Cell genomics最新文献_第9页

Topologically associating domains define the impact of de novo promoter variants on autism spectrum disorder risk. 拓扑关联域确定了新启动子变异对自闭症谱系障碍风险的影响。

Cell genomics Pub Date : 2024-02-14 Epub Date: 2024-01-26 DOI: 10.1016/j.xgen.2024.100488

Takumi Nakamura, Junko Ueda, Shota Mizuno, Kurara Honda, An-A Kazuno, Hirona Yamamoto, Tomonori Hara, Atsushi Takata

{"title":"Topologically associating domains define the impact of de novo promoter variants on autism spectrum disorder risk.","authors":"Takumi Nakamura, Junko Ueda, Shota Mizuno, Kurara Honda, An-A Kazuno, Hirona Yamamoto, Tomonori Hara, Atsushi Takata","doi":"10.1016/j.xgen.2024.100488","DOIUrl":"10.1016/j.xgen.2024.100488","url":null,"abstract":"Whole-genome sequencing (WGS) studies of autism spectrum disorder (ASD) have demonstrated the roles of rare promoter de novo variants (DNVs). However, most promoter DNVs in ASD are not located immediately upstream of known ASD genes. In this study analyzing WGS data of 5,044 ASD probands, 4,095 unaffected siblings, and their parents, we show that promoter DNVs within topologically associating domains (TADs) containing ASD genes are significantly and specifically associated with ASD. An analysis considering TADs as functional units identified specific TADs enriched for promoter DNVs in ASD and indicated that common variants in these regions also confer ASD heritability. Experimental validation using human induced pluripotent stem cells (iPSCs) showed that likely deleterious promoter DNVs in ASD can influence multiple genes within the same TAD, resulting in overall dysregulation of ASD-associated genes. These results highlight the importance of TADs and gene-regulatory mechanisms in better understanding the genetic architecture of ASD.","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10879036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139572416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Multiplex single-cell chemical genomics reveals the kinase dependence of the response to targeted therapy. 多重单细胞化学基因组学揭示了靶向治疗反应的激酶依赖性。

Cell genomics Pub Date : 2024-02-14 Epub Date: 2024-01-25 DOI: 10.1016/j.xgen.2023.100487

José L McFaline-Figueroa, Sanjay Srivatsan, Andrew J Hill, Molly Gasperini, Dana L Jackson, Lauren Saunders, Silvia Domcke, Samuel G Regalado, Paul Lazarchuck, Sarai Alvarez, Raymond J Monnat, Jay Shendure, Cole Trapnell

{"title":"Multiplex single-cell chemical genomics reveals the kinase dependence of the response to targeted therapy.","authors":"José L McFaline-Figueroa, Sanjay Srivatsan, Andrew J Hill, Molly Gasperini, Dana L Jackson, Lauren Saunders, Silvia Domcke, Samuel G Regalado, Paul Lazarchuck, Sarai Alvarez, Raymond J Monnat, Jay Shendure, Cole Trapnell","doi":"10.1016/j.xgen.2023.100487","DOIUrl":"10.1016/j.xgen.2023.100487","url":null,"abstract":"Chemical genetic screens are a powerful tool for exploring how cancer cells' response to drugs is shaped by their mutations, yet they lack a molecular view of the contribution of individual genes to the response to exposure. Here, we present sci-Plex-Gene-by-Environment (sci-Plex-GxE), a platform for combined single-cell genetic and chemical screening at scale. We highlight the advantages of large-scale, unbiased screening by defining the contribution of each of 522 human kinases to the response of glioblastoma to different drugs designed to abrogate signaling from the receptor tyrosine kinase pathway. In total, we probed 14,121 gene-by-environment combinations across 1,052,205 single-cell transcriptomes. We identify an expression signature characteristic of compensatory adaptive signaling regulated in a MEK/MAPK-dependent manner. Further analyses aimed at preventing adaptation revealed promising combination therapies, including dual MEK and CDC7/CDK9 or nuclear factor κB (NF-κB) inhibitors, as potent means of preventing transcriptional adaptation of glioblastoma to targeted therapy.","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10879025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139567682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Every repeat is unique: Exploring the genomic impact of human L1 retrotransposons at locus-specific resolution. 每个重复都是独一无二的以特定位点的分辨率探索人类 L1 逆转座子的基因组影响。

Cell genomics Pub Date : 2024-02-14 DOI: 10.1016/j.xgen.2024.100504

Stephanie Workman, Sandra R Richardson

引用次数: 0

Quantitative and qualitative mutational impact of ionizing radiation on normal cells. 电离辐射对正常细胞突变的定量和定性影响。

Cell genomics Pub Date : 2024-02-14 DOI: 10.1016/j.xgen.2024.100499

Jeonghwan Youk, Hyun Woo Kwon, Joonoh Lim, Eunji Kim, Taewoo Kim, Ryul Kim, Seongyeol Park, Kijong Yi, Chang Hyun Nam, Sara Jeon, Yohan An, Jinwook Choi, Hyelin Na, Eon-Seok Lee, Youngwon Cho, Dong-Wook Min, HyoJin Kim, Yeong-Rok Kang, Si Ho Choi, Min Ji Bae, Chang Geun Lee, Joon-Goon Kim, Young Seo Kim, Tosol Yu, Won-Chul Lee, Jong-Yeon Shin, Dong Soo Lee, Tae-You Kim, Taeyun Ku, Su Yeon Kim, Joo-Hyeon Lee, Bon-Kyoung Koo, Hyunsook Lee, On Vox Yi, Eon Chul Han, Ji Hyun Chang, Kyung Su Kim, Tae Gen Son, Young Seok Ju

{"title":"Quantitative and qualitative mutational impact of ionizing radiation on normal cells.","authors":"Jeonghwan Youk, Hyun Woo Kwon, Joonoh Lim, Eunji Kim, Taewoo Kim, Ryul Kim, Seongyeol Park, Kijong Yi, Chang Hyun Nam, Sara Jeon, Yohan An, Jinwook Choi, Hyelin Na, Eon-Seok Lee, Youngwon Cho, Dong-Wook Min, HyoJin Kim, Yeong-Rok Kang, Si Ho Choi, Min Ji Bae, Chang Geun Lee, Joon-Goon Kim, Young Seo Kim, Tosol Yu, Won-Chul Lee, Jong-Yeon Shin, Dong Soo Lee, Tae-You Kim, Taeyun Ku, Su Yeon Kim, Joo-Hyeon Lee, Bon-Kyoung Koo, Hyunsook Lee, On Vox Yi, Eon Chul Han, Ji Hyun Chang, Kyung Su Kim, Tae Gen Son, Young Seok Ju","doi":"10.1016/j.xgen.2024.100499","DOIUrl":"10.1016/j.xgen.2024.100499","url":null,"abstract":"The comprehensive genomic impact of ionizing radiation (IR), a carcinogen, on healthy somatic cells remains unclear. Using large-scale whole-genome sequencing (WGS) of clones expanded from irradiated murine and human single cells, we revealed that IR induces a characteristic spectrum of short insertions or deletions (indels) and structural variations (SVs), including balanced inversions, translocations, composite SVs (deletion-insertion, deletion-inversion, and deletion-translocation composites), and complex genomic rearrangements (CGRs), including chromoplexy, chromothripsis, and SV by breakage-fusion-bridge cycles. Our findings suggest that 1 Gy IR exposure causes an average of 2.33 mutational events per Gb genome, comprising 2.15 indels, 0.17 SVs, and 0.01 CGRs, despite a high level of inter-cellular stochasticity. The mutational burden was dependent on total irradiation dose, regardless of dose rate or cell type. The findings were further validated in IR-induced secondary cancers and single cells without clonalization. Overall, our study highlights a comprehensive and clear picture of IR effects on normal mammalian genomes.","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10879144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139742848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Advancing equity in human genomics through tissue-specific multi-ancestry molecular data. 通过组织特异性多基因组分子数据促进人类基因组学的公平性。

Cell genomics Pub Date : 2024-02-14 Epub Date: 2024-01-24 DOI: 10.1016/j.xgen.2023.100485

Ana Luiza Arruda, Andrew P Morris, Eleftheria Zeggini

引用次数: 0

Karyotypic stasis and swarming influenced the evolution of viral tolerance in a species-rich bat radiation. 核型停滞和蜂群影响了物种丰富的蝙蝠辐射中病毒耐受性的进化。

Cell genomics Pub Date : 2024-02-14 Epub Date: 2024-01-17 DOI: 10.1016/j.xgen.2023.100482

Nicole M Foley, Andrew J Harris, Kevin R Bredemeyer, Manuel Ruedi, Sebastien J Puechmaille, Emma C Teeling, Michael F Criscitiello, William J Murphy

{"title":"Karyotypic stasis and swarming influenced the evolution of viral tolerance in a species-rich bat radiation.","authors":"Nicole M Foley, Andrew J Harris, Kevin R Bredemeyer, Manuel Ruedi, Sebastien J Puechmaille, Emma C Teeling, Michael F Criscitiello, William J Murphy","doi":"10.1016/j.xgen.2023.100482","DOIUrl":"10.1016/j.xgen.2023.100482","url":null,"abstract":"The emergence of COVID-19 and severe acute respiratory syndrome (SARS) has prioritized understanding bats' viral tolerance. Myotis bats are exceptionally species rich and have evolved viral tolerance. They also exhibit swarming, a cryptic behavior where large, multi-species assemblages gather for mating, which has been hypothesized to promote interspecific hybridization. To resolve the coevolution of genome architecture and their unusual antiviral tolerance, we undertook a phylogenomic analysis of 60 Old World Myotis genomes. We demonstrate an extensive history of introgressive hybridization that has replaced the species phylogeny across 17%-93% of the genome except for pericentromeric regions of macrochromosomes. Introgression tracts were enriched on microchromosome regions containing key antiviral pathway genes overexpressed during viral challenge experiments. Together, these results suggest that the unusual Myotis karyotype may have evolved to selectively position immune-related genes in high recombining genomic regions prone to introgression of divergent alleles, including a diversity of interleukin loci responsible for the release of pro-inflammatory cytokines.","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10879000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139492881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ancestral genome reconstruction enhances transposable element annotation by identifying degenerate integrants. 祖先基因组重建通过识别退化整合子增强了转座元件注释。

Cell genomics Pub Date : 2024-02-14 Epub Date: 2024-01-30 DOI: 10.1016/j.xgen.2024.100497

Wayo Matsushima, Evarist Planet, Didier Trono

引用次数: 0

Trans-regulatory variant network contributes to missing heritability. 跨调控变异网络导致遗传性缺失。

Cell genomics Pub Date : 2024-01-10 DOI: 10.1016/j.xgen.2023.100470

Vanessa Pereira, Elena Kuzmin

引用次数: 0

A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs. 顺式调节因子通过自身免疫性疾病风险 SNPs 调节 ERAP2 的表达。

Cell genomics Pub Date : 2024-01-10 Epub Date: 2023-12-05 DOI: 10.1016/j.xgen.2023.100460

Wouter J Venema, Sanne Hiddingh, Jorg van Loosdregt, John Bowes, Brunilda Balliu, Joke H de Boer, Jeannette Ossewaarde-van Norel, Susan D Thompson, Carl D Langefeld, Aafke de Ligt, Lars T van der Veken, Peter H L Krijger, Wouter de Laat, Jonas J W Kuiper

{"title":"A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs.","authors":"Wouter J Venema, Sanne Hiddingh, Jorg van Loosdregt, John Bowes, Brunilda Balliu, Joke H de Boer, Jeannette Ossewaarde-van Norel, Susan D Thompson, Carl D Langefeld, Aafke de Ligt, Lars T van der Veken, Peter H L Krijger, Wouter de Laat, Jonas J W Kuiper","doi":"10.1016/j.xgen.2023.100460","DOIUrl":"10.1016/j.xgen.2023.100460","url":null,"abstract":"Single-nucleotide polymorphisms (SNPs) near the ERAP2 gene are associated with various autoimmune conditions, as well as protection against lethal infections. Due to high linkage disequilibrium, numerous trait-associated SNPs are correlated with ERAP2 expression; however, their functional mechanisms remain unidentified. We show by reciprocal allelic replacement that ERAP2 expression is directly controlled by the splice region variant rs2248374. However, disease-associated variants in the downstream LNPEP gene promoter are independently associated with ERAP2 expression. Allele-specific conformation capture assays revealed long-range chromatin contacts between the gene promoters of LNPEP and ERAP2 and showed that interactions were stronger in patients carrying the alleles that increase susceptibility to autoimmune diseases. Replacing the SNPs in the LNPEP promoter by reference sequences lowered ERAP2 expression. These findings show that multiple SNPs act in concert to regulate ERAP2 expression and that disease-associated variants can convert a gene promoter region into a potent enhancer of a distal gene.","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10794781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139378924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The human Y and inactive X chromosomes similarly modulate autosomal gene expression. 人类的 Y 染色体和非活性 X 染色体同样会调节常染色体基因的表达。

Cell genomics Pub Date : 2024-01-10 Epub Date: 2023-12-13 DOI: 10.1016/j.xgen.2023.100462

Adrianna K San Roman, Helen Skaletsky, Alexander K Godfrey, Neha V Bokil, Levi Teitz, Isani Singh, Laura V Blanton, Daniel W Bellott, Tatyana Pyntikova, Julian Lange, Natalia Koutseva, Jennifer F Hughes, Laura Brown, Sidaly Phou, Ashley Buscetta, Paul Kruszka, Nicole Banks, Amalia Dutra, Evgenia Pak, Patricia C Lasutschinkow, Colleen Keen, Shanlee M Davis, Angela E Lin, Nicole R Tartaglia, Carole Samango-Sprouse, Maximilian Muenke, David C Page

{"title":"The human Y and inactive X chromosomes similarly modulate autosomal gene expression.","authors":"Adrianna K San Roman, Helen Skaletsky, Alexander K Godfrey, Neha V Bokil, Levi Teitz, Isani Singh, Laura V Blanton, Daniel W Bellott, Tatyana Pyntikova, Julian Lange, Natalia Koutseva, Jennifer F Hughes, Laura Brown, Sidaly Phou, Ashley Buscetta, Paul Kruszka, Nicole Banks, Amalia Dutra, Evgenia Pak, Patricia C Lasutschinkow, Colleen Keen, Shanlee M Davis, Angela E Lin, Nicole R Tartaglia, Carole Samango-Sprouse, Maximilian Muenke, David C Page","doi":"10.1016/j.xgen.2023.100462","DOIUrl":"10.1016/j.xgen.2023.100462","url":null,"abstract":"Somatic cells of human males and females have 45 chromosomes in common, including the \"active\" X chromosome. In males the 46th chromosome is a Y; in females it is an \"inactive\" X (Xi). Through linear modeling of autosomal gene expression in cells from individuals with zero to three Xi and zero to four Y chromosomes, we found that Xi and Y impact autosomal expression broadly and with remarkably similar effects. Studying sex chromosome structural anomalies, promoters of Xi- and Y-responsive genes, and CRISPR inhibition, we traced part of this shared effect to homologous transcription factors-ZFX and ZFY-encoded by Chr X and Y. This demonstrates sex-shared mechanisms by which Xi and Y modulate autosomal expression. Combined with earlier analyses of sex-linked gene expression, our studies show that 21% of all genes expressed in lymphoblastoid cells or fibroblasts change expression significantly in response to Xi or Y chromosomes.","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10794785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139378927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0