DNA methylation is a type of epigenetic modification known to exhibit fluctuations in response to environmental factors. The association of macrosocial factors, such as interpersonal mobility, on methylation has seldom been investigated. This study aimed to examine the association of relational mobility, defined as the extent to which individuals can form and replace social relationships, on the DNA methylation of oxytocin receptor genes. DNA was extracted from the buccal cells of 95 adult participants (50 men and 45 women) and subjected to microarray analysis of DNA methylation using Illumina EPIC v2.0. The findings indicate that the oxytocin receptor gene's methylation level was higher in individuals residing in low relational mobility social environments. The CpG site associated with relational mobility is an enhancer region, indicating that social environments with low relational mobility exert a suppressive effect on the transcriptional efficiency of the oxytocin receptor gene.
众所周知，DNA 甲基化是一种表观遗传修饰，会随着环境因素的变化而波动。宏观社会因素（如人际流动性）与甲基化之间的关联还很少被研究。本研究旨在探讨人际流动性（即个人可以建立和更换社会关系的程度）与催产素受体基因 DNA 甲基化的关联。研究人员从 95 名成年参与者（50 名男性和 45 名女性）的口腔细胞中提取了 DNA，并使用 Illumina EPIC v2.0 对 DNA 甲基化进行了芯片分析。研究结果表明，在关系流动性较低的社会环境中，催产素受体基因的甲基化水平较高。与关系流动性相关的 CpG 位点是一个增强区，表明关系流动性低的社会环境对催产素受体基因的转录效率有抑制作用。
{"title":"Association Between Relational Mobility and DNA Methylation in Oxytocin Receptor Gene: A Social Epigenetic Study","authors":"Shubing Li, Junko Yamada, Toru Ishihara, Kuniyuki Nishina, Shota Nishitani, Tetsuhiko Sasaki, Tetsuya Matsuda, Miho Inoue-Murayama, Haruto Takagishi","doi":"10.1101/2024.08.27.609977","DOIUrl":"https://doi.org/10.1101/2024.08.27.609977","url":null,"abstract":"DNA methylation is a type of epigenetic modification known to exhibit fluctuations in response to environmental factors. The association of macrosocial factors, such as interpersonal mobility, on methylation has seldom been investigated. This study aimed to examine the association of relational mobility, defined as the extent to which individuals can form and replace social relationships, on the DNA methylation of oxytocin receptor genes. DNA was extracted from the buccal cells of 95 adult participants (50 men and 45 women) and subjected to microarray analysis of DNA methylation using Illumina EPIC v2.0. The findings indicate that the oxytocin receptor gene's methylation level was higher in individuals residing in low relational mobility social environments. The CpG site associated with relational mobility is an enhancer region, indicating that social environments with low relational mobility exert a suppressive effect on the transcriptional efficiency of the oxytocin receptor gene.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179782","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}
Pub Date : 2024-08-27DOI: 10.1101/2024.08.26.608813
Joshua F Shaffer, Alka Gupta, Geetika Kharkwal, Edgardo E Linares, Andrew D Holmes, Upasna Sharma
Sperm small RNAs are implicated in intergenerational transmission of paternal environmental effects. Small RNAs generated by cleavage of tRNAs, known as tRNA fragments (tRFs), are an abundant class of RNAs in mature sperm, and can be modulated by environmental conditions. The ribonuclease(s) responsible for the biogenesis of tRFs in the male reproductive tract remains unknown. Angiogenin, a member of the Ribonuclease A superfamily (RNase A), cleaves tRNAs to generate tRFs in response to cellular stress. Four paralogs of Angiogenin, namely Rnase9, Rnase10, Rnase11, and Rnase12, are specifically expressed in the epididymis -a long, convoluted tubule where sperm mature and acquire fertility and motility. The biological functions of these genes remain largely unknown. Here, by generating mice deleted for all four genes (Rnase9-12-/-, termed KO for Knock Out), we report that these genes regulate fertility and RNA processing. KO mice showed complete male sterility. KO sperm fertilized oocytes in vitro but failed to efficiently fertilize oocytes in vivo, likely due to an inability of sperm to pass through the utero-tubular junction. Intriguingly, there were decreased levels of fragments of tRNAs (tRFs) and rRNAs (rRNA-derived small RNAs or rsRNAs) in the KO epididymis and epididymal luminal fluid, implying that Rnase9-12 regulate the biogenesis and/or stability of tRFs and rsRNAs. Importantly, KO sperm showed a dramatic decrease in the levels of tRFs, demonstrating a role of Rnase9-12 in regulating sperm RNA composition. Together, our results reveal an unexpected role of four epididymis-specific non-canonical RNase A family genes in fertility and RNA processing.
{"title":"Epididymis-specific RNase A family genes regulate fertility and small RNA processing","authors":"Joshua F Shaffer, Alka Gupta, Geetika Kharkwal, Edgardo E Linares, Andrew D Holmes, Upasna Sharma","doi":"10.1101/2024.08.26.608813","DOIUrl":"https://doi.org/10.1101/2024.08.26.608813","url":null,"abstract":"Sperm small RNAs are implicated in intergenerational transmission of paternal environmental effects. Small RNAs generated by cleavage of tRNAs, known as tRNA fragments (tRFs), are an abundant class of RNAs in mature sperm, and can be modulated by environmental conditions. The ribonuclease(s) responsible for the biogenesis of tRFs in the male reproductive tract remains unknown. Angiogenin, a member of the Ribonuclease A superfamily (RNase A), cleaves tRNAs to generate tRFs in response to cellular stress. Four paralogs of Angiogenin, namely Rnase9, Rnase10, Rnase11, and Rnase12, are specifically expressed in the epididymis -a long, convoluted tubule where sperm mature and acquire fertility and motility. The biological functions of these genes remain largely unknown. Here, by generating mice deleted for all four genes (Rnase9-12-/-, termed KO for Knock Out), we report that these genes regulate fertility and RNA processing. KO mice showed complete male sterility. KO sperm fertilized oocytes in vitro but failed to efficiently fertilize oocytes in vivo, likely due to an inability of sperm to pass through the utero-tubular junction. Intriguingly, there were decreased levels of fragments of tRNAs (tRFs) and rRNAs (rRNA-derived small RNAs or rsRNAs) in the KO epididymis and epididymal luminal fluid, implying that Rnase9-12 regulate the biogenesis and/or stability of tRFs and rsRNAs. Importantly, KO sperm showed a dramatic decrease in the levels of tRFs, demonstrating a role of Rnase9-12 in regulating sperm RNA composition. Together, our results reveal an unexpected role of four epididymis-specific non-canonical RNase A family genes in fertility and RNA processing.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179783","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}
The non-homologous end-joining (NHEJ) pathway is critical for DNA double-strand break repair and is essential for lymphocyte development and maturation. The Ku70/Ku80 heterodimer (KU) binds to DNA ends, initiating NHEJ and recruiting DNA-dependent protein kinase catalytic subunits (DNA-PKcs) that caps the ends. To investigate the function of Ku70 C-terminal SAP domain, we generated a mouse model with knock-in deletion (Ku70delSAP/delSAP). Ku70delSAP supports KU stability and its recruitment to DNA damage sites. Contrary to the growth retardation and immunodeficiency of Ku70-/- mice, Ku70delSAP/delSAP mice have normal size and lymphocyte development. Structural modeling of KU on long dsDNA suggests that the SAP domain binds to an adjacent major groove and potentially limits KU rotation and lateral movement on dsDNA. Accordingly, with the loss of DNA-PKcs that caps the ends, Ku70delSAP fails to form stable damage foci. In DNA-PKcs-/-mice, Ku70delSAP abrogates the leaky T-cell development and compromises residual end-joining in vivo. In the absence of DNA-PKcs, purified Ku70delSAP has reduced affinity for DNA ends, dissociates more readily at lower concentrations, and accumulates as multimers at high concentrations. These findings revealed the role of the KU SAP domain in restricting KU rotation and lateral movement on DNA that is largely masked by DNA-PKcs.
非同源末端连接（NHEJ）途径是DNA双链断裂修复的关键，对淋巴细胞的发育和成熟至关重要。Ku70/Ku80异源二聚体（KU）与DNA末端结合，启动NHEJ，并招募DNA依赖性蛋白激酶催化亚基（DNA-PKcs）对末端进行封顶。为了研究Ku70 C端SAP结构域的功能，我们建立了一个基因敲入缺失的小鼠模型（Ku70delSAP/delSAP）。Ku70delSAP支持KU的稳定性及其在DNA损伤位点的招募。与 Ku70-/- 小鼠的生长迟缓和免疫缺陷相反，Ku70delSAP/delSAP 小鼠的体型和淋巴细胞发育正常。KU在长dsDNA上的结构模型表明，SAP结构域与相邻的主沟结合，可能会限制KU在dsDNA上的旋转和横向移动。因此，由于失去了覆盖末端的 DNA-PKcs，Ku70delSAP 无法形成稳定的损伤灶。在DNA-PKcs-/-小鼠中，Ku70delSAP会导致T细胞漏性发育，并损害体内残余的末端连接。在缺乏DNA-PKcs的情况下，纯化的Ku70delSAP对DNA末端的亲和力降低，在低浓度时更容易解离，在高浓度时以多聚体形式积累。这些发现揭示了 KU SAP 结构域在 DNA 上限制 KU 旋转和横向移动的作用，而 DNA-PKcs 在很大程度上掩盖了这一作用。
{"title":"The KU70-SAP domain has an overlapping function with DNA-PKcs in limiting the lateral movement of KU along DNA","authors":"Yimeng Zhu, Brian J Lee, Shingo Fujii, Sagun Jonchhe, Hanwen Zhang, Angelina Li, Kyle J Wang, Eli Rothenberg, Mauro Modesti, Shan Zha","doi":"10.1101/2024.08.26.609806","DOIUrl":"https://doi.org/10.1101/2024.08.26.609806","url":null,"abstract":"The non-homologous end-joining (NHEJ) pathway is critical for DNA double-strand break repair and is essential for lymphocyte development and maturation. The Ku70/Ku80 heterodimer (KU) binds to DNA ends, initiating NHEJ and recruiting DNA-dependent protein kinase catalytic subunits (DNA-PKcs) that caps the ends. To investigate the function of Ku70 C-terminal SAP domain, we generated a mouse model with knock-in deletion (Ku70delSAP/delSAP). Ku70delSAP supports KU stability and its recruitment to DNA damage sites. Contrary to the growth retardation and immunodeficiency of Ku70-/- mice, Ku70delSAP/delSAP mice have normal size and lymphocyte development. Structural modeling of KU on long dsDNA suggests that the SAP domain binds to an adjacent major groove and potentially limits KU rotation and lateral movement on dsDNA. Accordingly, with the loss of DNA-PKcs that caps the ends, Ku70delSAP fails to form stable damage foci. In DNA-PKcs-/-mice, Ku70delSAP abrogates the leaky T-cell development and compromises residual end-joining in vivo. In the absence of DNA-PKcs, purified Ku70delSAP has reduced affinity for DNA ends, dissociates more readily at lower concentrations, and accumulates as multimers at high concentrations. These findings revealed the role of the KU SAP domain in restricting KU rotation and lateral movement on DNA that is largely masked by DNA-PKcs.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"48 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179630","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}
Pub Date : 2024-08-27DOI: 10.1101/2024.08.27.609905
Ananya Nidamangala Srinivasa, Samuel Campbell, Shriram Venkatesan, Nicole L Nuckolls, Jeffrey J Lange, Randal Halfmann, Sarah E Zanders
Killer meiotic drivers are selfish DNA loci that sabotage the gametes that do not inherit them from a driver+/driver- heterozygote. These drivers often employ toxic proteins that target essential cellular functions to cause the destruction of driver- gametes. Identifying the mechanisms of drivers can expand our understanding of infertility and reveal novel insights about the cellular functions targeted by drivers. In this work, we explore the molecular mechanisms underlying the wtf family of killer meiotic drivers found in fission yeasts. Each wtf killer acts using a toxic Wtfpoison protein that can be neutralized by a corresponding Wtfantidote protein. The wtf genes are rapidly evolving and extremely diverse. Here we found that self-assembly of Wtfpoison proteins is broadly conserved and associated with toxicity across the gene family, despite minimal amino acid conservation. In addition, we found the toxicity of Wtfpoison assemblies can be modulated by protein tags designed to increase or decrease the extent of the Wtfpoison assembly, implicating assembly size in toxicity. We also identified a conserved, critical role for the specific co-assembly of the Wtfpoison and Wtfantidote proteins in promoting effective neutralization of Wtfpoison toxicity. Finally, we engineered wtf alleles that encode toxic Wtfpoison proteins that are not effectively neutralized by their corresponding Wtfantidote proteins. The possibility of such self-destructive alleles reveals functional constraints on wtf evolution and suggests similar alleles could be cryptic contributors to infertility in fission yeast populations. As rapidly evolving killer meiotic drivers are widespread in eukaryotes, analogous self-killing drive alleles could contribute to sporadic infertility in many lineages.
{"title":"Functional and evolutionary constraints of wtf killer meiotic drivers","authors":"Ananya Nidamangala Srinivasa, Samuel Campbell, Shriram Venkatesan, Nicole L Nuckolls, Jeffrey J Lange, Randal Halfmann, Sarah E Zanders","doi":"10.1101/2024.08.27.609905","DOIUrl":"https://doi.org/10.1101/2024.08.27.609905","url":null,"abstract":"Killer meiotic drivers are selfish DNA loci that sabotage the gametes that do not inherit them from a driver+/driver- heterozygote. These drivers often employ toxic proteins that target essential cellular functions to cause the destruction of driver- gametes. Identifying the mechanisms of drivers can expand our understanding of infertility and reveal novel insights about the cellular functions targeted by drivers. In this work, we explore the molecular mechanisms underlying the <em>wtf</em> family of killer meiotic drivers found in fission yeasts. Each <em>wtf</em> killer acts using a toxic Wtf<sup>poison</sup> protein that can be neutralized by a corresponding Wtf<sup>antidote</sup> protein. The <em>wtf</em> genes are rapidly evolving and extremely diverse. Here we found that self-assembly of Wtf<sup>poison</sup> proteins is broadly conserved and associated with toxicity across the gene family, despite minimal amino acid conservation. In addition, we found the toxicity of Wtf<sup>poison</sup> assemblies can be modulated by protein tags designed to increase or decrease the extent of the Wtf<sup>poison</sup> assembly, implicating assembly size in toxicity. We also identified a conserved, critical role for the specific co-assembly of the Wtf<sup>poison</sup> and Wtf<sup>antidote</sup> proteins in promoting effective neutralization of Wtf<sup>poison</sup> toxicity. Finally, we engineered wtf alleles that encode toxic Wtf<sup>poison</sup> proteins that are not effectively neutralized by their corresponding Wtf<sup>antidote</sup> proteins. The possibility of such self-destructive alleles reveals functional constraints on <em>wtf</em> evolution and suggests similar alleles could be cryptic contributors to infertility in fission yeast populations. As rapidly evolving killer meiotic drivers are widespread in eukaryotes, analogous self-killing drive alleles could contribute to sporadic infertility in many lineages.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179780","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}
Pub Date : 2024-08-27DOI: 10.1101/2024.08.27.608867
Uyen Tran, Andrew J Streets, Devon Smith, Eva Decker, Annemarie Kirschfink, Lahoucine Izem, Jessie Hassey, Briana Ruthland, Manoj K Valluru, Jan Hinrich Bräsen, Elisabeth Ott, Daniel Epting, Tobias Eisenberger, Albert CM Ong, Carsten Bergmann, Oliver Wessely
Background: Autosomal dominant polycystic kidney disease (ADPKD) is primarily of adult-onset and caused by pathogenic variants in PKD1 or PKD2. Yet, disease expression is highly variable and includes very early-onset PKD presentations in utero or infancy. In animal models, the RNA-binding molecule Bicc1 has been shown to play a crucial role in the pathogenesis of PKD. Methods: To study the interaction between BICC1, PKD1 and PKD2 we combined biochemical approaches, knockout studies in mice and Xenopus, genetic engineered human kidney cells as well as genetic association studies in a large ADPKD cohort. Results: We first demonstrated that BICC1 physically binds to the proteins Polycystin-1 and -2 encoded by PKD1 and PKD2 via distinct protein domains. Furthermore, PKD was aggravated in loss-of-function studies in Xenopus and mouse models resulting in more severe disease when Bicc1 was depleted in conjunction with Pkd1 or Pkd2. Finally, in a large human patient cohort, we identified a sibling pair with a homozygous BICC1 variant and patients with very early onset PKD (VEO-PKD) that exhibited compound heterozygosity of BICC1 in conjunction with PKD1 and PKD2 variants. Genome editing demonstrated that these BICC1 variants were hypomorphic in nature and impacted disease-relevant signaling pathways. Conclusions: These findings support the hypothesis that BICC1 cooperates functionally with PKD1 and PKD2, and that BICC1 variants may aggravate disease severity highlighting RNA metabolism as an important new concept for disease modification in ADPKD.
{"title":"BICC1 Interacts with PKD1 and PKD2 to Drive Cystogenesis in ADPKD","authors":"Uyen Tran, Andrew J Streets, Devon Smith, Eva Decker, Annemarie Kirschfink, Lahoucine Izem, Jessie Hassey, Briana Ruthland, Manoj K Valluru, Jan Hinrich Bräsen, Elisabeth Ott, Daniel Epting, Tobias Eisenberger, Albert CM Ong, Carsten Bergmann, Oliver Wessely","doi":"10.1101/2024.08.27.608867","DOIUrl":"https://doi.org/10.1101/2024.08.27.608867","url":null,"abstract":"Background: Autosomal dominant polycystic kidney disease (ADPKD) is primarily of adult-onset and caused by pathogenic variants in PKD1 or PKD2. Yet, disease expression is highly variable and includes very early-onset PKD presentations in utero or infancy. In animal models, the RNA-binding molecule Bicc1 has been shown to play a crucial role in the pathogenesis of PKD. Methods: To study the interaction between BICC1, PKD1 and PKD2 we combined biochemical approaches, knockout studies in mice and Xenopus, genetic engineered human kidney cells as well as genetic association studies in a large ADPKD cohort. Results: We first demonstrated that BICC1 physically binds to the proteins Polycystin-1 and -2 encoded by PKD1 and PKD2 via distinct protein domains. Furthermore, PKD was aggravated in loss-of-function studies in Xenopus and mouse models resulting in more severe disease when Bicc1 was depleted in conjunction with Pkd1 or Pkd2. Finally, in a large human patient cohort, we identified a sibling pair with a homozygous BICC1 variant and patients with very early onset PKD (VEO-PKD) that exhibited compound heterozygosity of BICC1 in conjunction with PKD1 and PKD2 variants. Genome editing demonstrated that these BICC1 variants were hypomorphic in nature and impacted disease-relevant signaling pathways. Conclusions: These findings support the hypothesis that BICC1 cooperates functionally with PKD1 and PKD2, and that BICC1 variants may aggravate disease severity highlighting RNA metabolism as an important new concept for disease modification in ADPKD.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179779","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}
Pub Date : 2024-08-26DOI: 10.1101/2024.08.17.608383
Alexandre P. Marand, Luguang Jiang, Fabio A Gomez-Cano, Mark A.A. Minow, Xuan Zhang, John Pablo Mendieta, Ziliang Luo, Sohyun Bang, Haidong Yan, Cullan Meyer, Luca Schlegel, Frank Johannes, Robert J. Schmitz
Gene expression and complex phenotypes are determined by the activity of cis-regulatory elements. However, an understanding of how extant genetic variants affect cis-regulatory activity remains limited. Here, we investigated the consequences of cis-regulatory diversity using single-cell genomics of >0.7 million nuclei across 172 maize inbreds. Our analyses pinpointed cis-regulatory elements distinct to domesticated maize and how transposons rewired the regulatory landscape. We found widespread chromatin accessibility variation associated with >4.6 million genetic variants with largely cell-type-specific effects. Variants in TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR binding sites were the most prevalent determinants of chromatin accessibility. Finally, integration of genetic variants associated with chromatin accessibility, organismal trait variation, and population differentiation revealed how local adaptation has rewired regulatory networks in unique cellular context to alter maize flowering phenotypes.
{"title":"The genetic architecture of cell-type-specific cis-regulation","authors":"Alexandre P. Marand, Luguang Jiang, Fabio A Gomez-Cano, Mark A.A. Minow, Xuan Zhang, John Pablo Mendieta, Ziliang Luo, Sohyun Bang, Haidong Yan, Cullan Meyer, Luca Schlegel, Frank Johannes, Robert J. Schmitz","doi":"10.1101/2024.08.17.608383","DOIUrl":"https://doi.org/10.1101/2024.08.17.608383","url":null,"abstract":"Gene expression and complex phenotypes are determined by the activity of <em>cis</em>-regulatory elements. However, an understanding of how extant genetic variants affect <em>cis</em>-regulatory activity remains limited. Here, we investigated the consequences of cis-regulatory diversity using single-cell genomics of >0.7 million nuclei across 172 maize inbreds. Our analyses pinpointed <em>cis</em>-regulatory elements distinct to domesticated maize and how transposons rewired the regulatory landscape. We found widespread chromatin accessibility variation associated with >4.6 million genetic variants with largely cell-type-specific effects. Variants in TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR binding sites were the most prevalent determinants of chromatin accessibility. Finally, integration of genetic variants associated with chromatin accessibility, organismal trait variation, and population differentiation revealed how local adaptation has rewired regulatory networks in unique cellular context to alter maize flowering phenotypes.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"83 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179786","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}
Pub Date : 2024-08-26DOI: 10.1101/2024.08.23.609452
Feng Zhou, William J Astle, Adam S Butterworth, Jennifer Lea Asimit
Genome-wide association studies (GWAS) of high-dimensional traits, such as molecular phenotypes or imaging features, often use univariate approaches, ignoring information from related traits. Biological mechanisms generating variation in high-dimensional traits can be captured parsimoniously through GWAS of a smaller number of latent factors from factor analysis. Here, we introduce a zero-correlation multi-trait fine-mapping approach, flashfmZero, for any number of latent factors. In our application to 25 latent factors derived from 99 blood cell traits in the INTERVAL cohort, we show how GWAS of latent factors enables detection of signals that have sub-threshold associations with several blood cell traits. FlashfmZero resulted in 99% credible sets with the same size or fewer variants than those for blood cell traits in 87% of our comparisons, and all latent trait fine-mapping credible sets were subsets of those from flashfmZero. These analysis techniques give enhanced power for discovery and fine-mapping for many traits.
{"title":"Improved genetic discovery and fine-mapping resolution through multivariate latent factor analysis of high-dimensional traits","authors":"Feng Zhou, William J Astle, Adam S Butterworth, Jennifer Lea Asimit","doi":"10.1101/2024.08.23.609452","DOIUrl":"https://doi.org/10.1101/2024.08.23.609452","url":null,"abstract":"Genome-wide association studies (GWAS) of high-dimensional traits, such as molecular phenotypes or imaging features, often use univariate approaches, ignoring information from related traits. Biological mechanisms generating variation in high-dimensional traits can be captured parsimoniously through GWAS of a smaller number of latent factors from factor analysis. Here, we introduce a zero-correlation multi-trait fine-mapping approach, flashfmZero, for any number of latent factors. In our application to 25 latent factors derived from 99 blood cell traits in the INTERVAL cohort, we show how GWAS of latent factors enables detection of signals that have sub-threshold associations with several blood cell traits. FlashfmZero resulted in 99% credible sets with the same size or fewer variants than those for blood cell traits in 87% of our comparisons, and all latent trait fine-mapping credible sets were subsets of those from flashfmZero. These analysis techniques give enhanced power for discovery and fine-mapping for many traits.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"54 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179784","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}
Pub Date : 2024-08-26DOI: 10.1101/2024.08.26.608843
Gillian L Meeks, Brooke Scelza, Hana M Asnake, Sean Prall, Etienne Patin, Alain Froment, Maud Fagny, Lluis Quintana-Murci, Brenna M Henn, Shyamalika Gopalan
Aging is associated with genome-wide changes in DNA methylation in humans, facilitating the development of epigenetic age prediction models. However, most of these models have been trained primarily on European-ancestry individuals, and none account for the impact of methylation quantitative trait loci (meQTL). To address these gaps, we analyzed the relationships between age, genotype, and CpG methylation in 3 understudied populations: central African Baka (n = 35), southern African ≠Khomani San (n = 52), and southern African Himba (n = 51). We find that published prediction methods yield higher mean errors in these cohorts compared to European-ancestry individuals, and find that unaccounted-for DNA sequence variation may be a significant factor underlying this loss of accuracy. We leverage information about the associations between DNA genotype and CpG methylation to develop an age predictor that is minimally influenced by meQTL, and show that this model remains accurate across a broad range of genetic backgrounds. Intriguingly, we also find that the older individuals and those exhibiting relatively lower epigenetic age acceleration in our cohorts tend to carry more epigenetic age-reducing genetic variants, suggesting a novel mechanism by which heritable factors can influence longevity.
衰老与人类 DNA 甲基化的全基因组变化有关，这促进了表观遗传年龄预测模型的开发。然而，这些模型大多主要是针对欧洲血统的个体进行训练的，而且都没有考虑甲基化定量性状位点（meQTL）的影响。为了填补这些空白，我们分析了 3 个未被充分研究的人群中年龄、基因型和 CpG 甲基化之间的关系：非洲中部的巴卡人（n = 35）、非洲南部的≠Khomani San 人（n = 52）和非洲南部的 Himba 人（n = 51）。我们发现，与欧洲血统的个体相比，已发表的预测方法在这些群体中产生的平均误差更大，并发现未计算在内的 DNA 序列变异可能是导致准确性下降的重要因素。我们利用 DNA 基因型与 CpG 甲基化之间的关联信息，开发出了一种受 meQTL 影响最小的年龄预测方法，并证明该模型在广泛的遗传背景下仍然准确。有趣的是，我们还发现，在我们的队列中，年龄较大的个体和表观遗传年龄加速度相对较低的个体往往携带更多的表观遗传年龄降低基因变异，这表明遗传因素可以通过一种新的机制影响寿命。
{"title":"Common DNA sequence variation influences epigenetic aging in African populations","authors":"Gillian L Meeks, Brooke Scelza, Hana M Asnake, Sean Prall, Etienne Patin, Alain Froment, Maud Fagny, Lluis Quintana-Murci, Brenna M Henn, Shyamalika Gopalan","doi":"10.1101/2024.08.26.608843","DOIUrl":"https://doi.org/10.1101/2024.08.26.608843","url":null,"abstract":"Aging is associated with genome-wide changes in DNA methylation in humans, facilitating the development of epigenetic age prediction models. However, most of these models have been trained primarily on European-ancestry individuals, and none account for the impact of methylation quantitative trait loci (meQTL). To address these gaps, we analyzed the relationships between age, genotype, and CpG methylation in 3 understudied populations: central African Baka (n = 35), southern African ≠Khomani San (n = 52), and southern African Himba (n = 51). We find that published prediction methods yield higher mean errors in these cohorts compared to European-ancestry individuals, and find that unaccounted-for DNA sequence variation may be a significant factor underlying this loss of accuracy. We leverage information about the associations between DNA genotype and CpG methylation to develop an age predictor that is minimally influenced by meQTL, and show that this model remains accurate across a broad range of genetic backgrounds. Intriguingly, we also find that the older individuals and those exhibiting relatively lower epigenetic age acceleration in our cohorts tend to carry more epigenetic age-reducing genetic variants, suggesting a novel mechanism by which heritable factors can influence longevity.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179785","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}
Pub Date : 2024-08-11DOI: 10.1101/2024.08.11.607498
Samuel Cooper, Juan Javier Diaz-Mejia, Brendan Innes, Elias Williams, Dylan Mendonca, Octavian Focsa, Allison Nixon, Swechha Singh, Ronen Schuster, Boris Hinz, Matthew Buechler
Today's single-cell RNA (scRNA) datasets remain siloed, due to significant challenges associated with their integration at scale. Moreover, most scRNA analysis tools that operate at scale leverage supervised techniques that are insufficient for cell-type identification and discovery. Here we demonstrate that alignment of scRNA data using unsupervised models is accurate at both an organism wide scale and between species. To do this we show how adversarial training of a deep-learning model we term batch-adversarial single-cell variational inference (BA-scVI) can be employed to align standardized benchmark datasets that comprise dozens of scRNA studies and span tissues in both humans and mice. Analysis of the learnt cell-type space then enables us to identify evolutionarily conserved cell-types, including underappreciated complement expressing macrophage and fibroblast types, paving the way to larger phylogenetic analysis of cell-type evolution. Finally, we provide broad access to scREF, scREF-mu and the BA-scVI model via an online interface for atlas exploration and drag-and-drop alignment of new data.
{"title":"Adversarial learning enables unbiased organism-wide cross-species alignment of single-cell RNA data","authors":"Samuel Cooper, Juan Javier Diaz-Mejia, Brendan Innes, Elias Williams, Dylan Mendonca, Octavian Focsa, Allison Nixon, Swechha Singh, Ronen Schuster, Boris Hinz, Matthew Buechler","doi":"10.1101/2024.08.11.607498","DOIUrl":"https://doi.org/10.1101/2024.08.11.607498","url":null,"abstract":"Today's single-cell RNA (scRNA) datasets remain siloed, due to significant challenges associated with their integration at scale. Moreover, most scRNA analysis tools that operate at scale leverage supervised techniques that are insufficient for cell-type identification and discovery. Here we demonstrate that alignment of scRNA data using unsupervised models is accurate at both an organism wide scale and between species. To do this we show how adversarial training of a deep-learning model we term batch-adversarial single-cell variational inference (BA-scVI) can be employed to align standardized benchmark datasets that comprise dozens of scRNA studies and span tissues in both humans and mice. Analysis of the learnt cell-type space then enables us to identify evolutionarily conserved cell-types, including underappreciated complement expressing macrophage and fibroblast types, paving the way to larger phylogenetic analysis of cell-type evolution. Finally, we provide broad access to scREF, scREF-mu and the BA-scVI model via an online interface for atlas exploration and drag-and-drop alignment of new data.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"77 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141934452","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}
Pub Date : 2024-08-10DOI: 10.1101/2024.08.10.607237
Umran Yaman, Gareth Banks, Emil K Gustavsson, Paige Mumford, Naciye Magusali, Orjona Stella Taso, Hannah Macpherson, Susana Carmona, Malgorzata Murray, Rasneer Sonia Bains, Hamish Forrest, Michelle Stewart, Connor Scott, Tatiana V Lipina, Zhao Cheng, Anna L Tierney, Richard D Unwin, Juan A Botia, Carlo Sala Frigerio, Sara E Wells, John Hardy, Lilach Soreq, Frances K Wiseman, Dervis A Salih
Genome-wide association studies (GWAS) have identified a transcriptional network of Alzheimer's disease (AD) risk genes that are primarily expressed in microglia and are associated with AD pathology. However, traditional short-read sequencers have limited our ability to fully characterize how GWAS variants exert their effects on gene expression regulation or alternative splicing in response to the pathology, particularly resulting in inaccurate detection of splicing. To address this gap, we utilized long-read RNA-sequencing (RNA-seq) in the App(NL-G-F) knock-in mouse model to identify changes in splicing and novel transcript isoforms in response to amyloid-β. We show that long-read RNA-seq can recapitulate the expected induction of microglial expressed risk genes such as Trem2 in response to amyloid-β at 9 months of age associated with ageing-dependent deficiencies in spatial short-term memory in the App(NL-G-F) knock-in mice. Our results not only identified novel splicing events and transcript isoform abundance in genes associated with AD, but also revealed the complex regulation of gene expression through splicing in response to amyloid plaques. Surprisingly, the regulation of alternative splicing in response to amyloid was seen in genes previously not identified as AD risk genes, expressed in microglia, neurons and oligodendrocytes, and included genes such as Syngr1 that modulate synaptic physiology. We saw alternative splicing in genes such as Ctsa, Clta, Dennd2a, Irf9 and Smad4 in mice in response to amyloid, and the orthologues of these genes also showed transcript usage changes in human AD brains. Our data suggests a model whereby induction of AD risk gene expression associated with microglial proliferation and activation is concomitant with alternative splicing in a different class of genes expressed by microglia and neurons, which act to adapt or preserve synaptic activity in response to amyloid-β during early stages of the disease. Our study provides new insights into the mechanisms and effects of the regulation of genes associated with amyloid pathology, which may ultimately enable better disease diagnosis, and improved tracking of disease progression. Additionally, our findings identify new therapeutic avenues for treatment of AD.
{"title":"Long-read transcriptomic identification of synaptic adaptation to amyloid pathology in the App(NL-G-F) knock-in mouse model of the earliest phase of Alzheimer's disease","authors":"Umran Yaman, Gareth Banks, Emil K Gustavsson, Paige Mumford, Naciye Magusali, Orjona Stella Taso, Hannah Macpherson, Susana Carmona, Malgorzata Murray, Rasneer Sonia Bains, Hamish Forrest, Michelle Stewart, Connor Scott, Tatiana V Lipina, Zhao Cheng, Anna L Tierney, Richard D Unwin, Juan A Botia, Carlo Sala Frigerio, Sara E Wells, John Hardy, Lilach Soreq, Frances K Wiseman, Dervis A Salih","doi":"10.1101/2024.08.10.607237","DOIUrl":"https://doi.org/10.1101/2024.08.10.607237","url":null,"abstract":"Genome-wide association studies (GWAS) have identified a transcriptional network of Alzheimer's disease (AD) risk genes that are primarily expressed in microglia and are associated with AD pathology. However, traditional short-read sequencers have limited our ability to fully characterize how GWAS variants exert their effects on gene expression regulation or alternative splicing in response to the pathology, particularly resulting in inaccurate detection of splicing. To address this gap, we utilized long-read RNA-sequencing (RNA-seq) in the App(NL-G-F) knock-in mouse model to identify changes in splicing and novel transcript isoforms in response to amyloid-β. We show that long-read RNA-seq can recapitulate the expected induction of microglial expressed risk genes such as Trem2 in response to amyloid-β at 9 months of age associated with ageing-dependent deficiencies in spatial short-term memory in the App(NL-G-F) knock-in mice. Our results not only identified novel splicing events and transcript isoform abundance in genes associated with AD, but also revealed the complex regulation of gene expression through splicing in response to amyloid plaques. Surprisingly, the regulation of alternative splicing in response to amyloid was seen in genes previously not identified as AD risk genes, expressed in microglia, neurons and oligodendrocytes, and included genes such as Syngr1 that modulate synaptic physiology. We saw alternative splicing in genes such as Ctsa, Clta, Dennd2a, Irf9 and Smad4 in mice in response to amyloid, and the orthologues of these genes also showed transcript usage changes in human AD brains. Our data suggests a model whereby induction of AD risk gene expression associated with microglial proliferation and activation is concomitant with alternative splicing in a different class of genes expressed by microglia and neurons, which act to adapt or preserve synaptic activity in response to amyloid-β during early stages of the disease. Our study provides new insights into the mechanisms and effects of the regulation of genes associated with amyloid pathology, which may ultimately enable better disease diagnosis, and improved tracking of disease progression. Additionally, our findings identify new therapeutic avenues for treatment of AD.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141934453","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}
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