Pub Date : 2024-03-28DOI: 10.1038/s41576-024-00709-x
Zhi Yu, Tim H. H. Coorens, Md Mesbah Uddin, Kristin G. Ardlie, Niall Lennon, Pradeep Natarajan
Germline variation and somatic mutation are intricately connected and together shape human traits and disease risks. Germline variants are present from conception, but they vary between individuals and accumulate over generations. By contrast, somatic mutations accumulate throughout life in a mosaic manner within an individual due to intrinsic and extrinsic sources of mutations and selection pressures acting on cells. Recent advancements, such as improved detection methods and increased resources for association studies, have drastically expanded our ability to investigate germline and somatic genetic variation and compare underlying mutational processes. A better understanding of the similarities and differences in the types, rates and patterns of germline and somatic variants, as well as their interplay, will help elucidate the mechanisms underlying their distinct yet interlinked roles in human health and biology. In this Review, the authors compare the characteristics and detection methods of germline and somatic variants. Furthermore, they outline how the interplay between the two types of genetic variation can affect human health.
{"title":"Genetic variation across and within individuals","authors":"Zhi Yu, Tim H. H. Coorens, Md Mesbah Uddin, Kristin G. Ardlie, Niall Lennon, Pradeep Natarajan","doi":"10.1038/s41576-024-00709-x","DOIUrl":"10.1038/s41576-024-00709-x","url":null,"abstract":"Germline variation and somatic mutation are intricately connected and together shape human traits and disease risks. Germline variants are present from conception, but they vary between individuals and accumulate over generations. By contrast, somatic mutations accumulate throughout life in a mosaic manner within an individual due to intrinsic and extrinsic sources of mutations and selection pressures acting on cells. Recent advancements, such as improved detection methods and increased resources for association studies, have drastically expanded our ability to investigate germline and somatic genetic variation and compare underlying mutational processes. A better understanding of the similarities and differences in the types, rates and patterns of germline and somatic variants, as well as their interplay, will help elucidate the mechanisms underlying their distinct yet interlinked roles in human health and biology. In this Review, the authors compare the characteristics and detection methods of germline and somatic variants. Furthermore, they outline how the interplay between the two types of genetic variation can affect human health.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 8","pages":"548-562"},"PeriodicalIF":39.1,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140310800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-27DOI: 10.1038/s41576-024-00726-w
Ning Xie
Reflecting on the importance of short tandem repeats (STRs) in population genetics, Ning Xie highlights a 2023 publication that characterized genome-wide STR variation in global human genomes to expand our understanding of STR genetic diversity within and across populations.
{"title":"Building a catalogue of short tandem repeats in diverse populations","authors":"Ning Xie","doi":"10.1038/s41576-024-00726-w","DOIUrl":"10.1038/s41576-024-00726-w","url":null,"abstract":"Reflecting on the importance of short tandem repeats (STRs) in population genetics, Ning Xie highlights a 2023 publication that characterized genome-wide STR variation in global human genomes to expand our understanding of STR genetic diversity within and across populations.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 7","pages":"457-457"},"PeriodicalIF":42.7,"publicationDate":"2024-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140306309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-27DOI: 10.1038/s41576-024-00728-8
Kirsty Minton
A paper in Nature reports a ‘Z-DNA-anchored’ model for the target specificity of the transcription factor AIRE, involving promoter poising at double-strand breaks.
{"title":"AIRE targets poised promoters enriched for Z-DNA","authors":"Kirsty Minton","doi":"10.1038/s41576-024-00728-8","DOIUrl":"10.1038/s41576-024-00728-8","url":null,"abstract":"A paper in Nature reports a ‘Z-DNA-anchored’ model for the target specificity of the transcription factor AIRE, involving promoter poising at double-strand breaks.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 6","pages":"375-375"},"PeriodicalIF":42.7,"publicationDate":"2024-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140306308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-20DOI: 10.1038/s41576-024-00727-9
Linda Koch
A publication in Nature reports the data release of around 245,000 clinical-grade whole-genome sequences as part of the NIH’s All of Us Research Programme. Several companion papers highlight the value of better capturing global genomic diversity.
自然》（Nature）杂志发表的一篇文章报道了作为美国国立卫生研究院（NIH）"我们所有人 "研究计划（All of Us Research Programme）一部分的约 245,000 个临床级全基因组序列的数据发布情况。几篇相关论文强调了更好地捕捉全球基因组多样性的价值。
{"title":"Global genomic diversity for All of Us","authors":"Linda Koch","doi":"10.1038/s41576-024-00727-9","DOIUrl":"10.1038/s41576-024-00727-9","url":null,"abstract":"A publication in Nature reports the data release of around 245,000 clinical-grade whole-genome sequences as part of the NIH’s All of Us Research Programme. Several companion papers highlight the value of better capturing global genomic diversity.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 5","pages":"303-303"},"PeriodicalIF":42.7,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140175765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-19DOI: 10.1038/s41576-024-00724-y
Yoav Ram
In this Journal Club, Yoav Ram recalls how he reconciled results from his own research with the reduction principle through the help of a paper published in PNAS by Altenberg et al.
{"title":"The evolution of modifier genes","authors":"Yoav Ram","doi":"10.1038/s41576-024-00724-y","DOIUrl":"10.1038/s41576-024-00724-y","url":null,"abstract":"In this Journal Club, Yoav Ram recalls how he reconciled results from his own research with the reduction principle through the help of a paper published in PNAS by Altenberg et al.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 6","pages":"380-380"},"PeriodicalIF":42.7,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140161913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-18DOI: 10.1038/s41576-024-00710-4
Dae Kwan Ko, Federica Brandizzi
Endoplasmic reticulum (ER) stress is a potentially lethal condition that is induced by the abnormal accumulation of unfolded or misfolded secretory proteins in the ER. In eukaryotes, ER stress is managed by the unfolded protein response (UPR) through a tightly regulated, yet highly dynamic, reprogramming of gene transcription. Although the core principles of the UPR are similar across eukaryotes, unique features of the plant UPR reflect the adaptability of plants to their ever-changing environments and the need to balance the demands of growth and development with the response to environmental stressors. The past decades have seen notable progress in understanding the mechanisms underlying ER stress sensing and signalling transduction pathways, implicating the UPR in the effects of physiological and induced ER stress on plant growth and crop yield. Facilitated by sequencing technologies and advances in genetic and genomic resources, recent efforts have driven the discovery of transcriptional regulators and elucidated the mechanisms that mediate the dynamic and precise gene regulation in response to ER stress at the systems level. Plants have uniquely adapted to manage endoplasmic reticulum stress triggered by protein misfolding. The authors review the dynamics of gene expression regulation underlying the unfolded protein response in plants, highlighting recent insights provided by systems-level approaches and omics data.
内质网（ER）应激是由ER中未折叠或折叠错误的分泌蛋白的异常积累诱发的一种潜在致死状态。在真核生物中，ER 应激由未折叠蛋白反应（UPR）通过严格调控但高度动态的基因转录重编程来管理。虽然 UPR 的核心原理与真核生物相似，但植物 UPR 的独特性反映了植物对不断变化的环境的适应性，以及平衡生长和发育需求与环境胁迫响应的需要。过去几十年来，人们在了解ER胁迫感应和信号转导途径的基本机制方面取得了显著进展，UPR与生理性和诱导性ER胁迫对植物生长和作物产量的影响有关。在测序技术以及基因和基因组资源进步的推动下，最近的研究工作推动了转录调控因子的发现，并阐明了在系统水平上介导响应 ER 胁迫的动态和精确基因调控的机制。
{"title":"Dynamics of ER stress-induced gene regulation in plants","authors":"Dae Kwan Ko, Federica Brandizzi","doi":"10.1038/s41576-024-00710-4","DOIUrl":"10.1038/s41576-024-00710-4","url":null,"abstract":"Endoplasmic reticulum (ER) stress is a potentially lethal condition that is induced by the abnormal accumulation of unfolded or misfolded secretory proteins in the ER. In eukaryotes, ER stress is managed by the unfolded protein response (UPR) through a tightly regulated, yet highly dynamic, reprogramming of gene transcription. Although the core principles of the UPR are similar across eukaryotes, unique features of the plant UPR reflect the adaptability of plants to their ever-changing environments and the need to balance the demands of growth and development with the response to environmental stressors. The past decades have seen notable progress in understanding the mechanisms underlying ER stress sensing and signalling transduction pathways, implicating the UPR in the effects of physiological and induced ER stress on plant growth and crop yield. Facilitated by sequencing technologies and advances in genetic and genomic resources, recent efforts have driven the discovery of transcriptional regulators and elucidated the mechanisms that mediate the dynamic and precise gene regulation in response to ER stress at the systems level. Plants have uniquely adapted to manage endoplasmic reticulum stress triggered by protein misfolding. The authors review the dynamics of gene expression regulation underlying the unfolded protein response in plants, highlighting recent insights provided by systems-level approaches and omics data.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 7","pages":"513-525"},"PeriodicalIF":42.7,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140158614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-12DOI: 10.1038/s41576-024-00722-0
Kirsty Minton
A study in Science reports that corn snakes use both PRDM9 and promoter-like features to direct meiotic recombination, indicating that these are not mutually exclusive.
{"title":"Competition between sites of meiotic recombination in snakes","authors":"Kirsty Minton","doi":"10.1038/s41576-024-00722-0","DOIUrl":"10.1038/s41576-024-00722-0","url":null,"abstract":"A study in Science reports that corn snakes use both PRDM9 and promoter-like features to direct meiotic recombination, indicating that these are not mutually exclusive.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 5","pages":"304-304"},"PeriodicalIF":42.7,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140110884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-11DOI: 10.1038/s41576-024-00719-9
Henry Ertl
A study in Nature Genetics identifies many regulators of genome-wide chromatin accessibility and then reports the mechanistic underpinnings for one of the identified transcription factors.
{"title":"The regulatory landscape of chromatin accessibility","authors":"Henry Ertl","doi":"10.1038/s41576-024-00719-9","DOIUrl":"10.1038/s41576-024-00719-9","url":null,"abstract":"A study in Nature Genetics identifies many regulators of genome-wide chromatin accessibility and then reports the mechanistic underpinnings for one of the identified transcription factors.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 5","pages":"305-305"},"PeriodicalIF":42.7,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140096941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-11DOI: 10.1038/s41576-024-00721-1
Bruce Budowle, Antti Sajantila
Short tandem repeats (STRs), also known as microsatellites, are the primary markers of forensic genetics for developing investigative leads in criminal cases and humanitarian efforts. Their variation in length and sequence provides genetic information even in samples of low quantity and quality, enabling high resolution for identification and attribution purposes, and culminating in the development of national DNA databases. Bruce Budowle and Antti Sajantila reflect on how short tandem repeats (STRs) became the primary markers of forensic genetics, including for developing investigative leads in criminal cases and humanitarian efforts.
短串联重复序列（STR），又称微卫星，是法医遗传学的主要标记，用于开发刑事案件和人道主义工作的调查线索。即使样本数量少、质量差，它们在长度和序列上的变化也能提供遗传信息，从而实现高分辨率的身份识别和归属目的，并最终促成了国家 DNA 数据库的开发。布鲁斯-布道尔（Bruce Budowle）和安蒂-萨扬蒂拉（Antti Sajantila）探讨了短串联重复序列 (STR) 如何成为法医遗传学的主要标记，包括用于开发刑事案件和人道主义工作的调查线索。
{"title":"Short tandem repeats — how microsatellites became the currency of forensic genetics","authors":"Bruce Budowle, Antti Sajantila","doi":"10.1038/s41576-024-00721-1","DOIUrl":"10.1038/s41576-024-00721-1","url":null,"abstract":"Short tandem repeats (STRs), also known as microsatellites, are the primary markers of forensic genetics for developing investigative leads in criminal cases and humanitarian efforts. Their variation in length and sequence provides genetic information even in samples of low quantity and quality, enabling high resolution for identification and attribution purposes, and culminating in the development of national DNA databases. Bruce Budowle and Antti Sajantila reflect on how short tandem repeats (STRs) became the primary markers of forensic genetics, including for developing investigative leads in criminal cases and humanitarian efforts.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 7","pages":"450-451"},"PeriodicalIF":42.7,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140096899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-11DOI: 10.1038/s41576-024-00696-z
Indhu-Shree Rajan-Babu, Egor Dolzhenko, Michael A. Eberle, Jan M. Friedman
Short tandem repeats (STRs) are a class of repetitive elements, composed of tandem arrays of 1–6 base pair sequence motifs, that comprise a substantial fraction of the human genome. STR expansions can cause a wide range of neurological and neuromuscular conditions, known as repeat expansion disorders, whose age of onset, severity, penetrance and/or clinical phenotype are influenced by the length of the repeats and their sequence composition. The presence of non-canonical motifs, depending on the type, frequency and position within the repeat tract, can alter clinical outcomes by modifying somatic and intergenerational repeat stability, gene expression and mutant transcript-mediated and/or protein-mediated toxicities. Here, we review the diverse structural conformations of repeat expansions, technological advances for the characterization of changes in sequence composition, their clinical correlations and the impact on disease mechanisms. This Review highlights the diversity in sequence composition of disease-related short tandem repeats. The authors discuss how to detect non-canonical motifs in repeat sequences from sequencing data and review the molecular and clinical consequences of sequence composition changes.
{"title":"Sequence composition changes in short tandem repeats: heterogeneity, detection, mechanisms and clinical implications","authors":"Indhu-Shree Rajan-Babu, Egor Dolzhenko, Michael A. Eberle, Jan M. Friedman","doi":"10.1038/s41576-024-00696-z","DOIUrl":"10.1038/s41576-024-00696-z","url":null,"abstract":"Short tandem repeats (STRs) are a class of repetitive elements, composed of tandem arrays of 1–6 base pair sequence motifs, that comprise a substantial fraction of the human genome. STR expansions can cause a wide range of neurological and neuromuscular conditions, known as repeat expansion disorders, whose age of onset, severity, penetrance and/or clinical phenotype are influenced by the length of the repeats and their sequence composition. The presence of non-canonical motifs, depending on the type, frequency and position within the repeat tract, can alter clinical outcomes by modifying somatic and intergenerational repeat stability, gene expression and mutant transcript-mediated and/or protein-mediated toxicities. Here, we review the diverse structural conformations of repeat expansions, technological advances for the characterization of changes in sequence composition, their clinical correlations and the impact on disease mechanisms. This Review highlights the diversity in sequence composition of disease-related short tandem repeats. The authors discuss how to detect non-canonical motifs in repeat sequences from sequencing data and review the molecular and clinical consequences of sequence composition changes.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 7","pages":"476-499"},"PeriodicalIF":42.7,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140096929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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