Pub Date : 2024-10-14DOI: 10.1038/s41588-024-01942-0
Ben J. Hayes, Timothy J. Mahony, Kira Villiers, Christie Warburton, Kathryn E. Kemper, Eric Dinglasan, Hannah Robinson, Owen Powell, Kai Voss-Fels, Ian D. Godwin, Lee T. Hickey
Many thousands and, in some cases, millions of individuals from the major crop and livestock species have been genotyped and phenotyped for the purpose of genomic selection. ‘Ultimate genotypes’, in which the marker allele haplotypes with the most favorable effects on a target trait or traits in the population are combined together in silico, can be constructed from these datasets. Ultimate genotypes display up to six times the performance of the current best individuals in the population, as demonstrated for net profit in dairy cattle (incorporating a range of economic traits), yield in wheat and 100-seed weight in chickpea. However, current breeding strategies that aim to assemble ultimate genotypes through conventional crossing take many generations. As a hypothetical thought piece, here, we contemplate three future pathways for rapidly achieving ultimate genotypes: accelerated recombination with gene editing, direct editing of whole-genome haplotype sequences and synthetic biology. This Perspective discusses approaches to generate ultimate genotypes, combining the best chromosome segments in livestock and crop populations, to increase key production, sustainability and welfare traits, compared with the current best individuals.
{"title":"Potential approaches to create ultimate genotypes in crops and livestock","authors":"Ben J. Hayes, Timothy J. Mahony, Kira Villiers, Christie Warburton, Kathryn E. Kemper, Eric Dinglasan, Hannah Robinson, Owen Powell, Kai Voss-Fels, Ian D. Godwin, Lee T. Hickey","doi":"10.1038/s41588-024-01942-0","DOIUrl":"10.1038/s41588-024-01942-0","url":null,"abstract":"Many thousands and, in some cases, millions of individuals from the major crop and livestock species have been genotyped and phenotyped for the purpose of genomic selection. ‘Ultimate genotypes’, in which the marker allele haplotypes with the most favorable effects on a target trait or traits in the population are combined together in silico, can be constructed from these datasets. Ultimate genotypes display up to six times the performance of the current best individuals in the population, as demonstrated for net profit in dairy cattle (incorporating a range of economic traits), yield in wheat and 100-seed weight in chickpea. However, current breeding strategies that aim to assemble ultimate genotypes through conventional crossing take many generations. As a hypothetical thought piece, here, we contemplate three future pathways for rapidly achieving ultimate genotypes: accelerated recombination with gene editing, direct editing of whole-genome haplotype sequences and synthetic biology. This Perspective discusses approaches to generate ultimate genotypes, combining the best chromosome segments in livestock and crop populations, to increase key production, sustainability and welfare traits, compared with the current best individuals.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2310-2317"},"PeriodicalIF":31.7,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142430547","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 : 2024-10-14DOI: 10.1038/s41588-024-01949-7
Hoon Kim, Soyeon Kim, Taylor Wade, Eunchae Yeo, Anuja Lipsa, Anna Golebiewska, Kevin C. Johnson, Sepil An, Junyong Ko, Yoonjoo Nam, Hwa Yeon Lee, Seunghyun Kang, Heesuk Chung, Simone P. Niclou, Hyo-Eun Moon, Sun Ha Paek, Vineet Bafna, Jens Luebeck, Roel G. W. Verhaak
To understand the role of extrachromosomal DNA (ecDNA) amplifications in cancer progression, we detected and classified focal amplifications in 8,060 newly diagnosed primary cancers, untreated metastases and heavily pretreated tumors. The ecDNAs were detected at significantly higher frequency in untreated metastatic and pretreated tumors compared to newly diagnosed cancers. Tumors from chemotherapy-pretreated patients showed significantly higher ecDNA frequency compared to untreated cancers. In particular, tubulin inhibition associated with ecDNA increases, suggesting a role for ecDNA in treatment response. In longitudinally matched tumor samples, ecDNAs were more likely to be retained compared to chromosomal amplifications. EcDNAs shared between time points, and ecDNAs in advanced cancers were more likely to harbor localized hypermutation events compared to private ecDNAs and ecDNAs in newly diagnosed tumors. Relatively high variant allele fractions of ecDNA localized hypermutations implicated early ecDNA mutagenesis. Our findings nominate ecDNAs to provide tumors with competitive advantages during cancer progression and metastasis. A pan-cancer genomic analysis finds an increase of extrachromosomal DNA (ecDNA) in treated and metastatic tumors compared to primary, untreated samples, as well as ecDNA features enriched in advanced disease.
{"title":"Mapping extrachromosomal DNA amplifications during cancer progression","authors":"Hoon Kim, Soyeon Kim, Taylor Wade, Eunchae Yeo, Anuja Lipsa, Anna Golebiewska, Kevin C. Johnson, Sepil An, Junyong Ko, Yoonjoo Nam, Hwa Yeon Lee, Seunghyun Kang, Heesuk Chung, Simone P. Niclou, Hyo-Eun Moon, Sun Ha Paek, Vineet Bafna, Jens Luebeck, Roel G. W. Verhaak","doi":"10.1038/s41588-024-01949-7","DOIUrl":"10.1038/s41588-024-01949-7","url":null,"abstract":"To understand the role of extrachromosomal DNA (ecDNA) amplifications in cancer progression, we detected and classified focal amplifications in 8,060 newly diagnosed primary cancers, untreated metastases and heavily pretreated tumors. The ecDNAs were detected at significantly higher frequency in untreated metastatic and pretreated tumors compared to newly diagnosed cancers. Tumors from chemotherapy-pretreated patients showed significantly higher ecDNA frequency compared to untreated cancers. In particular, tubulin inhibition associated with ecDNA increases, suggesting a role for ecDNA in treatment response. In longitudinally matched tumor samples, ecDNAs were more likely to be retained compared to chromosomal amplifications. EcDNAs shared between time points, and ecDNAs in advanced cancers were more likely to harbor localized hypermutation events compared to private ecDNAs and ecDNAs in newly diagnosed tumors. Relatively high variant allele fractions of ecDNA localized hypermutations implicated early ecDNA mutagenesis. Our findings nominate ecDNAs to provide tumors with competitive advantages during cancer progression and metastasis. A pan-cancer genomic analysis finds an increase of extrachromosomal DNA (ecDNA) in treated and metastatic tumors compared to primary, untreated samples, as well as ecDNA features enriched in advanced disease.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2447-2454"},"PeriodicalIF":31.7,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01949-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142430546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-10DOI: 10.1038/s41588-024-01945-x
Marketa Tomkova, Michael John McClellan, Gilles Crevel, Akbar Muhammed Shahid, Nandini Mozumdar, Jakub Tomek, Emelie Shepherd, Sue Cotterill, Benjamin Schuster-Böckler, Skirmantas Kriaucionis
C-to-T transitions in CpG dinucleotides are the most prevalent mutations in human cancers and genetic diseases. These mutations have been attributed to deamination of 5-methylcytosine (5mC), an epigenetic modification found on CpGs. We recently linked CpG>TpG mutations to replication and hypothesized that errors introduced by polymerase ε (Pol ε) may represent an alternative source of mutations. Here we present a new method called polymerase error rate sequencing (PER-seq) to measure the error spectrum of DNA polymerases in isolation. We find that the most common human cancer-associated Pol ε mutant (P286R) produces an excess of CpG>TpG errors, phenocopying the mutation spectrum of tumors carrying this mutation and deficiencies in mismatch repair. Notably, we also discover that wild-type Pol ε has a sevenfold higher error rate when replicating 5mCpG compared to C in other contexts. Together, our results from PER-seq and human cancers demonstrate that replication errors are a major contributor to CpG>TpG mutagenesis in replicating cells, fundamentally changing our understanding of this important disease-causing mutational mechanism. A new method called polymerase error rate sequencing (PER-seq) can measure the nucleotide misincorporation rate of DNA polymerases. DNA polymerase ε mutants produce an excess of CpG
CpG 二核苷酸的 C-T 转换是人类癌症和遗传疾病中最常见的突变。这些突变归因于 5-甲基胞嘧啶（5mC）的脱氨基作用，5-甲基胞嘧啶是 CpGs 上的一种表观遗传修饰。我们最近将 CpG>TpG 突变与复制联系起来，并假设聚合酶 ε（Pol ε）引入的错误可能是突变的另一个来源。在这里，我们提出了一种称为聚合酶错误率测序（PER-seq）的新方法，用于单独测量 DNA 聚合酶的错误谱。我们发现，最常见的人类癌症相关 Pol ε 突变体（P286R）产生了过多的 CpG>TpG 错误，表征了携带这种突变和错配修复缺陷的肿瘤的突变谱。值得注意的是，我们还发现野生型 Pol ε 复制 5mCpG 时的错误率比其他情况下的 C 高七倍。我们从 PER-seq 和人类癌症中获得的结果共同证明，复制错误是复制细胞中 CpG>TpG 诱变的主要因素，从根本上改变了我们对这一重要致病突变机制的认识。
{"title":"Human DNA polymerase ε is a source of C>T mutations at CpG dinucleotides","authors":"Marketa Tomkova, Michael John McClellan, Gilles Crevel, Akbar Muhammed Shahid, Nandini Mozumdar, Jakub Tomek, Emelie Shepherd, Sue Cotterill, Benjamin Schuster-Böckler, Skirmantas Kriaucionis","doi":"10.1038/s41588-024-01945-x","DOIUrl":"10.1038/s41588-024-01945-x","url":null,"abstract":"C-to-T transitions in CpG dinucleotides are the most prevalent mutations in human cancers and genetic diseases. These mutations have been attributed to deamination of 5-methylcytosine (5mC), an epigenetic modification found on CpGs. We recently linked CpG>TpG mutations to replication and hypothesized that errors introduced by polymerase ε (Pol ε) may represent an alternative source of mutations. Here we present a new method called polymerase error rate sequencing (PER-seq) to measure the error spectrum of DNA polymerases in isolation. We find that the most common human cancer-associated Pol ε mutant (P286R) produces an excess of CpG>TpG errors, phenocopying the mutation spectrum of tumors carrying this mutation and deficiencies in mismatch repair. Notably, we also discover that wild-type Pol ε has a sevenfold higher error rate when replicating 5mCpG compared to C in other contexts. Together, our results from PER-seq and human cancers demonstrate that replication errors are a major contributor to CpG>TpG mutagenesis in replicating cells, fundamentally changing our understanding of this important disease-causing mutational mechanism. A new method called polymerase error rate sequencing (PER-seq) can measure the nucleotide misincorporation rate of DNA polymerases. DNA polymerase ε mutants produce an excess of CpG","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2506-2516"},"PeriodicalIF":31.7,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01945-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142397747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-09DOI: 10.1038/s41588-024-01946-w
C-to-T mutations in CpG dinucleotides are widespread in cancers and are also observed in normal cells. By developing and using a technique to quantify DNA polymerase errors (polymerase error rate sequencing, PER-seq), we reveal that C-to-T mutations in CpG dinucleotides constitute part of the error signature of both wild-type and mutant cancer-associated DNA polymerase ε.
{"title":"DNA polymerase ε produces elevated C-to-T mutations at methylated CpG dinucleotides","authors":"","doi":"10.1038/s41588-024-01946-w","DOIUrl":"10.1038/s41588-024-01946-w","url":null,"abstract":"C-to-T mutations in CpG dinucleotides are widespread in cancers and are also observed in normal cells. By developing and using a technique to quantify DNA polymerase errors (polymerase error rate sequencing, PER-seq), we reveal that C-to-T mutations in CpG dinucleotides constitute part of the error signature of both wild-type and mutant cancer-associated DNA polymerase ε.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2304-2305"},"PeriodicalIF":31.7,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391958","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 : 2024-10-08DOI: 10.1038/s41588-024-01939-9
Lincoln M. P. Shade, Yuriko Katsumata, Erin L. Abner, Khine Zin Aung, Steven A. Claas, Qi Qiao, Bernardo Aguzzoli Heberle, J. Anthony Brandon, Madeline L. Page, Timothy J. Hohman, Shubhabrata Mukherjee, Richard P. Mayeux, Lindsay A. Farrer, Gerard D. Schellenberg, Jonathan L. Haines, Walter A. Kukull, Kwangsik Nho, Andrew J. Saykin, David A. Bennett, Julie A. Schneider, The National Alzheimer’s Coordinating Center, Mark T. W. Ebbert, Peter T. Nelson, David W. Fardo
Genome-wide association studies (GWAS) have identified >80 Alzheimer’s disease and related dementias (ADRD)-associated genetic loci. However, the clinical outcomes used in most previous studies belie the complex nature of underlying neuropathologies. Here we performed GWAS on 11 ADRD-related neuropathology endophenotypes with participants drawn from the following three sources: the National Alzheimer’s Coordinating Center, the Religious Orders Study and Rush Memory and Aging Project, and the Adult Changes in Thought study (n = 7,804 total autopsied participants). We identified eight independent significantly associated loci, of which four were new (COL4A1, PIK3R5, LZTS1 and APOC2). Separately testing known ADRD loci, 19 loci were significantly associated with at least one neuropathology after false-discovery rate adjustment. Genetic colocalization analyses identified pleiotropic effects and quantitative trait loci. Methylation in the cerebral cortex at two sites near APOC2 was associated with cerebral amyloid angiopathy. Studies that include neuropathology endophenotypes are an important step in understanding the mechanisms underlying genetic ADRD risk. Genome-wide analyses identify common variants associated with 11 distinct neuropathology endophenotypes, providing insights into the mechanisms underlying the genetic risk of Alzheimer’s disease and related dementias.
{"title":"GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia","authors":"Lincoln M. P. Shade, Yuriko Katsumata, Erin L. Abner, Khine Zin Aung, Steven A. Claas, Qi Qiao, Bernardo Aguzzoli Heberle, J. Anthony Brandon, Madeline L. Page, Timothy J. Hohman, Shubhabrata Mukherjee, Richard P. Mayeux, Lindsay A. Farrer, Gerard D. Schellenberg, Jonathan L. Haines, Walter A. Kukull, Kwangsik Nho, Andrew J. Saykin, David A. Bennett, Julie A. Schneider, The National Alzheimer’s Coordinating Center, Mark T. W. Ebbert, Peter T. Nelson, David W. Fardo","doi":"10.1038/s41588-024-01939-9","DOIUrl":"10.1038/s41588-024-01939-9","url":null,"abstract":"Genome-wide association studies (GWAS) have identified >80 Alzheimer’s disease and related dementias (ADRD)-associated genetic loci. However, the clinical outcomes used in most previous studies belie the complex nature of underlying neuropathologies. Here we performed GWAS on 11 ADRD-related neuropathology endophenotypes with participants drawn from the following three sources: the National Alzheimer’s Coordinating Center, the Religious Orders Study and Rush Memory and Aging Project, and the Adult Changes in Thought study (n = 7,804 total autopsied participants). We identified eight independent significantly associated loci, of which four were new (COL4A1, PIK3R5, LZTS1 and APOC2). Separately testing known ADRD loci, 19 loci were significantly associated with at least one neuropathology after false-discovery rate adjustment. Genetic colocalization analyses identified pleiotropic effects and quantitative trait loci. Methylation in the cerebral cortex at two sites near APOC2 was associated with cerebral amyloid angiopathy. Studies that include neuropathology endophenotypes are an important step in understanding the mechanisms underlying genetic ADRD risk. Genome-wide analyses identify common variants associated with 11 distinct neuropathology endophenotypes, providing insights into the mechanisms underlying the genetic risk of Alzheimer’s disease and related dementias.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2407-2421"},"PeriodicalIF":31.7,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01939-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-08DOI: 10.1038/s41588-024-01947-9
Alicia Huerta-Chagoya, Philip Schroeder, Ravi Mandla, Jiang Li, Lowri Morris, Maheak Vora, Ahmed Alkanaq, Dorka Nagy, Lukasz Szczerbinski, Jesper G. S. Madsen, Silvia Bonàs-Guarch, Fanny Mollandin, Joanne B. Cole, Bianca Porneala, Kenneth Westerman, Josephine H. Li, Toni I. Pollin, Jose C. Florez, Anna L. Gloyn, David J. Carey, Inês Cebola, Uyenlinh L. Mirshahi, Alisa K. Manning, Aaron Leong, Miriam Udler, Josep M. Mercader
Type 2 diabetes (T2D) genome-wide association studies (GWASs) often overlook rare variants as a result of previous imputation panels’ limitations and scarce whole-genome sequencing (WGS) data. We used TOPMed imputation and WGS to conduct the largest T2D GWAS meta-analysis involving 51,256 cases of T2D and 370,487 controls, targeting variants with a minor allele frequency as low as 5 × 10−5. We identified 12 new variants, including a rare African/African American-enriched enhancer variant near the LEP gene (rs147287548), associated with fourfold increased T2D risk. We also identified a rare missense variant in HNF4A (p.Arg114Trp), associated with eightfold increased T2D risk, previously reported in maturity-onset diabetes of the young with reduced penetrance, but observed here in a T2D GWAS. We further leveraged these data to analyze 1,634 ClinVar variants in 22 genes related to monogenic diabetes, identifying two additional rare variants in HNF1A and GCK associated with fivefold and eightfold increased T2D risk, respectively, the effects of which were modified by the individual’s polygenic risk score. For 21% of the variants with conflicting interpretations or uncertain significance in ClinVar, we provided support of being benign based on their lack of association with T2D. Our work provides a framework for using rare variant GWASs to identify large-effect variants and assess variant pathogenicity in monogenic diabetes genes. Rare variant analyses identify a new type 2 diabetes risk allele near the LEP gene, which encodes leptin, and other risk alleles of intermediate penetrance in genes previously implicated in monogenic forms of diabetes.
{"title":"Rare variant analyses in 51,256 type 2 diabetes cases and 370,487 controls reveal the pathogenicity spectrum of monogenic diabetes genes","authors":"Alicia Huerta-Chagoya, Philip Schroeder, Ravi Mandla, Jiang Li, Lowri Morris, Maheak Vora, Ahmed Alkanaq, Dorka Nagy, Lukasz Szczerbinski, Jesper G. S. Madsen, Silvia Bonàs-Guarch, Fanny Mollandin, Joanne B. Cole, Bianca Porneala, Kenneth Westerman, Josephine H. Li, Toni I. Pollin, Jose C. Florez, Anna L. Gloyn, David J. Carey, Inês Cebola, Uyenlinh L. Mirshahi, Alisa K. Manning, Aaron Leong, Miriam Udler, Josep M. Mercader","doi":"10.1038/s41588-024-01947-9","DOIUrl":"10.1038/s41588-024-01947-9","url":null,"abstract":"Type 2 diabetes (T2D) genome-wide association studies (GWASs) often overlook rare variants as a result of previous imputation panels’ limitations and scarce whole-genome sequencing (WGS) data. We used TOPMed imputation and WGS to conduct the largest T2D GWAS meta-analysis involving 51,256 cases of T2D and 370,487 controls, targeting variants with a minor allele frequency as low as 5 × 10−5. We identified 12 new variants, including a rare African/African American-enriched enhancer variant near the LEP gene (rs147287548), associated with fourfold increased T2D risk. We also identified a rare missense variant in HNF4A (p.Arg114Trp), associated with eightfold increased T2D risk, previously reported in maturity-onset diabetes of the young with reduced penetrance, but observed here in a T2D GWAS. We further leveraged these data to analyze 1,634 ClinVar variants in 22 genes related to monogenic diabetes, identifying two additional rare variants in HNF1A and GCK associated with fivefold and eightfold increased T2D risk, respectively, the effects of which were modified by the individual’s polygenic risk score. For 21% of the variants with conflicting interpretations or uncertain significance in ClinVar, we provided support of being benign based on their lack of association with T2D. Our work provides a framework for using rare variant GWASs to identify large-effect variants and assess variant pathogenicity in monogenic diabetes genes. Rare variant analyses identify a new type 2 diabetes risk allele near the LEP gene, which encodes leptin, and other risk alleles of intermediate penetrance in genes previously implicated in monogenic forms of diabetes.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 11","pages":"2370-2379"},"PeriodicalIF":31.7,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01947-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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