Pub Date : 2024-09-02DOI: 10.1101/2024.08.30.610585
Elizabeth Thompson
Motivated originally by the increasing number of examples where a lone member of a once thriving population or even species now survives, we investigate what genomes of that population the survivor may represent. More generally it is of interest to consider what genomes of our ancestry each of us may represent. We consider only diploid dioecious organisms, and consider primarily the ancestry of a haploid genome, for example the maternal autosomes of the focal individual. Our ancestors are many and, in an unbounded population, increase exponentially in number. Our genetic ancestors are few, bounded by the number of ancestral genome segments which increases linearly over past generations. First we show that the major loss of potential ancestral lineages is at 8-11 generations, and that thereafter the number of genetic ancestors increases approximately linearly, but does not approach the upper bound. Over many generations, there remain tightly linked but not contiguous segments that result from the same ancestral lineage. Second we analyze the process of these "repeated" ancestral segments that continue to be formed in distant ancestry, even as others are lost by recombination. Thirdly, we consider the effect of a finite population, with one model of a geographically structured population. Ancestors are many, and soon fill the entire species range even with low migration rates. Genetic ancestors are not only few, but remain geographically local.
{"title":"The ancestry of a genome","authors":"Elizabeth Thompson","doi":"10.1101/2024.08.30.610585","DOIUrl":"https://doi.org/10.1101/2024.08.30.610585","url":null,"abstract":"Motivated originally by the increasing number of examples where a lone member of a once thriving population or even species now survives, we investigate what genomes of that population the survivor may represent. More generally it is of interest to consider what genomes of our ancestry each of us may represent. We consider only diploid dioecious organisms, and consider primarily the ancestry of a haploid genome, for example the maternal autosomes of the focal individual. Our ancestors are many and, in an unbounded population, increase exponentially in number. Our genetic ancestors are few, bounded by the number of ancestral genome segments which increases linearly over past generations. First we show that the major loss of potential ancestral lineages is at 8-11 generations, and that thereafter the number of genetic ancestors increases approximately linearly, but does not approach the upper bound. Over many generations, there remain tightly linked but not contiguous segments that result from the same ancestral lineage. Second we analyze the process of these \"repeated\" ancestral segments that continue to be formed in distant ancestry, even as others are lost by recombination. Thirdly, we consider the effect of a finite population, with one model of a geographically structured population. Ancestors are many, and soon fill the entire species range even with low migration rates. Genetic ancestors are not only few, but remain geographically local.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179757","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 : 2024-08-31DOI: 10.1101/2024.08.16.608307
Franco Marsico
The search for missing persons is a complex process that involves the comparison of data from two entities: unidentified persons (UP), who may be alive or deceased, and missing persons (MP), whose whereabouts are unknown. Although existing tools support DNA-based kinship analyses for the search, they typically do not integrate or statistically evaluate diverse lines of evidence collected throughout the investigative process. Examples of alternative lines of evidence are pigmentation traits, biological sex, and age, among others. The package Mispitools fills this gap by providing comprehensive statistical methods adapted to a holistic investigation workflow. Mispitools systematically assesses the data from each investigative stage, computing the statistical weight of various types of evidence through a likelihood ratio (LR) approach. It also provides models for combining obtained LRs. Furthermore, Mispitools offers customized visualizations and a user-friendly interface, broadening its applicability among forensic practitioners and genealogical researchers.
搜寻失踪人员是一个复杂的过程，需要对两个实体的数据进行比较：身份不明人员（UP）和失踪人员（MP），前者可能还活着，也可能已经死亡，后者下落不明。虽然现有工具支持基于 DNA 的亲属关系分析，但它们通常无法整合或统计评估整个调查过程中收集的各种证据。其他证据包括色素特征、生物性别和年龄等。Mispitools 软件包提供了适合整体调查工作流程的综合统计方法，填补了这一空白。Mispitools 系统地评估每个调查阶段的数据，通过似然比 (LR) 方法计算各类证据的统计权重。它还提供了组合所获 LR 的模型。此外，Mispitools 还提供定制的可视化和用户友好界面，扩大了其在法医从业人员和家谱研究人员中的适用性。
{"title":"Mispitools: An R Package for Comprehensive Statistical Methods in Kinship Inference","authors":"Franco Marsico","doi":"10.1101/2024.08.16.608307","DOIUrl":"https://doi.org/10.1101/2024.08.16.608307","url":null,"abstract":"The search for missing persons is a complex process that involves the comparison of data from two entities: unidentified persons (UP), who may be alive or deceased, and missing persons (MP), whose whereabouts are unknown. Although existing tools support DNA-based kinship analyses for the search, they typically do not integrate or statistically evaluate diverse lines of evidence collected throughout the investigative process. Examples of alternative lines of evidence are pigmentation traits, biological sex, and age, among others. The package Mispitools fills this gap by providing comprehensive statistical methods adapted to a holistic investigation workflow. Mispitools systematically assesses the data from each investigative stage, computing the statistical weight of various types of evidence through a likelihood ratio (LR) approach. It also provides models for combining obtained LRs. Furthermore, Mispitools offers customized visualizations and a user-friendly interface, broadening its applicability among forensic practitioners and genealogical researchers.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179761","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 : 2024-08-31DOI: 10.1101/2024.08.31.610262
Jiazheng Zhu, Georgios Kalantzis, Ali Pazokitoroudi, Árni Freyr Gunnarsson, Hrushikesh Loya, Han Chen, Sriram Sankararaman, Pier Francesco Palamara
Recent algorithmic advancements have enabled the inference of genome-wide ancestral recombination graphs (ARGs) from genomic data in large cohorts. These inferred ARGs provide a detailed representation of genealogical relatedness along the genome and have been shown to complement genotype imputation in complex trait analyses by capturing the effects of unobserved genomic variants. An inferred ARG can be used to construct a genetic relatedness matrix, which can be leveraged within a linear mixed model for the analysis of complex traits. However, these analyses are computationally infeasible for large datasets. We introduce a computationally efficient approach, called ARG-RHE, to estimate narrow-sense heritability and perform region-based association testing using an ARG. ARG-RHE relies on scalable randomized algorithms to estimate variance components and assess their statistical significance, and can be applied to multiple quantitative traits in parallel. We conduct extensive simulations to verify the computational efficiency, statistical power, and robustness of this approach. We then apply it to detect associations between 21,374 genes and 52 blood-related traits, using an ARG inferred from genotype data of 337,464 individuals from the UK Biobank. In these analyses, combining ARG-based and imputation-based testing yields 8% more gene-trait associations than using imputation alone, suggesting that inferred genome-wide genealogies may effectively complement genotype imputation in the analysis of complex traits.
{"title":"Fast variance component analysis using large-scale ancestral recombination graphs","authors":"Jiazheng Zhu, Georgios Kalantzis, Ali Pazokitoroudi, Árni Freyr Gunnarsson, Hrushikesh Loya, Han Chen, Sriram Sankararaman, Pier Francesco Palamara","doi":"10.1101/2024.08.31.610262","DOIUrl":"https://doi.org/10.1101/2024.08.31.610262","url":null,"abstract":"Recent algorithmic advancements have enabled the inference of genome-wide ancestral recombination graphs (ARGs) from genomic data in large cohorts. These inferred ARGs provide a detailed representation of genealogical relatedness along the genome and have been shown to complement genotype imputation in complex trait analyses by capturing the effects of unobserved genomic variants. An inferred ARG can be used to construct a genetic relatedness matrix, which can be leveraged within a linear mixed model for the analysis of complex traits. However, these analyses are computationally infeasible for large datasets. We introduce a computationally efficient approach, called ARG-RHE, to estimate narrow-sense heritability and perform region-based association testing using an ARG. ARG-RHE relies on scalable randomized algorithms to estimate variance components and assess their statistical significance, and can be applied to multiple quantitative traits in parallel. We conduct extensive simulations to verify the computational efficiency, statistical power, and robustness of this approach. We then apply it to detect associations between 21,374 genes and 52 blood-related traits, using an ARG inferred from genotype data of 337,464 individuals from the UK Biobank. In these analyses, combining ARG-based and imputation-based testing yields 8% more gene-trait associations than using imputation alone, suggesting that inferred genome-wide genealogies may effectively complement genotype imputation in the analysis of complex traits.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"83 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179764","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 : 2024-08-30DOI: 10.1101/2024.08.29.610369
Ruth V Nichols, Lauren Rylaarsdam, Brendan L O'Connell, Zohar Shipony, Nika Iremadze, Sonia N Acharya, Andrew Adey
Single-cell methods to assess DNA methylation have not yet achieved the same level of cell throughput compared to other modalities. Here, we describe sciMETv3, a combinatorial indexing-based technique that builds on our prior technology, sciMETv2. SciMETv3 achieves nearly a 100-fold improvement in cell throughput by increasing the index space while simultaneously reducing hands-on time and total costs per experiment. To reduce the sequencing burden of the assay, we demonstrate compatibility of sciMETv3 with capture techniques that enrich for regulatory regions, as well as the ability to leverage enzymatic conversion which can yield higher library diversity. We showcase the throughput of sciMETv3 by producing a >140k cell library from human middle frontal gyrus split across four multiplexed individuals using both Illumina and Ultima sequencing instrumentation. This library was prepared over two days by one individual and required no expensive equipment (e.g. a flow sorter, as required by sciMETv2). The same experiment produced an estimated 650k additional cells that were not sequenced, representing the power of sciMETv3 to meet the throughput needs of the most demanding atlas-scale projects. Finally, we demonstrate the compatibility of sciMETv3 with multimodal assays by introducing sciMET+ATAC, which will enable high-throughput exploration of the interplay between two layers of epigenetic regulation within the same cell, as well as the ability to directly integrate single-cell methylation datasets with existing single-cell ATAC-seq.
{"title":"Atlas-scale Single-cell DNA Methylation Profiling with sciMETv3","authors":"Ruth V Nichols, Lauren Rylaarsdam, Brendan L O'Connell, Zohar Shipony, Nika Iremadze, Sonia N Acharya, Andrew Adey","doi":"10.1101/2024.08.29.610369","DOIUrl":"https://doi.org/10.1101/2024.08.29.610369","url":null,"abstract":"Single-cell methods to assess DNA methylation have not yet achieved the same level of cell throughput compared to other modalities. Here, we describe sciMETv3, a combinatorial indexing-based technique that builds on our prior technology, sciMETv2. SciMETv3 achieves nearly a 100-fold improvement in cell throughput by increasing the index space while simultaneously reducing hands-on time and total costs per experiment. To reduce the sequencing burden of the assay, we demonstrate compatibility of sciMETv3 with capture techniques that enrich for regulatory regions, as well as the ability to leverage enzymatic conversion which can yield higher library diversity. We showcase the throughput of sciMETv3 by producing a >140k cell library from human middle frontal gyrus split across four multiplexed individuals using both Illumina and Ultima sequencing instrumentation. This library was prepared over two days by one individual and required no expensive equipment (e.g. a flow sorter, as required by sciMETv2). The same experiment produced an estimated 650k additional cells that were not sequenced, representing the power of sciMETv3 to meet the throughput needs of the most demanding atlas-scale projects. Finally, we demonstrate the compatibility of sciMETv3 with multimodal assays by introducing sciMET+ATAC, which will enable high-throughput exploration of the interplay between two layers of epigenetic regulation within the same cell, as well as the ability to directly integrate single-cell methylation datasets with existing single-cell ATAC-seq.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179763","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 : 2024-08-30DOI: 10.1101/2024.08.29.610354
Faidra Karkala, Roy B. Simons, Floor Claessens, Vivian Kalamara, Manfred Kayser, Athina Vidaki
Human DNA methylation profiling offers great promises in various biomedical applications, including ageing, cancer and even forensics. So far, most DNA methylation techniques are based on a chemical process called sodium bisulfite conversion, which specifically converts non-methylated cytosines into uracils. However, despite the popularity of this approach, it is known to cause DNA fragmentation and loss affecting standardization, while incomplete conversion may result in potential misinterpretation of methylation-based outcomes. To offer the community a solution, we developed qBiCo - a novel quality-control method to address the quantity and quality of bisulfite-converted DNA. qBiCo is a 5-plex, TaqMan® probe-based, quantitative (q)PCR assay that amplifies single- and multi-copy DNA fragments of converted and non-converted nature. It estimates four parameters: converted DNA concentration, fragmentation, global conversion efficiency, and potential PCR inhibition. We optimized qBiCo using synthetic DNA standards and assessed it using standard developmental validation criteria, showcasing that qBiCo is reliable, robust and sensitive down to picogram level. We also evaluated its performance by testing decreasing DNA amounts using several commercial bisulfite conversion kits. Depending on the starting DNA quantity, bisulfite-converted DNA recoveries ranged from 8.5 – 100 %, conversion efficiencies from 78 – 99.9 %, while certain kits highly fragment DNA, demonstrating large variability in their performance. Towards building a prototype tool, we further optimized key functionalities, for example, by replacing the poorest performing single-plex assay and creating a more representative DNA standard. Aiming to scale-up and move towards implementation, we successfully transferred and validated our novel method in six different qPCR platforms from different major manufacturers. Overall, with the present study, we offer researchers in the epigenetic field a novel long-awaited QC tool that for the first time allows them to measure key quality and quantity parameters of the most popular DNA conversion process. The tool also enables standardization to prevent inconsistent data and false outcomes in the future, regardless of the downstream experimental analysis of DNA methylation-based research and applications across different fields of biology and biomedicine.
人类 DNA 甲基化分析为各种生物医学应用，包括老龄化、癌症甚至法医学，提供了巨大的前景。迄今为止，大多数 DNA 甲基化技术都是基于一种称为亚硫酸氢钠转化的化学过程，该过程专门将非甲基化胞嘧啶转化为尿嘧啶。然而，尽管这种方法很受欢迎，但众所周知，它会导致 DNA 断裂，影响标准化，而不完全的转化可能会导致对基于甲基化的结果产生潜在的误读。qBiCo 是一种基于 TaqMan® 探针的 5 复式定量（q）PCR 检测方法，可扩增已转化和未转化的单拷贝和多拷贝 DNA 片段。它能估算四个参数：转化 DNA 浓度、片段、整体转化效率和潜在的 PCR 抑制。我们使用合成 DNA 标准对 qBiCo 进行了优化，并使用标准开发验证标准对其进行了评估，结果表明 qBiCo 可靠、稳健且灵敏度低至皮克级。我们还使用几种商业亚硫酸氢盐转换试剂盒测试了 DNA 数量的减少，从而评估了它的性能。根据起始 DNA 数量的不同，亚硫酸氢盐转化 DNA 的回收率从 8.5 % 到 100 % 不等，转化效率从 78 % 到 99.9 % 不等，而某些试剂盒会对 DNA 进行高度片段化，这表明它们的性能存在很大差异。为了建立工具原型，我们进一步优化了关键功能，例如，替换了性能最差的单复式检测方法，并创建了更具代表性的 DNA 标准。为了扩大规模并付诸实施，我们成功地在来自不同主要制造商的六种不同 qPCR 平台上转移并验证了我们的新方法。总之，通过本研究，我们为表观遗传学领域的研究人员提供了一种期待已久的新型质量控制工具，首次允许他们测量最流行的 DNA 转换过程的关键质量和数量参数。该工具还实现了标准化，以防止将来出现数据不一致和错误结果，无论基于 DNA 甲基化的下游实验分析研究和应用涉及不同的生物学和生物医学领域。
{"title":"qBiCo: A method to assess global DNA conversion performance in epigenetics via single-copy genes and repetitive elements","authors":"Faidra Karkala, Roy B. Simons, Floor Claessens, Vivian Kalamara, Manfred Kayser, Athina Vidaki","doi":"10.1101/2024.08.29.610354","DOIUrl":"https://doi.org/10.1101/2024.08.29.610354","url":null,"abstract":"Human DNA methylation profiling offers great promises in various biomedical applications, including ageing, cancer and even forensics. So far, most DNA methylation techniques are based on a chemical process called sodium bisulfite conversion, which specifically converts non-methylated cytosines into uracils. However, despite the popularity of this approach, it is known to cause DNA fragmentation and loss affecting standardization, while incomplete conversion may result in potential misinterpretation of methylation-based outcomes. To offer the community a solution, we developed qBiCo - a novel quality-control method to address the quantity and quality of bisulfite-converted DNA. qBiCo is a 5-plex, TaqMan® probe-based, quantitative (q)PCR assay that amplifies single- and multi-copy DNA fragments of converted and non-converted nature. It estimates four parameters: converted DNA concentration, fragmentation, global conversion efficiency, and potential PCR inhibition. We optimized qBiCo using synthetic DNA standards and assessed it using standard developmental validation criteria, showcasing that qBiCo is reliable, robust and sensitive down to picogram level. We also evaluated its performance by testing decreasing DNA amounts using several commercial bisulfite conversion kits. Depending on the starting DNA quantity, bisulfite-converted DNA recoveries ranged from 8.5 – 100 %, conversion efficiencies from 78 – 99.9 %, while certain kits highly fragment DNA, demonstrating large variability in their performance. Towards building a prototype tool, we further optimized key functionalities, for example, by replacing the poorest performing single-plex assay and creating a more representative DNA standard. Aiming to scale-up and move towards implementation, we successfully transferred and validated our novel method in six different qPCR platforms from different major manufacturers. Overall, with the present study, we offer researchers in the epigenetic field a novel long-awaited QC tool that for the first time allows them to measure key quality and quantity parameters of the most popular DNA conversion process. The tool also enables standardization to prevent inconsistent data and false outcomes in the future, regardless of the downstream experimental analysis of DNA methylation-based research and applications across different fields of biology and biomedicine.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179759","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}
Meiosis is required for the formation of gametes in all sexually reproducing species and the process is well conserved across the tree of life. However, meiosis is sensitive to a variety of external factors, which can impact chromosome pairing, recombination, and fertility. For example, the optimal temperature for successful meiosis varies between species of plants and animals. This suggests that meiosis is temperature sensitive, and that natural selection may act on variation in meiotic success as organisms adapt to different environmental conditions. To understand how temperature alters the successful completion of meiosis, we utilized two species of the budding yeast Saccharomyces with different temperature preferences: thermotolerant Saccharomyces cerevisiae and cold tolerant Saccharomyces uvarum. We surveyed three metrics of meiosis: sporulation efficiency, spore viability, and recombination rate in multiple strains of each species. As per our predictions, the proportion of cells that complete meiosis and form spores is temperature sensitive, with thermotolerant S. cerevisiae having a higher temperature threshold for successful meiosis than cold tolerant S. uvarum. We confirmed previous observations that S. cerevisiae recombination rate varies between strains and across genomic regions, and add new results that S. uvarum has higher recombination rates than S. cerevisiae. We find that temperature significantly influences recombination rate plasticity in S. cerevisiae and S. uvarum, in agreement with studies in animals and plants. Overall, these results suggest that meiotic thermal sensitivity is associated with organismal thermal tolerance, and may even result in temporal reproductive isolation as populations diverge in thermal profiles.
减数分裂是所有有性生殖物种形成配子的必要条件，这一过程在整个生命之树上都得到了很好的保留。然而，减数分裂对各种外部因素很敏感，这些因素会影响染色体配对、重组和繁殖力。例如，减数分裂成功的最佳温度因动植物物种而异。这表明减数分裂对温度很敏感，自然选择可能在生物适应不同环境条件时对减数分裂成功率的变化产生作用。为了了解温度如何改变减数分裂的成功完成，我们利用了两种对温度有不同偏好的芽殖酵母：耐热的酿酒酵母和耐寒的酿酒酵母。我们调查了减数分裂的三个指标：孢子效率、孢子活力和每个物种多个菌株的重组率。根据我们的预测，完成减数分裂并形成孢子的细胞比例对温度很敏感，耐热的麦角菌减数分裂成功的温度阈值比耐寒的乌瓦鲁菌要高。我们证实了之前的观察结果，即麦角菌的重组率在不同菌株和不同基因组区域之间存在差异，并补充了新的结果，即uvarum的重组率高于麦角菌。我们发现，温度对 S. cerevisiae 和 S. uvarum 的重组率可塑性影响很大，这与动物和植物的研究结果一致。总之，这些结果表明，减数分裂热敏感性与生物体的热耐受性有关，甚至可能随着种群热分布的差异而导致时间上的生殖隔离。
{"title":"Temperature affects recombination rate plasticity and meiotic success between thermotolerant and cold tolerant yeast species","authors":"Jessica McNeill, Nathan Brandt, Enrique J. Schwarzkopf, Mili Jimenez Gallardo, Caiti Smukowski Heil","doi":"10.1101/2024.08.28.610152","DOIUrl":"https://doi.org/10.1101/2024.08.28.610152","url":null,"abstract":"Meiosis is required for the formation of gametes in all sexually reproducing species and the process is well conserved across the tree of life. However, meiosis is sensitive to a variety of external factors, which can impact chromosome pairing, recombination, and fertility. For example, the optimal temperature for successful meiosis varies between species of plants and animals. This suggests that meiosis is temperature sensitive, and that natural selection may act on variation in meiotic success as organisms adapt to different environmental conditions. To understand how temperature alters the successful completion of meiosis, we utilized two species of the budding yeast <em>Saccharomyces</em> with different temperature preferences: thermotolerant <em>Saccharomyces cerevisiae</em> and cold tolerant <em>Saccharomyces uvarum</em>. We surveyed three metrics of meiosis: sporulation efficiency, spore viability, and recombination rate in multiple strains of each species. As per our predictions, the proportion of cells that complete meiosis and form spores is temperature sensitive, with thermotolerant <em>S. cerevisiae</em> having a higher temperature threshold for successful meiosis than cold tolerant <em>S. uvarum</em>. We confirmed previous observations that <em>S. cerevisiae</em> recombination rate varies between strains and across genomic regions, and add new results that <em>S. uvarum</em> has higher recombination rates than <em>S. cerevisiae</em>. We find that temperature significantly influences recombination rate plasticity in <em>S. cerevisiae</em> and <em>S. uvarum</em>, in agreement with studies in animals and plants. Overall, these results suggest that meiotic thermal sensitivity is associated with organismal thermal tolerance, and may even result in temporal reproductive isolation as populations diverge in thermal profiles.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179760","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 : 2024-08-29DOI: 10.1101/2024.08.28.610135
Yanyu Liang, 23andMe Research Team, Adam Auton, Xin Wang
Bayesian fine-mapping to obtain credible sets has been widely applied post GWAS to pinpoint causal variants. The calculation of credible sets generally assumes that all variants have been equally well genotyped, which is often not the case when a GWAS has been run on imputed data. In this work, we investigate the behavior of credible sets in imputed datasets utilizing 'held out' genotyped variants to measure accuracy. We show, via simulation, that: i) the coverage of credible sets decreases when using imputed variants in GWAS; ii) rare causal variants often fail to be tagged in credible sets when they are not present in the GWAS variant set. We develop a reweighting approach to take imputation quality into account during fine-mapping that only requires summary statistics, and demonstrate the approach with real data.
{"title":"Credible set is sensitive to imputation quality and missing variants","authors":"Yanyu Liang, 23andMe Research Team, Adam Auton, Xin Wang","doi":"10.1101/2024.08.28.610135","DOIUrl":"https://doi.org/10.1101/2024.08.28.610135","url":null,"abstract":"Bayesian fine-mapping to obtain credible sets has been widely applied post GWAS to pinpoint causal variants. The calculation of credible sets generally assumes that all variants have been equally well genotyped, which is often not the case when a GWAS has been run on imputed data. In this work, we investigate the behavior of credible sets in imputed datasets utilizing 'held out' genotyped variants to measure accuracy. We show, via simulation, that: i) the coverage of credible sets decreases when using imputed variants in GWAS; ii) rare causal variants often fail to be tagged in credible sets when they are not present in the GWAS variant set. We develop a reweighting approach to take imputation quality into account during fine-mapping that only requires summary statistics, and demonstrate the approach with real data.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179762","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 : 2024-08-28DOI: 10.1101/2024.08.28.610059
Rakesh Kumar, Fan Zhang, Shreyas Niphadkar, Chisom Onu, Anil Kumar Vijjamarri, Miriam L Greenberg, Sunil Laxman, Alan G Hinnebusch
Degradation of many yeast mRNAs involves decapping by the Dcp1:Dcp2 complex. Previous studies on decapping activators Edc3 and Scd6 suggested their limited roles in mRNA decay. RNA-seq analysis of mutants lacking one or both proteins revealed that Scd6 and Edc3 have largely redundant activities in targeting numerous mRNAs for degradation that are masked in the single mutants. These transcripts also are frequently targeted by decapping activators Dhh1 and Pat1, and the collective evidence suggests that Scd6/Edc3 act interchangeably to recruit Dhh1 to Dcp2. Ribosome profiling shows that redundancy between Scd6 and Edc3 and their functional interactions with Dhh1 and Pat1 extend to translational repression of particular transcripts, including a cohort of poorly translated mRNAs displaying interdependent regulation by all four factors. Scd6/Edc3 also participate with Dhh1/Pat1 in post-transcriptional repression of proteins required for respiration and catabolism of alternative carbon sources, which are normally expressed only in limiting glucose. Simultaneously eliminating Scd6/Edc3 increases mitochondrial membrane potential and elevates metabolites of the tricarboxylic acid and glyoxylate cycles typically observed only during growth in low glucose. Thus, Scd6/Edc3 act redundantly, in parallel with Dhh1 and in cooperation with Pat1, to adjust gene expression to nutrient availability by controlling mRNA decapping and decay.
{"title":"Decapping activators Edc3 and Scd6 act redundantly with Dhh1 in post-transcriptional repression of starvation-induced pathways","authors":"Rakesh Kumar, Fan Zhang, Shreyas Niphadkar, Chisom Onu, Anil Kumar Vijjamarri, Miriam L Greenberg, Sunil Laxman, Alan G Hinnebusch","doi":"10.1101/2024.08.28.610059","DOIUrl":"https://doi.org/10.1101/2024.08.28.610059","url":null,"abstract":"Degradation of many yeast mRNAs involves decapping by the Dcp1:Dcp2 complex. Previous studies on decapping activators Edc3 and Scd6 suggested their limited roles in mRNA decay. RNA-seq analysis of mutants lacking one or both proteins revealed that Scd6 and Edc3 have largely redundant activities in targeting numerous mRNAs for degradation that are masked in the single mutants. These transcripts also are frequently targeted by decapping activators Dhh1 and Pat1, and the collective evidence suggests that Scd6/Edc3 act interchangeably to recruit Dhh1 to Dcp2. Ribosome profiling shows that redundancy between Scd6 and Edc3 and their functional interactions with Dhh1 and Pat1 extend to translational repression of particular transcripts, including a cohort of poorly translated mRNAs displaying interdependent regulation by all four factors. Scd6/Edc3 also participate with Dhh1/Pat1 in post-transcriptional repression of proteins required for respiration and catabolism of alternative carbon sources, which are normally expressed only in limiting glucose. Simultaneously eliminating Scd6/Edc3 increases mitochondrial membrane potential and elevates metabolites of the tricarboxylic acid and glyoxylate cycles typically observed only during growth in low glucose. Thus, Scd6/Edc3 act redundantly, in parallel with Dhh1 and in cooperation with Pat1, to adjust gene expression to nutrient availability by controlling mRNA decapping and decay.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"109 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179654","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 : 2024-08-28DOI: 10.1101/2024.08.28.610024
Jaison Jeevan Sequeira, M Chaitra, Ananya Rai N R, M Sudeepthi, R Shalini, Mohammed S Mustak, Jagriti Khanna, Shivkant Sharma, Rajendra V E Chilukuri, George van Driem, Pankaj Shrivastava
Earlier models of grouping Indian populations were based on language families, social stratification and geographical location. Such grouping system has often resulted in oversimplification of ancestry inferences. Moreover, we do not find many studies focused on studying the variation within these groups and the role of past demographic events in shaping them. We analysed the Y-chromosome Short Tandem Repeats haplotypes from 8153 males from India and Eurasia to explore the impact of Holocene migration on the Indian gene pool. We used haplotype variation and date estimates to understand the characteristics of each haplogroup with respect to the different grouping models. Our findings show that the Neolithic agricultural expansion has had a strong influence in shaping the male gene pool of the Indian subcontinent. Haplogroups F, L and R1a contribute greatly towards stratifying Indian populations as hunter-gatherer related, farming-related and priestly groups respectively. Although the caste system enforced endogamy, a traditional occupation based admixture existed since the Neolithic times. Dispersal of haplogroup L from the Near East played a major role in the formation of an agriculturist population that formed an intermediary between the primitive tribes and the R1a-rich priestly group. This study shows that the frequency of R1a in the hunter-gatherer tribes (1.5%) is much lower than previously reported based on other models of population clustering.
早期的印第安人种群划分模式以语系、社会阶层和地理位置为基础。这种分组系统往往导致对祖先的推断过于简单化。此外，我们并没有发现多少研究侧重于研究这些群体内部的变异以及过去的人口事件在塑造这些群体方面所起的作用。我们分析了来自印度和欧亚大陆的 8153 名男性的 Y 染色体短串联重复单倍型，以探讨全新世移民对印度基因库的影响。我们利用单倍型变异和日期估计来了解每个单倍群在不同分组模式下的特征。我们的研究结果表明，新石器时代的农业扩张对印度次大陆男性基因库的形成有很大影响。单倍群 F、L 和 R1a 在很大程度上将印度人分为与狩猎采集相关的群体、与农业相关的群体和祭司群体。尽管种姓制度强制实行内婚制，但自新石器时代以来，基于传统职业的混血现象就一直存在。来自近东的单倍群 L 在农业人口的形成过程中发挥了重要作用，农业人口是原始部落和富含 R1a 的祭司群体之间的中介。这项研究表明，R1a 在狩猎采集部落中的频率（1.5%）远远低于之前根据其他人口聚类模型所报告的频率。
{"title":"Y chromosome STR variation reveals traditional occupation based population structure in India","authors":"Jaison Jeevan Sequeira, M Chaitra, Ananya Rai N R, M Sudeepthi, R Shalini, Mohammed S Mustak, Jagriti Khanna, Shivkant Sharma, Rajendra V E Chilukuri, George van Driem, Pankaj Shrivastava","doi":"10.1101/2024.08.28.610024","DOIUrl":"https://doi.org/10.1101/2024.08.28.610024","url":null,"abstract":"Earlier models of grouping Indian populations were based on language families, social stratification and geographical location. Such grouping system has often resulted in oversimplification of ancestry inferences. Moreover, we do not find many studies focused on studying the variation within these groups and the role of past demographic events in shaping them. We analysed the Y-chromosome Short Tandem Repeats haplotypes from 8153 males from India and Eurasia to explore the impact of Holocene migration on the Indian gene pool. We used haplotype variation and date estimates to understand the characteristics of each haplogroup with respect to the different grouping models. Our findings show that the Neolithic agricultural expansion has had a strong influence in shaping the male gene pool of the Indian subcontinent. Haplogroups F, L and R1a contribute greatly towards stratifying Indian populations as hunter-gatherer related, farming-related and priestly groups respectively. Although the caste system enforced endogamy, a traditional occupation based admixture existed since the Neolithic times. Dispersal of haplogroup L from the Near East played a major role in the formation of an agriculturist population that formed an intermediary between the primitive tribes and the R1a-rich priestly group. This study shows that the frequency of R1a in the hunter-gatherer tribes (1.5%) is much lower than previously reported based on other models of population clustering.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179781","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 : 2024-08-28DOI: 10.1101/2024.08.27.601563
Allison E Mann, Eyðfinn Magnussen, Christopher R Tillquist
The Faroe Islands are a small archipelago located in the North Atlantic likely colonized by a small group of founders sometime between 50 and 300 CE. Post colonization, the Faroese people have been largely isolated from admixture with mainland and other island populations in the region. As such, the initial founder effect and subsequent genetic drift are likely major contributors to the modern genetic diversity found among the Faroese. In this study, we assess the utility of Y-chromosomal microsatellites to detect founder effect in the Faroe Islands through the construction of haplotype networks and a novel empirical method, mutational distance from modal haplotype histograms (MDM), for the visualization and evaluation of population bottlenecks. We compared samples from the Faroe Islands and Iceland to possible regional source populations and documented a loss of diversity associated with founder events. Additionally, within-haplogroup diversity statistics reveals lower haplotype diversity and richness within both the Faroe Islands and Iceland, consistent with a small founder population colonizing both regions. However, in the within-haplogroup networks, the Faroe Islands are found within the larger set of potential source populations while Iceland is consistently found on isolated branches. Moreover, comparisons of within-haplogroup MDM histograms document a clear founder signal in the Faroes and Iceland, but the strength of this signal is haplogroup-dependent which may be indicative of more recent admixture or other demographic processes. The results of the current study and lack of conformity between Icelandic and Faroese haplotypes implies that the two populations were founded by different paternal gene pools and there is no detectable post-founder admixture between the two groups.
法罗群岛是位于北大西洋的一个小群岛，很可能是在公元 50 至 300 年间由一小群创始者殖民的。殖民之后，法罗群岛人基本上与该地区的大陆和其他岛屿居民隔离开来。因此，最初的创始者效应和随后的遗传漂移可能是法罗群岛现代遗传多样性的主要原因。在本研究中，我们通过构建单倍型网络和一种新的经验性方法--模态单倍型直方图（MDM）中的突变距离，评估了 Y 染色体微卫星在检测法罗群岛始祖效应方面的实用性，从而对种群瓶颈进行可视化评估。我们将法罗群岛和冰岛的样本与可能的区域来源人群进行了比较，并记录了与创始者事件相关的多样性损失。此外，单倍群内多样性统计显示，法罗群岛和冰岛的单倍型多样性和丰富度都较低，这与这两个地区都有少量始祖种群的情况一致。然而，在单倍群内网络中，法罗群岛被发现在更大的潜在来源人群中，而冰岛则一直被发现在孤立的分支中。此外，通过比较单倍群内 MDM 直方图，可以发现法罗群岛和冰岛存在明显的创始者信号，但这一信号的强弱取决于单倍群，这可能表明了更近期的混血或其他人口统计过程。目前的研究结果以及冰岛人和法罗群岛人单倍型之间缺乏一致性，意味着这两个人群是由不同的父系基因库创建的，两个群体之间不存在可检测到的创建者之后的混杂。
{"title":"Early founder effects have determined paternal population structure in the Faroe Islands","authors":"Allison E Mann, Eyðfinn Magnussen, Christopher R Tillquist","doi":"10.1101/2024.08.27.601563","DOIUrl":"https://doi.org/10.1101/2024.08.27.601563","url":null,"abstract":"The Faroe Islands are a small archipelago located in the North Atlantic likely colonized by a small group of founders sometime between 50 and 300 CE. Post colonization, the Faroese people have been largely isolated from admixture with mainland and other island populations in the region. As such, the initial founder effect and subsequent genetic drift are likely major contributors to the modern genetic diversity found among the Faroese. In this study, we assess the utility of Y-chromosomal microsatellites to detect founder effect in the Faroe Islands through the construction of haplotype networks and a novel empirical method, mutational distance from modal haplotype histograms (MDM), for the visualization and evaluation of population bottlenecks. We compared samples from the Faroe Islands and Iceland to possible regional source populations and documented a loss of diversity associated with founder events. Additionally, within-haplogroup diversity statistics reveals lower haplotype diversity and richness within both the Faroe Islands and Iceland, consistent with a small founder population colonizing both regions. However, in the within-haplogroup networks, the Faroe Islands are found within the larger set of potential source populations while Iceland is consistently found on isolated branches. Moreover, comparisons of within-haplogroup MDM histograms document a clear founder signal in the Faroes and Iceland, but the strength of this signal is haplogroup-dependent which may be indicative of more recent admixture or other demographic processes. The results of the current study and lack of conformity between Icelandic and Faroese haplotypes implies that the two populations were founded by different paternal gene pools and there is no detectable post-founder admixture between the two groups.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142227617","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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