rare diseases.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRISPR-based dissection of miRNA binding sites using isogenic cell lines is hampered by pervasive noise.","authors":"Mahendra K. Prajapat, Joana A Vidigal","doi":"10.1101/2024.09.03.611048","DOIUrl":"https://doi.org/10.1101/2024.09.03.611048","url":null,"abstract":"Non-coding regulatory sequences play essential roles in adjusting gene output to cellular needs and are thus critical to animal development and health. Numerous such sequences have been identified in mammalian genomes ranging from transcription factors binding motifs to recognition sites for RNA-binding proteins and non-coding RNAs. The advent of CRISPR has raised the possibility of assigning functionality to individual endogenous regulatory sites by facilitating the generation of isogenic cell lines that differ by a defined set of genetic modifications. Here we investigate the usefulness of this approach to assign function to individual miRNA binding sites. We find that the process of generating isogenic pairs of mammalian cell lines with CRISPR-mediated mutations introduces extensive molecular and phenotypic variability between biological replicates making any attempt of assigning function to the binding site essentially impossible. Our work highlights an important consideration when employing CRISPR editing to characterize non-coding regulatory sequences in cell lines and calls for the development and adoption of alternative strategies to address this question in the future.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial direct repeat reduction as a strategy for enhancing human longevity: the case of the common repeat","authors":"Victor A. Shamanskiy, Konstantin V. Gunbin, Evgenii O. Tretiakov, Ilia O. Mazunin, Victoria Skripskaya, Alina A. Mihailova, Alina G. Mikhailova, Natalia Ree, Valeriia Timonina, Dmitry Knorre, Wolfram S. Kunz, Yukinori Okada, Nathan Fiorell, Alexandre Reymond, Georgii A. Bazykin, Jacques Fellay, Masashi Tanaka, Konstantin Khrapko, Konstantin Popadin","doi":"10.1101/2024.09.02.610808","DOIUrl":"https://doi.org/10.1101/2024.09.02.610808","url":null,"abstract":"Aging, characterized by a series of functional declines correlated with advancing chronological age, has a significant mitochondrial DNA (mtDNA) component, with somatic mtDNA deletions playing a central role. In post-mitotic or slow-dividing cells like neurons and skeletal muscles, selfish mtDNA deletions clonally expand within a cell, ultimately leading to the deterioration and death of host cells and appearence of age-related phenotypes. Thus reducing the burden of somatic deletions could have far-reaching systemic benefits for the entire human body. Given the crucial role of direct nucleotide repeats in the formation of mitochondrial deletions, we hypothesize that minimizing these repeats in the human mitochondrial genome could enhance healthspan by decreasing somatic deletions. To investigate this hypothesis, we focus on the \"common repeat\", a 13-base pair perfect direct repeat sequence (ACCTCCCTCACCA) located at positions 8470-8482 and 13447-13459, respectively. This perfect repeat: (i) is highly prevalent, with its potential deleterious consequences affecting the majority of humans; (ii) represents one of the most fragile sites, highly prone to forming deletions; (iii) when disrupted, is associated with a decreased somatic deletion load and enhanced human healthspan; (iv) is likely to experience positive selection in the present or near future due to indirect fitness effects, such as the \"grandmother effect\", and direct fitness effects, such as (v) a decreased mutation rate. These observations support the argument that reducing the mtDNA somatic deletion load through targeted disruption of these repeats, or by using naturally occurring polymorphisms with disrupted repeats in mitochondrial medicine, could be an effective approach to increasing human longevity.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A scalable approach for genome-wide inference of ancestral recombination graphs","authors":"Árni Freyr Gunnarsson, Jiazheng Zhu, Brian C. Zhang, Zoi Tsangalidou, Alex Allmont, Pier Francesco Palamara","doi":"10.1101/2024.08.31.610248","DOIUrl":"https://doi.org/10.1101/2024.08.31.610248","url":null,"abstract":"The ancestral recombination graph (ARG) is a graph-like structure that encodes a detailed genealogical history of a set of individuals along the genome. ARGs that are accurately reconstructed from genomic data have several downstream applications, but inference from data sets comprising millions of samples and variants remains computationally challenging. We introduce Threads, a threading-based method that significantly reduces the computational costs of ARG inference while retaining high accuracy. We apply Threads to infer the ARG of 487,409 genomes from the UK Biobank using ~10 million high-quality imputed variants, reconstructing a detailed genealogical history of the samples while compressing the input genotype data. Additionally, we develop ARG-based imputation strategies that increase genotype imputation accuracy for ultra-rare variants (MAC ≤ 10) from UK Biobank exome sequencing data by 5-10%. We leverage ARGs inferred by Threads to detect associations with 52 quantitative traits in non-European UK Biobank samples, identifying 22.5% more signals than ARG-Needle. These analyses underscore the value of using computationally efficient genealogical modeling to improve and complement genotype imputation in large-scale genomic studies.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developing simple DNA extraction and PCR-RFLP for MALE STERILITY 4 (MS4) gene in Cryptomeria japonica D. Don: Toward an environmentally friendly protocol","authors":"Saneyoshi Ueno, Yukiko Ito, Yoichi Hasegawa, Yoshinari Moriguchi","doi":"10.1101/2024.08.31.610595","DOIUrl":"https://doi.org/10.1101/2024.08.31.610595","url":null,"abstract":"This study presents the development of a simple DNA extraction method and a novel PCR-RFLP technique for genotyping the <em>MALE STERILITY 4</em> (<em>MS4</em>) gene in <em>Cryptomeria japonica</em>. Traditional CTAB-based DNA extraction methods, while effective, involve hazardous chemicals and require high-speed centrifugation, which are impractical in many field settings. Our approach utilizes a household dish detergent-based buffer, sodium chloride, and polyvinylpyrrolidone K-30 to extract DNA from <em>C. japonica</em> needle leaf tissues. The simplicity of this method makes it more accessible and environmentally friendly. The extracted DNA was successfully used in PCR-RFLP analysis, targeting a single nucleotide polymorphism in the <em>MS4</em> gene, demonstrating its efficacy for genotyping. The PCR-RFLP markers reliably discriminated between individual genotypes, confirming the practical application of our simple extraction method, even for conifers containing inhibitory substances. This technique is particularly advantageous for use in arboretums and field stations, where the use of hazardous chemicals and specialized equipment is limited. Our study contributes to genetic resource management by providing an easy, reliable, and safer method for DNA extraction and genetic analysis.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A nuclear hormone receptor nhr-76 programs age-dependent chemotaxis decline in C. elegans","authors":"Rikuou Yokosaka, Kentaro Noma","doi":"10.1101/2024.08.30.609799","DOIUrl":"https://doi.org/10.1101/2024.08.30.609799","url":null,"abstract":"A decline in food-searching behavior of post-reproductive animals can be beneficial for the population and possibly programmed by the genome. We investigated the genetic program of age-dependent decline in chemotaxis behavior toward an odorant secreted from bacterial food in C. elegans. Through a forward genetic screen, we identified a nuclear hormone receptor, nhr-76, whose mutants ameliorate the age-dependent chemotaxis decline. We found that nhr-76 downregulates the expression of the odorant receptor during aging. Because NHR-76 expression and localization did not change during aging, secretion of its hydrophobic ligands might alter the activity of NHR-76 to cause age-dependent chemotaxis decline. Our findings imply that post-reproductive behavioral decline can be genetically programmed.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}