Nature genetics最新文献

{"title":"Consensus prediction of cell type labels in single-cell data with popV","authors":"Can Ergen, Galen Xing, Chenling Xu, Martin Kim, Michael Jayasuriya, Erin McGeever, Angela Oliveira Pisco, Aaron Streets, Nir Yosef","doi":"10.1038/s41588-024-01993-3","DOIUrl":"10.1038/s41588-024-01993-3","url":null,"abstract":"Cell-type classification is a crucial step in single-cell sequencing analysis. Various methods have been proposed for transferring a cell-type label from an annotated reference atlas to unannotated query datasets. Existing methods for transferring cell-type labels lack proper uncertainty estimation for the resulting annotations, limiting interpretability and usefulness. To address this, we propose popular Vote (popV), an ensemble of prediction models with an ontology-based voting scheme. PopV achieves accurate cell-type labeling and provides uncertainty scores. In multiple case studies, popV confidently annotates the majority of cells while highlighting cell populations that are challenging to annotate by label transfer. This additional step helps to reduce the load of manual inspection, which is often a necessary component of the annotation process, and enables one to focus on the most problematic parts of the annotation, streamlining the overall annotation process. Popular Vote (popV) is a simple, ensemble popular vote approach for cell type annotation in single-cell omic data, flexibly incorporating various methods in an open-source Python framework. Across various challenging input datasets, popV offers consistent, accurate performance.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2731-2738"},"PeriodicalIF":31.7,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01993-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678343","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}

{"title":"Author Correction: Brca1 haploinsufficiency promotes early tumor onset and epigenetic alterations in a mouse model of hereditary breast cancer","authors":"Carman Man-Chung Li, Alyssa Cordes, Michael U. J. Oliphant, S. Aidan Quinn, Mayura Thomas, Laura M. Selfors, Francesca Silvestri, Nomeda Girnius, Gianmarco Rinaldi, Jason J. Zoeller, Hana Shapiro, Christina Tsiobikas, Kushali P. Gupta, Shailja Pathania, Aviv Regev, Cigall Kadoch, Senthil K. Muthuswamy, Joan S. Brugge","doi":"10.1038/s41588-024-02034-9","DOIUrl":"10.1038/s41588-024-02034-9","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2842-2842"},"PeriodicalIF":31.7,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02034-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673169","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}

{"title":"A multilineage screen identifies actionable synthetic lethal interactions in human cancers","authors":"Samson H. Fong, Brent M. Kuenzi, Nicole M. Mattson, John Lee, Kyle Sanchez, Ana Bojorquez-Gomez, Kyle Ford, Brenton P. Munson, Katherine Licon, Sarah Bergendahl, John Paul Shen, Jason F. Kreisberg, Prashant Mali, Jeffrey H. Hager, Michael A. White, Trey Ideker","doi":"10.1038/s41588-024-01971-9","DOIUrl":"https://doi.org/10.1038/s41588-024-01971-9","url":null,"abstract":"<p>Cancers are driven by alterations in diverse genes, creating dependencies that can be therapeutically targeted. However, many genetic dependencies have proven inconsistent across tumors. Here we describe SCHEMATIC, a strategy to identify a core network of highly penetrant, actionable genetic interactions. First, fundamental cellular processes are perturbed by systematic combinatorial knockouts across tumor lineages, identifying 1,805 synthetic lethal interactions (95% unreported). Interactions are then analyzed by hierarchical pooling, revealing that half segregate reliably by tissue type or biomarker status (51%) and a substantial minority are penetrant across lineages (34%). Interactions converge on 49 multigene systems, including MAPK signaling and BAF transcriptional regulatory complexes, which become essential on disruption of polymerases. Some 266 interactions translate to robust biomarkers of drug sensitivity, including frequent genetic alterations in the KDM5C/6A histone demethylases, which sensitize to inhibition of TIPARP (PARP7). SCHEMATIC offers a context-aware, data-driven approach to match genetic alterations to targeted therapies.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"168 1","pages":""},"PeriodicalIF":30.8,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665532","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}

{"title":"Intermediate cells with activated JAK/STAT signaling in prostate regeneration and diseases","authors":"","doi":"10.1038/s41588-024-01977-3","DOIUrl":"10.1038/s41588-024-01977-3","url":null,"abstract":"NKX3.1-expressing intermediate Basal-B cells represent a transient basal stem cell state during prostate regeneration, inflammation and cancer initiation. Remarkably, activation of JAK/STAT signaling is essential in regulating expansion and differentiation of Basal-B-like cells during prostate inflammation, identifying this signaling pathway as a potential therapeutic target in prostatitis associated with increased Basal-B signature.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2606-2607"},"PeriodicalIF":31.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637043","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}

{"title":"Toward GDPR compliance with the Helmholtz Munich genotype imputation server","authors":"N. William Rayner,&nbsp;Young-Chan Park,&nbsp;Christian Fuchsberger,&nbsp;Andrei Barysenka,&nbsp;Eleftheria Zeggini","doi":"10.1038/s41588-024-02012-1","DOIUrl":"10.1038/s41588-024-02012-1","url":null,"abstract":"","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2580-2581"},"PeriodicalIF":31.7,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637060","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}

{"title":"JAK/STAT signaling maintains an intermediate cell population during prostate basal cell fate determination","authors":"Wangxin Guo,&nbsp;Xiaoyu Zhang,&nbsp;Lin Li,&nbsp;Pengfei Shao,&nbsp;Chao Liang,&nbsp;Hongjiong Zhang,&nbsp;Kuo Liu,&nbsp;Shuoming Wang,&nbsp;Yunyi Peng,&nbsp;Jun Luo,&nbsp;Yi Ju,&nbsp;Angelo M. De Marzo,&nbsp;Chen Yu,&nbsp;Luonan Chen,&nbsp;Bin Zhou,&nbsp;Dong Gao","doi":"10.1038/s41588-024-01979-1","DOIUrl":"10.1038/s41588-024-01979-1","url":null,"abstract":"Unipotent basal and luminal stem cells maintain prostate homeostasis, with an intermediate cell population emerging during prostate inflammation or cancer. However, the identities of basal stem cell and intermediate cell population remain unclear. Here we identified a rare intermediate cell population expressing luminal markers (termed Basal-B) with enhanced organoid formation capacity, and a larger basal population (termed Basal-A). Genetic lineage tracing revealed Basal-B cells represented a transient basal stem cell state during prostate homeostasis and androgen-mediated regeneration. Activated JAK/STAT signaling was identified in Basal-B cells, and its inhibition significantly reduced Basal-B markers expression. Inflammation increased Basal-B-to-luminal cell transdifferentiation, but JAK/STAT inhibition notably attenuated this effect. Pten gene deletion increased Nkx3.1-expressing Basal-B-like cell population and led to neoplasia. In humans, h-Basal-B cells were more prevalent in benign prostate hyperplasia. This study reveals the identities of intermediate Basal-B cells and underscores the role of JAK/STAT signaling in prostate cell fate determination. This study identifies Basal-B cells as a transient cell state during prostate homeostasis and androgen-mediated regeneration. These cells exist in humans and increase in number with prostatitis and inflammation.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2776-2789"},"PeriodicalIF":31.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601020","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}

{"title":"Engineering structural variants to interrogate genome function","authors":"Jonas Koeppel,&nbsp;Juliane Weller,&nbsp;Thomas Vanderstichele,&nbsp;Leopold Parts","doi":"10.1038/s41588-024-01981-7","DOIUrl":"10.1038/s41588-024-01981-7","url":null,"abstract":"Structural variation, such as deletions, duplications, inversions and complex rearrangements, can have profound effects on gene expression, genome stability, phenotypic diversity and disease susceptibility. Structural variants can encompass up to millions of bases and have the potential to rearrange substantial segments of the genome. They contribute considerably more to genetic diversity in human populations and have larger effects on phenotypic traits than point mutations. Until recently, our understanding of the effects of structural variants was driven mainly by studying naturally occurring variation. New genome-engineering tools capable of generating deletions, insertions, inversions and translocations, together with the discovery of new recombinases and advances in creating synthetic DNA constructs, now enable the design and generation of an extended range of structural variation. Here, we discuss these tools and examples of their application and highlight existing challenges that will need to be overcome to fully harness their potential. Structural variations (SVs) impact gene expression, genome stability and disease susceptibility. This Review discusses recent advances in genome-engineering tools that enable precise SV generation and highlights the challenges that remain.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2623-2635"},"PeriodicalIF":31.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599616","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}

{"title":"Toward advances in retinoblastoma genetics in Kenya","authors":"Helen Dimaras,&nbsp;Beatrice Omweri,&nbsp;Daniel Muema,&nbsp;Loice Kanda,&nbsp;Rosaline Wanjiru Macharia,&nbsp;John Gitau,&nbsp;Catherine Mutinda,&nbsp;Kahaki Kimani,&nbsp;Wairimu Waweru,&nbsp;Stephen Gichuhi,&nbsp;Marianne W. Mureithi,&nbsp;Lucy Njambi","doi":"10.1038/s41588-024-01974-6","DOIUrl":"10.1038/s41588-024-01974-6","url":null,"abstract":"Despite extensive advancements in cancer genetics in North America and Europe, the African continent remains underrepresented in this vital research area. Here we highlight a pioneering collaborative project in Kenya, with a focus on expanding cancer genetics services and research into retinoblastoma, a prototypical heritable cancer syndrome.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2585-2588"},"PeriodicalIF":31.7,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598339","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}

{"title":"Genetic architecture of cerebrospinal fluid and brain metabolite levels and the genetic colocalization of metabolites with human traits","authors":"Ciyang Wang,&nbsp;Chengran Yang,&nbsp;Daniel Western,&nbsp;Muhammad Ali,&nbsp;Yueyao Wang,&nbsp;Chia-Ling Phuah,&nbsp;John Budde,&nbsp;Lihua Wang,&nbsp;Priyanka Gorijala,&nbsp;Jigyasha Timsina,&nbsp;Agustin Ruiz,&nbsp;Pau Pastor,&nbsp;Maria Victoria Fernandez,&nbsp;Dominantly Inherited Alzheimer Network (DIAN),&nbsp;The Alzheimer’s Disease Neuroimaging Initiative (ADNI),&nbsp;Daniel J. Panyard,&nbsp;Corinne D. Engelman,&nbsp;Yuetiva Deming,&nbsp;Merce Boada,&nbsp;Amanda Cano,&nbsp;Pablo Garcia-Gonzalez,&nbsp;Neill R. Graff-Radford,&nbsp;Hiroshi Mori,&nbsp;Jae-Hong Lee,&nbsp;Richard J. Perrin,&nbsp;Laura Ibanez,&nbsp;Yun Ju Sung,&nbsp;Carlos Cruchaga","doi":"10.1038/s41588-024-01973-7","DOIUrl":"10.1038/s41588-024-01973-7","url":null,"abstract":"Brain metabolism perturbation can contribute to traits and diseases. We conducted a genome-wide association study for cerebrospinal fluid (CSF) and brain metabolite levels, identifying 205 independent associations (47.3% new signals, containing 11 new loci) for 139 CSF metabolites, and 32 independent associations (43.8% new signals, containing 4 new loci) for 31 brain metabolites. Of these, 96.9% (CSF) and 71.4% (brain) of the new signals belonged to previously analyzed metabolites in blood or urine. We integrated the metabolite quantitative trait loci (MQTLs) with 23 neurological, psychiatric and common human traits and diseases through colocalization to identify metabolites and biological processes implicated in these phenotypes. Combining CSF and brain, we identified 71 metabolite–trait associations, such as glycerophosphocholines with Alzheimer’s disease, O-sulfo-l-tyrosine with Parkinson’s disease, glycine, xanthine with waist-to-hip ratio and ergothioneine with inflammatory bowel disease. Our study expanded the knowledge of MQTLs in the central nervous system, providing insights into human traits. Genome-wide association study of cerebrospinal fluid and brain metabolites highlights the unique genetic architecture of metabolite levels and metabolite–trait associations with brain-related phenotypes.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2685-2695"},"PeriodicalIF":31.7,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598340","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}

{"title":"Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease","authors":"Daniel Western,&nbsp;Jigyasha Timsina,&nbsp;Lihua Wang,&nbsp;Ciyang Wang,&nbsp;Chengran Yang,&nbsp;Bridget Phillips,&nbsp;Yueyao Wang,&nbsp;Menghan Liu,&nbsp;Muhammad Ali,&nbsp;Aleksandra Beric,&nbsp;Priyanka Gorijala,&nbsp;Pat Kohlfeld,&nbsp;John Budde,&nbsp;Allan I. Levey,&nbsp;John C. Morris,&nbsp;Richard J. Perrin,&nbsp;Agustin Ruiz,&nbsp;Marta Marquié,&nbsp;Mercè Boada,&nbsp;Itziar de Rojas,&nbsp;Jarod Rutledge,&nbsp;Hamilton Oh,&nbsp;Edward N. Wilson,&nbsp;Yann Le Guen,&nbsp;Lianne M. Reus,&nbsp;Betty Tijms,&nbsp;Pieter Jelle Visser,&nbsp;Sven J. van der Lee,&nbsp;Yolande A. L. Pijnenburg,&nbsp;Charlotte E. Teunissen,&nbsp;Marta del Campo Milan,&nbsp;Ignacio Alvarez,&nbsp;Miquel Aguilar,&nbsp;Dominantly Inherited Alzheimer Network (DIAN),&nbsp;the Alzheimer’s Disease Neuroimaging Initiative (ADNI),&nbsp;Michael D. Greicius,&nbsp;Pau Pastor,&nbsp;David J. Pulford,&nbsp;Laura Ibanez,&nbsp;Tony Wyss-Coray,&nbsp;Yun Ju Sung,&nbsp;Carlos Cruchaga","doi":"10.1038/s41588-024-01972-8","DOIUrl":"10.1038/s41588-024-01972-8","url":null,"abstract":"The integration of quantitative trait loci (QTLs) with disease genome-wide association studies (GWASs) has proven successful in prioritizing candidate genes at disease-associated loci. QTL mapping has been focused on multi-tissue expression QTLs or plasma protein QTLs (pQTLs). We generated a cerebrospinal fluid (CSF) pQTL atlas by measuring 6,361 proteins in 3,506 samples. We identified 3,885 associations for 1,883 proteins, including 2,885 new pQTLs, demonstrating unique genetic regulation in CSF. We identified CSF-enriched pleiotropic regions on chromosome (chr)3q28 near OSTN and chr19q13.32 near APOE that were enriched for neuron specificity and neurological development. We integrated our associations with Alzheimer’s disease (AD) through proteome-wide association study (PWAS), colocalization and Mendelian randomization and identified 38 putative causal proteins, 15 of which have drugs available. Finally, we developed a proteomics-based AD prediction model that outperforms genetics-based models. These findings will be instrumental to further understand the biology and identify causal and druggable proteins for brain and neurological traits. Proteogenomic analysis of human cerebrospinal fluid by measuring 6,361 proteins in 3,506 individuals identifies new protein QTLs and highlights genetic regulation involved in neurological processes.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2672-2684"},"PeriodicalIF":31.7,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598343","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}