Nature genetics最新文献

{"title":"A blueprint to discovering synthetic lethal gene interactions for precision oncology","authors":"","doi":"10.1038/s41588-024-02024-x","DOIUrl":"10.1038/s41588-024-02024-x","url":null,"abstract":"The SCHEMATIC resource combines CRISPR pairwise gene knockout experiments across tumor cell types with large-scale drug sensitivity assays to identify a core network of highly penetrant, synthetic lethal genetic interactions that can help to match individuals with cancer to targeted therapies.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"9-10"},"PeriodicalIF":31.7,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760425","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":"Single-cell RNA sequencing of peripheral blood links cell-type-specific regulation of splicing to autoimmune and inflammatory diseases","authors":"Chi Tian, Yuntian Zhang, Yihan Tong, Kian Hong Kock, Donald Yuhui Sim, Fei Liu, Jiaqi Dong, Zhixuan Jing, Wenjing Wang, Junbin Gao, Le Min Tan, Kyung Yeon Han, Yoshihiko Tomofuji, Masahiro Nakano, Eliora Violain Buyamin, Radhika Sonthalia, Yoshinari Ando, Hiroaki Hatano, Kyuto Sonehara, Asian Immune Diversity Atlas Network, Xin Jin, Marie Loh, John Chambers, Chung-Chau Hon, Murim Choi, Jong-Eun Park, Kazuyoshi Ishigaki, Tomohisa Okamura, Keishi Fujio, Yukinori Okada, Woong-Yang Park, Jay W. Shin, Xavier Roca, Shyam Prabhakar, Boxiang Liu","doi":"10.1038/s41588-024-02019-8","DOIUrl":"10.1038/s41588-024-02019-8","url":null,"abstract":"Alternative splicing contributes to complex traits, but whether this differs in trait-relevant cell types across diverse genetic ancestries is unclear. Here we describe cell-type-specific, sex-biased and ancestry-biased alternative splicing in ~1 M peripheral blood mononuclear cells from 474 healthy donors from the Asian Immune Diversity Atlas. We identify widespread sex-biased and ancestry-biased differential splicing, most of which is cell-type-specific. We identify 11,577 independent cis-splicing quantitative trait loci (sQTLs), 607 trans-sGenes and 107 dynamic sQTLs. Colocalization between cis-eQTLs and trans-sQTLs revealed a cell-type-specific regulatory relationship between HNRNPLL and PTPRC. We observed an enrichment of cis-sQTL effects in autoimmune and inflammatory disease heritability. Specifically, we functionally validated an Asian-specific sQTL disrupting the 5′ splice site of TCHP exon 4 that putatively modulates the risk of Graves’ disease in East Asian populations. Our work highlights the impact of ancestral diversity on splicing and provides a roadmap to dissect its role in complex diseases at single-cell resolution. This analysis of single-cell RNA sequencing data from peripheral blood mononuclear cells for 474 individuals of diverse Asian ancestries in the Asian Immune Diversity Atlas links cell-type-specific splicing variation with autoimmune and inflammatory disease risk.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2739-2752"},"PeriodicalIF":31.7,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-02019-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142759931","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":"Genome-wide association analyses identify distinct genetic architectures for age-related macular degeneration across ancestries","authors":"Bryan R. Gorman, Georgios Voloudakis, Robert P. Igo Jr., Tyler Kinzy, Christopher W. Halladay, Tim B. Bigdeli, Biao Zeng, Sanan Venkatesh, Jessica N. Cooke Bailey, Dana C. Crawford, Kyriacos Markianos, Frederick Dong, Patrick A. Schreiner, Wen Zhang, VA Million Veteran Program, International AMD Genomics Consortium (IAMDGC), Tamer Hadi, Matthew D. Anger, Amy Stockwell, Ronald B. Melles, Jie Yin, Hélène Choquet, Rebecca Kaye, Karina Patasova, Praveen J. Patel, Brian L. Yaspan, Eric Jorgenson, Pirro G. Hysi, Andrew J. Lotery, J. Michael Gaziano, Philip S. Tsao, Steven J. Fliesler, Jack M. Sullivan, Paul B. Greenberg, Wen-Chih Wu, Themistocles L. Assimes, Saiju Pyarajan, Panos Roussos, Neal S. Peachey, Sudha K. Iyengar","doi":"10.1038/s41588-024-01764-0","DOIUrl":"10.1038/s41588-024-01764-0","url":null,"abstract":"To effectively reduce vision loss due to age-related macular generation (AMD) on a global scale, knowledge of its genetic architecture in diverse populations is necessary. A critical element, AMD risk profiles in African and Hispanic/Latino ancestries, remains largely unknown. We combined data in the Million Veteran Program with five other cohorts to conduct the first multi-ancestry genome-wide association study of AMD and discovered 63 loci (30 novel). We observe marked cross-ancestry heterogeneity at major risk loci, especially in African-ancestry populations which demonstrate a primary signal in a major histocompatibility complex class II haplotype and reduced risk at the established CFH and ARMS2/HTRA1 loci. Dissecting local ancestry in admixed individuals, we find significantly smaller marginal effect sizes for CFH risk alleles in African ancestry haplotypes. Broadening efforts to include ancestrally distinct populations helped uncover genes and pathways that boost risk in an ancestry-dependent manner and are potential targets for corrective therapies. Multi-ancestry genome-wide analyses identify new risk loci for age-related macular degeneration. Ancestry-specific analyses identify distinct effects at major risk loci, including smaller effect sizes for CFH risk alleles in haplotypes of African ancestry.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2659-2671"},"PeriodicalIF":31.7,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758369","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":"A cautionary tale for Alzheimer’s disease GWAS by proxy","authors":"Emil M. Pedersen, Theresa Wimberley, Bjarni J. Vilhjálmsson","doi":"10.1038/s41588-024-02023-y","DOIUrl":"10.1038/s41588-024-02023-y","url":null,"abstract":"Using reported parental disease history to decipher the genetics of Alzheimer’s disease may be promising, but this approach is also susceptible to complex selection and information bias that can mislead researchers if not accounted for.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2590-2591"},"PeriodicalIF":31.7,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758508","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":"Single-cell genomics breaks new ground in cell cycle detection","authors":"Qian Du","doi":"10.1038/s41588-024-01987-1","DOIUrl":"10.1038/s41588-024-01987-1","url":null,"abstract":"A novel method for analyzing single-cell genomics enables direct inference of cell cycle and proliferation status, highlighting the diversity of proliferation rates in clonal cancer. This approach opens a new avenue for high-resolution exploration of the role of proliferation in cancer evolution at the single-cell level.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"3-5"},"PeriodicalIF":31.7,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142742586","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":"Characterizing the evolutionary dynamics of cancer proliferation in single-cell clones with SPRINTER","authors":"Olivia Lucas, Sophia Ward, Rija Zaidi, Abigail Bunkum, Alexander M. Frankell, David A. Moore, Mark S. Hill, Wing Kin Liu, Daniele Marinelli, Emilia L. Lim, Sonya Hessey, Cristina Naceur-Lombardelli, Andrew Rowan, Sukhveer Kaur Purewal-Mann, Haoran Zhai, Michelle Dietzen, Boyue Ding, Gary Royle, Samuel Aparicio, TRACERx Consortium, PEACE Consortium, Nicholas McGranahan, Mariam Jamal-Hanjani, Nnennaya Kanu, Charles Swanton, Simone Zaccaria","doi":"10.1038/s41588-024-01989-z","DOIUrl":"10.1038/s41588-024-01989-z","url":null,"abstract":"Proliferation is a key hallmark of cancer, but whether it differs between evolutionarily distinct clones co-existing within a tumor is unknown. We introduce the Single-cell Proliferation Rate Inference in Non-homogeneous Tumors through Evolutionary Routes (SPRINTER) algorithm that uses single-cell whole-genome DNA sequencing data to enable accurate identification and clone assignment of S- and G2-phase cells, as assessed by generating accurate ground truth data. Applied to a newly generated longitudinal, primary-metastasis-matched dataset of 14,994 non-small cell lung cancer cells, SPRINTER revealed widespread clone proliferation heterogeneity, orthogonally supported by Ki-67 staining, nuclei imaging and clinical imaging. We further demonstrated that high-proliferation clones have increased metastatic seeding potential, increased circulating tumor DNA shedding and clone-specific altered replication timing in proliferation- or metastasis-related genes associated with expression changes. Applied to previously generated datasets of 61,914 breast and ovarian cancer cells, SPRINTER revealed increased single-cell rates of different genomic variants and enrichment of proliferation-related gene amplifications in high-proliferation clones. Single-cell Proliferation Rate Inference in Non-homogeneous Tumors through Evolutionary Routes (SPRINTER) allows users to infer proliferation rates of individual clones within a tumor from single-cell DNA sequencing data. Applying SPRINTER to human tumor datasets highlighted a link between proliferation and metastatic potential.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"57 1","pages":"103-114"},"PeriodicalIF":31.7,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41588-024-01989-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142742587","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":"Single-cell analysis dissects heterogeneity of leukemias with complex karyotypes","authors":"","doi":"10.1038/s41588-024-02006-z","DOIUrl":"10.1038/s41588-024-02006-z","url":null,"abstract":"Chromosomal instability plays a crucial part in tumor progression, shaping cancer cell phenotypes and driving treatment resistance. We harnessed two single-cell multiomics methods to characterize the heterogeneity of acute myeloid leukemia with complex karyotype (CK-AML). Our data link genetic, non-genetic and functional heterogeneity and reveal intriguing therapeutic sensitivities.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2608-2609"},"PeriodicalIF":31.7,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142718195","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":"Exploring gene expression in the maturing human brain at the single-cell level","authors":"","doi":"10.1038/s41588-024-01991-5","DOIUrl":"10.1038/s41588-024-01991-5","url":null,"abstract":"Advancements in single-cell analysis technologies are enabling exploration of the intricacies of the human brain at unprecedented resolution. However, most research thus far has focused on the adult brain. Here, these tools are applied to reveal cell-type-specific gene-expression dynamics as the brain grows from childhood to adulthood.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2598-2599"},"PeriodicalIF":31.7,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142718341","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":"Copy number alterations in normal breast tissues revealed by single-cell whole-genome sequencing","authors":"","doi":"10.1038/s41588-024-02018-9","DOIUrl":"10.1038/s41588-024-02018-9","url":null,"abstract":"Using single-cell whole-genome sequencing, we reveal the landscape of copy number alterations in normal breast tissue from both BRCA carriers and wild-type individuals.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2604-2605"},"PeriodicalIF":31.7,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142713097","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":"Estimating uncertainty in reference-based cell type annotation in single-cell genomics","authors":"","doi":"10.1038/s41588-024-01995-1","DOIUrl":"10.1038/s41588-024-01995-1","url":null,"abstract":"PopV is an ensemble method for cell type labeling in single-cell genomics. A Cell Ontology-inspired voting procedure across different algorithms highlights low confidence annotations, thereby guiding human-in-the loop components of the annotation process.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"56 12","pages":"2600-2601"},"PeriodicalIF":31.7,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142713098","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}