bioRxiv - Genomics最新文献

{"title":"EpipwR: Efficient Power Analysis for EWAS with Continuous Outcomes","authors":"Jackson P Barth, Austin W. Reynolds","doi":"10.1101/2024.09.06.611713","DOIUrl":"https://doi.org/10.1101/2024.09.06.611713","url":null,"abstract":"Motivation: Epigenome-wide association studies (EWAS) have emerged as a popular way to investigate the pathophysiology of complex diseases and to assist in bridging the gap between genotypes and phenotypes. Despite the increasing popularity of EWAS, very few tools exist to aid researchers in power estimation and those are limited to case-control studies. The existence of user-friendly tools, expanding power calculation functionality to additional study designs would be a significant aid to researchers planning EWAS. Results: We introduce EpipwR, an open-source R package that can efficiently estimate power for EWAS with continuous outcomes. EpipwR uses a quasi-simulated approach, meaning that data is generated only for CpG sites with methylation associated with the outcome, while p-values are generated directly for those with no association (when necessary). Like existing EWAS power calculators, reference datasets of empirical EWAS are used to guide the data generation process. Two simulation studies show the effect of the selected empirical dataset on the generated correlations and the relative speed of EpipwR compared to similar approaches. Availability and Implementation: The EpipwR R-package is currently available for download at\u0000github.com/jbarth216/EpipwR.","PeriodicalId":501161,"journal":{"name":"bioRxiv - Genomics","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142214112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uncovering Plaque-Glia Niches in Human Alzheimer's Disease Brains Using Spatial Transcriptomics","authors":"Denis R. Avey, Bernard Ng, Ricardo A. Vialle, Nicola A. Kearns, Katia de Paiva Lopes, Artemis Iatrou, Sashini De Tissera, Himanshu Vyas, Devin M. Saunders, Daniel J. Flood, Jishu Xu, Shinya Tasaki, Chris Gaiteri, David A Bennett, Yanling Wang","doi":"10.1101/2024.09.05.611566","DOIUrl":"https://doi.org/10.1101/2024.09.05.611566","url":null,"abstract":"Amyloid-beta (Abeta) plaques and surrounding glial activation are prominent histopathological hallmarks of Alzheimer's Disease (AD). However, it is unclear how Abeta plaques interact with surrounding glial cells in the human brain. Here, we applied spatial transcriptomics (ST) and immunohistochemistry (IHC) for Abeta, GFAP, and IBA1 to acquire data from 258,987 ST spots within 78 postmortem brain sections of 21 individuals. By coupling ST and adjacent-section IHC, we showed that low Abeta spots exhibit transcriptomic profiles indicative of greater neuronal loss than high Abeta spots, and high-glia spots present transcriptomic changes indicative of more significant inflammation and neurodegeneration. Furthermore, we observed that this ST glial response bears signatures of reported mouse gene modules of plaque-induced genes (PIG), oligodendrocyte (OLIG) response, disease-associated microglia (DAM), and disease-associated astrocytes (DAA), as well as different microglia (MG) states identified in human AD brains, indicating that multiple glial cell states arise around plaques and contribute to local immune response. We then validated the observed effects of Abeta on cell apoptosis and plaque-surrounding glia on inflammation and synaptic loss using IHC. In addition, transcriptomic changes of iPSC-derived microglia-like cells upon short-interval Abeta treatment mimic the ST glial response and mirror the reported activated MG states. Our results demonstrate an exacerbation of synaptic and neuronal loss in low-Aβ or high-glia areas, indicating that microglia response to Abeta-oligomers likely initiates glial activation in plaque-glia niches. Our study lays the groundwork for future pathology genomics studies, opening the door for investigating pathological heterogeneity and causal effects in neurodegenerative diseases.","PeriodicalId":501161,"journal":{"name":"bioRxiv - Genomics","volume":"59 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142214114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A near-complete genome assembly of the bearded dragon Pogona vitticeps provides insights into the origin of Pogona sex chromosomes","authors":"Qunfei Guo, Youliang Pan, Wei Dai, Fei Guo, Tao Zeng, Wanyi Chen, Yaping Mi, Yanshu Zhang, Shuaizhen Shi, Wei Jiang, Huimin Cai, Beiying Wu, Yang Zhou, Ying Wang, Chentao Yang, Xiao Shi, Xu Yan, Junyi Chen, Chongyang Cai, Jingnan Yang, Xun Xu, Ying Gu, Yuliang Dong, Qiye Li","doi":"10.1101/2024.09.05.611321","DOIUrl":"https://doi.org/10.1101/2024.09.05.611321","url":null,"abstract":"Background: The agamid dragon lizard Pogona vitticeps is one of the most popular domesticated reptiles to be kept as pets worldwide. The capacity of breeding in captivity also makes it emerging as a model species for a range of scientific research, especially for the studies of sex chromosome origin and sex determination mechanisms.\u0000Results: By leveraging the CycloneSEQ and DNBSEQ sequencing technologies, we conducted whole genome and long-range sequencing for a captive-bred ZZ male to construct a chromosome-scale reference genome for P. vitticeps. The new reference genome is ~1.8 Gb in length, with a contig N50 of 202.5 Mb and all contigs anchored onto 16 chromosomes. Genome annotation assisted by long-read RNA sequencing greatly expanded the P. vitticeps lncRNA catalog. With the chromosome-scale genome, we were able to characterize the whole Z sex chromosome for the first time. We found that over 80% of the Z chromosome remains as pseudo-autosomal region (PAR) where recombination is not suppressed. The sexually differentiated region (SDR) is small and occupied mostly by transposons, yet it aggregates genes involved in male development, such as AMH, AMHR2 and BMPR1A. Finally, by tracking the evolutionary origin and developmental expression of the SDR genes, we proposed a model for the origin of P. vitticeps sex chromosomes which considered the Z-linked AMH as the master sex-determining gene.\u0000Conclusions: Our study provides novel insights into the sex chromosome origin and sex determination of this model lizard. The near-complete P. vitticeps reference genome will also benefit future study of amniote evolution and may facilitate genome-assisted breeding.","PeriodicalId":501161,"journal":{"name":"bioRxiv - Genomics","volume":"318 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142226994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Greenland shark (Somniosus microcephalus) genome provides insights into extreme longevity","authors":"Arne Sahm, Alexander Cherkasov, Hequn Liu, Danila Voronov, Kanstantsin Siniuk, Robert Schwarz, Oliver Ohlenschlaeger, Silke Foerste, Martin Bens, Marco Groth, Ivonne Goerlich, Sonia Paturej, Sven Klages, Bjoern Braendl, Jesper Olsen, Peter Bushnell, Amalie Bech Poulsen, Sara Ferrando, Fulvio Garibaldi, Davide Lorenzo Drago, Eva Terzibasi Tozzini, Franz-Josef Mueller, Martin Fischer, Helene Kretzmer, Paolo Domenici, John Fleng Steffensen, Alessandro Cellerino, Steve Hoffmann","doi":"10.1101/2024.09.09.611499","DOIUrl":"https://doi.org/10.1101/2024.09.09.611499","url":null,"abstract":"The Greenland shark (Somniosus microcephalus) is the longest-lived vertebrate known, with an estimated lifespan of ~ 400 years. Here, we present a chromosome-level assembly of the 6.45 Gb Greenland shark, rendering it one of the largest non-tetrapod genomes sequenced so far. Expansion of the genome is mostly accounted for by a substantial expansion of transposable elements. Using public shark genomes as a comparison, we found that genes specifically duplicated in the Greenland shark form a functionally connected network enriched for DNA repair function. Furthermore, we identified a unique insertion in the conserved C-terminal region of the key tumor suppressor p53. We also provide a public browser to explore its genome.","PeriodicalId":501161,"journal":{"name":"bioRxiv - Genomics","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142214111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic changes are varied across congeneric species pairs","authors":"Warren R Francis, Sergio Vargas, Gert Woerheide","doi":"10.1101/2024.09.05.611358","DOIUrl":"https://doi.org/10.1101/2024.09.05.611358","url":null,"abstract":"Synteny, the shared arrangement of genes on chromosomes between related species, is a marker of shared ancestry, and synteny-breaking events can result in genomic incompatibilities between populations and ultimately lead to speciation events. Despite its pivotal role as a driver of speciation, the role of synteny breaks on speciation is poorly studied due to a lack of chromosome-level genome assemblies for a taxonomically broad sample of organisms. Here, using 22 congeneric animal genome pairs, we find a link between protein identity, microsynteny, and macrosynteny, but no evidence for a universal path of genomic change during divergence. We observed varied trajectories of synteny conservation relative to protein identity in non-model organisms, with many species pairs showing no karyotypic changes and others displaying large genomic rearrangements. This contrasts with previous studies on model organisms and indicates that the genomic changes preceding or resulting from speciation are likely very contextual between clades.","PeriodicalId":501161,"journal":{"name":"bioRxiv - Genomics","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142213916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single cell genome and epigenome co-profiling reveals hardwiring and plasticity in breast cancer","authors":"Kaile Wang, Yun Yan, Heba Elgamal, Jianzhuo Li, Chenling Tang, Shanshan Bai, Zhenna Xiao, Emi Sei, Yiyun Lin, Junke Wang, Jessica Montalvan, Chandandeep Nagi, Alastair Thompson, Nicholas Navin","doi":"10.1101/2024.09.06.611519","DOIUrl":"https://doi.org/10.1101/2024.09.06.611519","url":null,"abstract":"Understanding the impact of genetic alterations on epigenomic phenotypes during breast cancer progression is challenging with unimodal measurements. Here, we report wellDA-seq, the first high-genomic resolution, high-throughput method that can simultaneously measure the whole genome and chromatin accessibility profiles of thousands of single cells. Using wellDA-seq, we profiled 22,123 single cells from 2 normal and 9 tumors breast tissues. By directly mapping the epigenomic phenotypes to genetic lineages across cancer subclones, we found evidence of both genetic hardwiring and epigenetic plasticity. In 6 estrogen-receptor positive breast cancers, we directly identified the ancestral cancer cells, and found that their epithelial cell-of-origin was Luminal Hormone Responsive cells. We also identified cell types with copy number aberrations (CNA) in normal breast tissues and discovered non-epithelial cell types in the microenvironment with CNAs in breast cancers. These data provide insights into the complex relationship between genetic alterations and epigenomic phenotypes during breast tumor evolution.","PeriodicalId":501161,"journal":{"name":"bioRxiv - Genomics","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142226991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A blended genome and exome sequencing method captures genetic variation in an unbiased, high-quality, and cost-effective manner","authors":"Toni A Boltz, Benjamin B Chu, Calwing Liao, Julia M Sealock, Robert Ye, Lerato Majara, Jack M Fu, Susan Service, Lingyu Zhan, Sarah E Medland, Sinead B Chapman, Simone Rubinacci, Matthew DeFelice, Jonna L Grimsby, Tamrat Abebe, Melkam Alemayehu, Fred K Ashaba, Elizabeth G Atkinson, Tim Bigdeli, Amanda B Bradway, Harrison Brand, Lori B Chibnik, Abebaw Fekadu, Michael Gatzen, Bizu Gelaye, Stella Gichuru, Marissa L Gildea, Toni C Hill, Hailiang Huang, Kalyn M Hubbard, Wilfred E. Injera, Roxanne James, Moses Joloba, Christopher Kachulis, Phillip R Kalmbach, Rogers Kamulegeya, Gabriel Kigen, Soyeon Kim, Nastassja Koen, Edith K. Kwobah, Joseph Kyebuzibwa, Seungmo Lee, Niall J Lennon, Penelope A Lind, Esteban A Lopera-Maya, Johnstone Makale, Serghei Mangul, Justin McMahon, Pierre Mowlem, Henry Musinguzi, Rehema M. Mwema, Noeline Nakasujja, Carter P Newman, Lethukuthula L Nkambule, Conor R O'Neil, Ana Maria Olivares, Catherine M. Olsen, Linnet Ongeri, Sophie J Parsa, Adele Pretorius, Raj Ramesar, Faye L Reagan, Chiara Sabatti, Jacquelyn A Schneider, Welelta Shiferaw, Anne Stevenson, Erik Stricker, Rocky E. Stroud, Jessie Tang, David Whiteman, Mary T Yohannes, Mingrui Yu, Kai Yuan, NeuroGAP Psychosis, Dickens Akena, Lukoye Atwoli, Symon M. Kariuki, Karestan C. Koenen, Charles R. J. C. Newton, Dan J. Stein, Solomon Teferra, Zukiswa Zingela, Carlos N Pato, Michele T Pato, Carlos Lopez-Jaramillo, Nelson Freimer, Roel A Ophoff, Loes M Olde Loohuis, Michael E Talkowski, Benjamin M Neale, Daniel P Howrigan, Alicia R Martin","doi":"10.1101/2024.09.06.611689","DOIUrl":"https://doi.org/10.1101/2024.09.06.611689","url":null,"abstract":"We deployed the Blended Genome Exome (BGE), a DNA library blending approach that generates low pass whole genome (1-4x mean depth) and deep whole exome (30-40x mean depth) data in a single sequencing run. This technology is cost-effective, empowers most genomic discoveries possible with deep whole genome sequencing, and provides an unbiased method to capture the diversity of common SNP variation across the globe. To evaluate this new technology at scale, we applied BGE to sequence >53,000 samples from the Populations Underrepresented in Mental Illness Associations Studies (PUMAS) Project, which included participants across African, African American, and Latin American populations. We evaluated the accuracy of BGE imputed genotypes against raw genotype calls from the Illumina Global Screening Array. All PUMAS cohorts had R2 concordance >=95% among SNPs with MAF>=1%, and never fell below >=90% R2 for SNPs with MAF<1%. Furthermore, concordance rates among local ancestries within two recently admixed cohorts were consistent among SNPs with MAF>=1%, with only minor deviations in SNPs with MAF<1%. We also benchmarked the discovery capacity of BGE to access protein-coding copy number variants (CNVs) against deep whole genome data, finding that deletions and duplications spanning at least 3 exons had a positive predicted value of ~90%. Our results demonstrate BGE scalability and efficacy in capturing SNPs, indels, and CNVs in the human genome at 28% of the cost of deep whole-genome sequencing. BGE is poised to enhance access to genomic testing and empower genomic discoveries, particularly in underrepresented populations.","PeriodicalId":501161,"journal":{"name":"bioRxiv - Genomics","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142214120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GENETIC DIVERSITY OF T. B. RHODESIENSE SERUM RESISTANCE ASSOCIATED GENE IN MALAWIAN ISOLATES","authors":"Peter Nambala, Calorine Claucus, Harry Noyes, Annette MacLeod, Joyce Namulondo, Oscar Nyangiri, Janelisa Musaya, Enock Matovu, Pius Vincent Alibu, Barbara Nerima, Priscilla Chammudzi, Julius Mulindwa","doi":"10.1101/2024.09.07.611819","DOIUrl":"https://doi.org/10.1101/2024.09.07.611819","url":null,"abstract":"Background: Human African Trypanosomiasis (HAT) is a health burden in most remote areas of Sub-Saharan Africa. Only 2 species of the Trypanosome parasites, namely, T. b. rhodesiense and T. b. gambiense can establish infection in humans whereas other trypanosome parasites are lysed by human serum APOL-1 protein. The mechanism of T. b. gambiense resistance to APOL-1 activity is complex and involves several parasite factors. On the other hand, T. b. rhodesiense evades the lytic activity of APOL-1 by intracellular expression of a Serum Resistance Associated (SRA) gene that binds to APOL-1 when uptaken by the parasite thereby disabling APOL-1 from causing cellular membrane rupture. APOL-1 has 2 variants, namely, APOL-1 G1 and APOL-1 G2 with the later having mutations on the SRA binding sites which restores APOL-1 lytic activity in parasite lysis assays. This phenomenon remains elusive in clinical setting as limited data is available. In the present study we investigated the genetic diversity of T. b. rhodesiense SRA gene and APOL-1 genotypes in Malawian r-HAT clinical phenotypes.\u0000Methods: T. b. rhodesiense SRA gene from Malawi endemic HAT samples (n= 77) as well as from Zambia and Uganda (n= 13) was amplified by PCR and PCR products were commercially sequenced. APOL-1 variants were identified by restriction fragment length polymorphism (RFLP) after a PCR amplification (n= 61).\u0000Results and conclusion: Sequencing data revealed a heterozygosity of the SRA gene within Malawi T. b. rhodesiense isolates. Malawian SRA gene was genetically different from some isolates in Uganda and Zambia. Contrary to the current understanding that APOL-1 G2 variants are immune to T. b. rhodesiense infection, severe cases of r-HAT in G2 individuals were identified. This study has brought new insight in understanding the determinants of r-HAT severity.","PeriodicalId":501161,"journal":{"name":"bioRxiv - Genomics","volume":"78 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142213864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic diversity and demographic history of the largest remaining migratory population of blue wildebeest (Connochaetes taurinus taurinus) in southern Africa","authors":"Stephanie Szarmach, Katherine C Teeter, Jassiel M’soka, Egil Dröge, Hellen Ndakala, Clive Chifunte, Matthew S Becker, Alec R Lindsay","doi":"10.1101/2024.09.05.611351","DOIUrl":"https://doi.org/10.1101/2024.09.05.611351","url":null,"abstract":"The blue wildebeest (Connochaetes taurinus taurinus) is a keystone species in the savannahs of southern Africa, where it maintains shortgrass plains and serves as an important prey source for large carnivores. Despite being the second largest migratory wildebeest population, the wildebeest of the Greater Liuwa Ecosystem (GLE) of western Zambia have remained largely unstudied, until recently. While studies have increased understanding of recent demography, migration, and population limiting factors, the level of genetic diversity, patterns of gene flow, and long-term demographic history of blue wildebeest in the GLE remains unknown. Most genetic studies of wildebeest have focused on small, heavily-managed populations, rather than large, migratory populations of high conservation significance. We used restriction-site associated DNA sequencing (RAD-seq) to assess genetic diversity, population structure, and demographic history of blue wildebeest in the GLE. Using SNPs from 1,730 loci genotyped across 75 individuals, we found moderate levels of genetic diversity in GLE blue wildebeest (He = 0.210), no evidence of inbreeding (FIS = 0.033), and an effective population size of about one tenth the estimated population size. No genetic population structure was evident within the GLE. Analyses of the site frequency spectrum found signatures of expansion during the Middle Pleistocene followed by population decline in the Late Pleistocene and early Holocene, a pattern previously observed in other African ungulates. These results will supplement field studies in developing effective conservation plans for wildebeest as they face continued and increasing threats of habitat loss, poaching, and other human impacts across their remaining range.","PeriodicalId":501161,"journal":{"name":"bioRxiv - Genomics","volume":"282 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142214115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcription factor networks disproportionately enrich for heritability of blood cell phenotypes","authors":"Jorge Diego Martin-Rufino, Alexis Caulier, Seayoung Lee, Nicole Castano, Emily King, Samantha Joubran, Marcus Jones, Seth R. Goldman, Uma P. Arora, Lara Wahlster, Eric S. Lander, Vijay G. Sankaran","doi":"10.1101/2024.09.09.611392","DOIUrl":"https://doi.org/10.1101/2024.09.09.611392","url":null,"abstract":"Most phenotype-associated genetic variants map to non-coding regulatory regions of the human genome. Moreover, variants associated with blood cell phenotypes are enriched in regulatory regions active during hematopoiesis. To systematically explore the nature of these regions, we developed a highly efficient strategy, Perturb-multiome, that makes it possible to simultaneously profile both chromatin accessibility and gene expression in single cells with CRISPR-mediated perturbation of a range of master transcription factors (TFs). This approach allowed us to examine the connection between TFs, accessible regions, and gene expression across the genome throughout hematopoietic differentiation. We discovered that variants within the TF-sensitive accessible chromatin regions, while representing less than 0.3% of the genome, show a ~100-fold enrichment in heritability across certain blood cell phenotypes; this enrichment is strikingly higher than for other accessible chromatin regions. Our approach facilitates large-scale mechanistic understanding of phenotype-associated genetic variants by connecting key cis-regulatory elements and their target genes within gene regulatory networks.","PeriodicalId":501161,"journal":{"name":"bioRxiv - Genomics","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142214118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}