Pub Date : 2024-04-22DOI: 10.1038/s41576-024-00718-w
Heng Li, Richard Durbin
Genome sequences largely determine the biology and encode the history of an organism, and de novo assembly — the process of reconstructing the genome sequence of an organism from sequencing reads — has been a central problem in bioinformatics for four decades. Until recently, genomes were typically assembled into fragments of a few megabases at best, but now technological advances in long-read sequencing enable the near-complete assembly of each chromosome — also known as telomere-to-telomere assembly — for many organisms. Here, we review recent progress on assembly algorithms and protocols, with a focus on how to derive near-telomere-to-telomere assemblies. We also discuss the additional developments that will be required to resolve remaining assembly gaps and to assemble non-diploid genomes. In this Review, Li and Durbin discuss how to generate telomere-to-telomere assemblies for large haploid or diploid genomes using currently available data types and algorithms, and outline remaining challenges in resolving highly repetitive sequences and polyploid genomes.
{"title":"Genome assembly in the telomere-to-telomere era","authors":"Heng Li, Richard Durbin","doi":"10.1038/s41576-024-00718-w","DOIUrl":"10.1038/s41576-024-00718-w","url":null,"abstract":"Genome sequences largely determine the biology and encode the history of an organism, and de novo assembly — the process of reconstructing the genome sequence of an organism from sequencing reads — has been a central problem in bioinformatics for four decades. Until recently, genomes were typically assembled into fragments of a few megabases at best, but now technological advances in long-read sequencing enable the near-complete assembly of each chromosome — also known as telomere-to-telomere assembly — for many organisms. Here, we review recent progress on assembly algorithms and protocols, with a focus on how to derive near-telomere-to-telomere assemblies. We also discuss the additional developments that will be required to resolve remaining assembly gaps and to assemble non-diploid genomes. In this Review, Li and Durbin discuss how to generate telomere-to-telomere assemblies for large haploid or diploid genomes using currently available data types and algorithms, and outline remaining challenges in resolving highly repetitive sequences and polyploid genomes.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 9","pages":"658-670"},"PeriodicalIF":39.1,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140632363","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 : 2024-04-18DOI: 10.1038/s41576-024-00712-2
Xavier Rambout, Lynne E. Maquat
Proper regulation of mRNA production in the nucleus is critical for the maintenance of cellular homoeostasis during adaptation to internal and environmental cues. Over the past 25 years, it has become clear that the nuclear machineries governing gene transcription, pre-mRNA processing, pre-mRNA and mRNA decay, and mRNA export to the cytoplasm are inextricably linked to control the quality and quantity of mRNAs available for translation. More recently, an ever-expanding diversity of new mechanisms by which nuclear RNA decay factors finely tune the expression of protein-encoding genes have been uncovered. Here, we review the current understanding of how mammalian cells shape their protein-encoding potential by regulating the decay of pre-mRNAs and mRNAs in the nucleus. In this Review, the authors summarize our current understanding of nuclear pre-mRNA and mRNA decay pathways. They describe how aberrantly processed mRNAs are targeted for decay in the nucleus and how this process is regulated to finely control gene expression.
{"title":"Nuclear mRNA decay: regulatory networks that control gene expression","authors":"Xavier Rambout, Lynne E. Maquat","doi":"10.1038/s41576-024-00712-2","DOIUrl":"10.1038/s41576-024-00712-2","url":null,"abstract":"Proper regulation of mRNA production in the nucleus is critical for the maintenance of cellular homoeostasis during adaptation to internal and environmental cues. Over the past 25 years, it has become clear that the nuclear machineries governing gene transcription, pre-mRNA processing, pre-mRNA and mRNA decay, and mRNA export to the cytoplasm are inextricably linked to control the quality and quantity of mRNAs available for translation. More recently, an ever-expanding diversity of new mechanisms by which nuclear RNA decay factors finely tune the expression of protein-encoding genes have been uncovered. Here, we review the current understanding of how mammalian cells shape their protein-encoding potential by regulating the decay of pre-mRNAs and mRNAs in the nucleus. In this Review, the authors summarize our current understanding of nuclear pre-mRNA and mRNA decay pathways. They describe how aberrantly processed mRNAs are targeted for decay in the nucleus and how this process is regulated to finely control gene expression.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 10","pages":"679-697"},"PeriodicalIF":39.1,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140620238","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 : 2024-04-17DOI: 10.1038/s41576-024-00723-z
Andreas Werner, Aditi Kanhere, Claes Wahlestedt, John S. Mattick
Long non-coding RNAs (lncRNAs) are emerging as a major class of gene products that have central roles in cell and developmental biology. Natural antisense transcripts (NATs) are an important subset of lncRNAs that are expressed from the opposite strand of protein-coding and non-coding genes and are a genome-wide phenomenon in both eukaryotes and prokaryotes. In eukaryotes, a myriad of NATs participate in regulatory pathways that affect expression of their cognate sense genes. Recent developments in the study of NATs and lncRNAs and large-scale sequencing and bioinformatics projects suggest that whether NATs regulate expression, splicing, stability or translation of the sense transcript is influenced by the pattern and degrees of overlap between the sense–antisense pair. Moreover, epigenetic gene regulatory mechanisms prevail in somatic cells whereas mechanisms dependent on the formation of double-stranded RNA intermediates are prevalent in germ cells. The modulating effects of NATs on sense transcript expression make NATs rational targets for therapeutic interventions. In this Perspective, Werner and colleagues discuss the many potential mechanisms by which natural antisense transcripts (NATs) can regulate expression of their complementary sense transcripts, the biological implications of their regulatory effects and the potential of NATs for therapeutic applications.
{"title":"Natural antisense transcripts as versatile regulators of gene expression","authors":"Andreas Werner, Aditi Kanhere, Claes Wahlestedt, John S. Mattick","doi":"10.1038/s41576-024-00723-z","DOIUrl":"10.1038/s41576-024-00723-z","url":null,"abstract":"Long non-coding RNAs (lncRNAs) are emerging as a major class of gene products that have central roles in cell and developmental biology. Natural antisense transcripts (NATs) are an important subset of lncRNAs that are expressed from the opposite strand of protein-coding and non-coding genes and are a genome-wide phenomenon in both eukaryotes and prokaryotes. In eukaryotes, a myriad of NATs participate in regulatory pathways that affect expression of their cognate sense genes. Recent developments in the study of NATs and lncRNAs and large-scale sequencing and bioinformatics projects suggest that whether NATs regulate expression, splicing, stability or translation of the sense transcript is influenced by the pattern and degrees of overlap between the sense–antisense pair. Moreover, epigenetic gene regulatory mechanisms prevail in somatic cells whereas mechanisms dependent on the formation of double-stranded RNA intermediates are prevalent in germ cells. The modulating effects of NATs on sense transcript expression make NATs rational targets for therapeutic interventions. In this Perspective, Werner and colleagues discuss the many potential mechanisms by which natural antisense transcripts (NATs) can regulate expression of their complementary sense transcripts, the biological implications of their regulatory effects and the potential of NATs for therapeutic applications.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 10","pages":"730-744"},"PeriodicalIF":39.1,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140608105","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 : 2024-04-15DOI: 10.1038/s41576-024-00732-y
Jenny Tung
In this Journal Club article, Jenny Tung reflects on a 1975 paper from King and Wilson that emphasized the importance of gene regulatory changes in human evolution.
在这篇期刊俱乐部文章中，Jenny Tung 回顾了 King 和 Wilson 1975 年发表的一篇论文，该论文强调了基因调控变化在人类进化中的重要性。
{"title":"Understanding human uniqueness in the pre-genomic era","authors":"Jenny Tung","doi":"10.1038/s41576-024-00732-y","DOIUrl":"10.1038/s41576-024-00732-y","url":null,"abstract":"In this Journal Club article, Jenny Tung reflects on a 1975 paper from King and Wilson that emphasized the importance of gene regulatory changes in human evolution.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 7","pages":"459-459"},"PeriodicalIF":42.7,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140553393","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 : 2024-04-12DOI: 10.1038/s41576-024-00729-7
Dongsheng Bai, Chenxu Zhu
In this Tools of the Trade article, Dongsheng Bai and Chenxu Zhu describe SIMPLE-seq, a scalable single-cell sequencing method that simultaneously decodes the cytosine modifications 5mC and 5hmC.
在这篇 "贸易工具"（Tools of the Trade）文章中，白东升（Dongsheng Bai）和朱晨旭（Chenxu Zhu）介绍了一种可扩展的单细胞测序方法 SIMPLE-seq，该方法可同时解码胞嘧啶修饰 5mC 和 5hmC。
{"title":"SIMPLE-seq to decode DNA methylation dynamics in single cells","authors":"Dongsheng Bai, Chenxu Zhu","doi":"10.1038/s41576-024-00729-7","DOIUrl":"10.1038/s41576-024-00729-7","url":null,"abstract":"In this Tools of the Trade article, Dongsheng Bai and Chenxu Zhu describe SIMPLE-seq, a scalable single-cell sequencing method that simultaneously decodes the cytosine modifications 5mC and 5hmC.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 6","pages":"377-377"},"PeriodicalIF":42.7,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140550379","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 : 2024-04-12DOI: 10.1038/s41576-024-00730-0
Henry Ertl
A paper in Nature Genetics identifies a mechanism involving the transcription factor DUXBL that controls the development of early embryonic mouse cells past stages marked by totipotency.
{"title":"A developmental exit from totipotency","authors":"Henry Ertl","doi":"10.1038/s41576-024-00730-0","DOIUrl":"10.1038/s41576-024-00730-0","url":null,"abstract":"A paper in Nature Genetics identifies a mechanism involving the transcription factor DUXBL that controls the development of early embryonic mouse cells past stages marked by totipotency.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 6","pages":"376-376"},"PeriodicalIF":42.7,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140550477","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 : 2024-04-11DOI: 10.1038/s41576-024-00715-z
Sarah M. Waldvogel, Jennifer E. Posey, Margaret A. Goodell
Nearly every mammalian cell division is accompanied by a mutational event that becomes fixed in a daughter cell. When carried forward to additional cell progeny, a clone of variant cells can emerge. As a result, mammals are complex mosaics of clones that are genetically distinct from one another. Recent high-throughput sequencing studies have revealed that mosaicism is common, clone sizes often increase with age and specific variants can affect tissue function and disease development. Variants that are acquired during early embryogenesis are shared by multiple cell types and can affect numerous tissues. Within tissues, variant clones compete, which can result in their expansion or elimination. Embryonic mosaicism has clinical implications for genetic disease severity and transmission but is likely an under-recognized phenomenon. To better understand its implications for mosaic individuals, it is essential to leverage research tools that can elucidate the mechanisms by which expanded embryonic variants influence development and disease. Genetic variants acquired early during embryogenesis can affect numerous tissues. The authors review the phenomenon of embryonic mosaicism, with a focus on small variants, and discuss mechanisms of cell competition that allow mosaic clones to expand, as well as the functional consequences of mosaicism for embryo viability and the health of the organism.
{"title":"Human embryonic genetic mosaicism and its effects on development and disease","authors":"Sarah M. Waldvogel, Jennifer E. Posey, Margaret A. Goodell","doi":"10.1038/s41576-024-00715-z","DOIUrl":"10.1038/s41576-024-00715-z","url":null,"abstract":"Nearly every mammalian cell division is accompanied by a mutational event that becomes fixed in a daughter cell. When carried forward to additional cell progeny, a clone of variant cells can emerge. As a result, mammals are complex mosaics of clones that are genetically distinct from one another. Recent high-throughput sequencing studies have revealed that mosaicism is common, clone sizes often increase with age and specific variants can affect tissue function and disease development. Variants that are acquired during early embryogenesis are shared by multiple cell types and can affect numerous tissues. Within tissues, variant clones compete, which can result in their expansion or elimination. Embryonic mosaicism has clinical implications for genetic disease severity and transmission but is likely an under-recognized phenomenon. To better understand its implications for mosaic individuals, it is essential to leverage research tools that can elucidate the mechanisms by which expanded embryonic variants influence development and disease. Genetic variants acquired early during embryogenesis can affect numerous tissues. The authors review the phenomenon of embryonic mosaicism, with a focus on small variants, and discuss mechanisms of cell competition that allow mosaic clones to expand, as well as the functional consequences of mosaicism for embryo viability and the health of the organism.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 10","pages":"698-714"},"PeriodicalIF":39.1,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140547502","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 : 2024-04-02DOI: 10.1038/s41576-024-00711-3
Trudy F. C. Mackay, Robert R. H. Anholt
Pleiotropy (whereby one genetic polymorphism affects multiple traits) and epistasis (whereby non-linear interactions between genetic polymorphisms affect the same trait) are fundamental aspects of the genetic architecture of quantitative traits. Recent advances in the ability to characterize the effects of polymorphic variants on molecular and organismal phenotypes in human and model organism populations have revealed the prevalence of pleiotropy and unexpected shared molecular genetic bases among quantitative traits, including diseases. By contrast, epistasis is common between polymorphic loci associated with quantitative traits in model organisms, such that alleles at one locus have different effects in different genetic backgrounds, but is rarely observed for human quantitative traits and common diseases. Here, we review the concepts and recent inferences about pleiotropy and epistasis, and discuss factors that contribute to similarities and differences between the genetic architecture of quantitative traits in model organisms and humans. In this Review, Mackay and Anholt discuss how epistasis and pleiotropy contribute to the genetic architecture of quantitative traits and outline factors that might explain observed differences in their prevalence between model organisms and humans.
{"title":"Pleiotropy, epistasis and the genetic architecture of quantitative traits","authors":"Trudy F. C. Mackay, Robert R. H. Anholt","doi":"10.1038/s41576-024-00711-3","DOIUrl":"10.1038/s41576-024-00711-3","url":null,"abstract":"Pleiotropy (whereby one genetic polymorphism affects multiple traits) and epistasis (whereby non-linear interactions between genetic polymorphisms affect the same trait) are fundamental aspects of the genetic architecture of quantitative traits. Recent advances in the ability to characterize the effects of polymorphic variants on molecular and organismal phenotypes in human and model organism populations have revealed the prevalence of pleiotropy and unexpected shared molecular genetic bases among quantitative traits, including diseases. By contrast, epistasis is common between polymorphic loci associated with quantitative traits in model organisms, such that alleles at one locus have different effects in different genetic backgrounds, but is rarely observed for human quantitative traits and common diseases. Here, we review the concepts and recent inferences about pleiotropy and epistasis, and discuss factors that contribute to similarities and differences between the genetic architecture of quantitative traits in model organisms and humans. In this Review, Mackay and Anholt discuss how epistasis and pleiotropy contribute to the genetic architecture of quantitative traits and outline factors that might explain observed differences in their prevalence between model organisms and humans.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"25 9","pages":"639-657"},"PeriodicalIF":39.1,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140343299","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 : 2024-03-28DOI: 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}
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