American journal of human genetics最新文献

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Advancing long-read nanopore genome assembly and accurate variant calling for rare disease detection. 推进用于罕见病检测的长线程纳米孔基因组组装和准确的变异调用。
IF 8.1 1区 生物学
American journal of human genetics Pub Date : 2025-02-06 Epub Date: 2025-01-24 DOI: 10.1016/j.ajhg.2025.01.002
Shloka Negi, Sarah L Stenton, Seth I Berger, Paolo Canigiula, Brandy McNulty, Ivo Violich, Joshua Gardner, Todd Hillaker, Sara M O'Rourke, Melanie C O'Leary, Elizabeth Carbonell, Christina Austin-Tse, Gabrielle Lemire, Jillian Serrano, Brian Mangilog, Grace VanNoy, Mikhail Kolmogorov, Eric Vilain, Anne O'Donnell-Luria, Emmanuèle Délot, Karen H Miga, Jean Monlong, Benedict Paten
{"title":"Advancing long-read nanopore genome assembly and accurate variant calling for rare disease detection.","authors":"Shloka Negi, Sarah L Stenton, Seth I Berger, Paolo Canigiula, Brandy McNulty, Ivo Violich, Joshua Gardner, Todd Hillaker, Sara M O'Rourke, Melanie C O'Leary, Elizabeth Carbonell, Christina Austin-Tse, Gabrielle Lemire, Jillian Serrano, Brian Mangilog, Grace VanNoy, Mikhail Kolmogorov, Eric Vilain, Anne O'Donnell-Luria, Emmanuèle Délot, Karen H Miga, Jean Monlong, Benedict Paten","doi":"10.1016/j.ajhg.2025.01.002","DOIUrl":"10.1016/j.ajhg.2025.01.002","url":null,"abstract":"<p><p>More than 50% of families with suspected rare monogenic diseases remain unsolved after whole-genome analysis by short-read sequencing (SRS). Long-read sequencing (LRS) could help bridge this diagnostic gap by capturing variants inaccessible to SRS, facilitating long-range mapping and phasing and providing haplotype-resolved methylation profiling. To evaluate LRS's additional diagnostic yield, we sequenced a rare-disease cohort of 98 samples from 41 families, using nanopore sequencing, achieving per sample ∼36× average coverage and 32-kb read N50 from a single flow cell. Our Napu pipeline generated assemblies, phased variants, and methylation calls. LRS covered, on average, coding exons in ∼280 genes and ∼5 known Mendelian disease-associated genes that were not covered by SRS. In comparison to SRS, LRS detected additional rare, functionally annotated variants, including structural variants (SVs) and tandem repeats, and completely phased 87% of protein-coding genes. LRS detected additional de novo variants and could be used to distinguish postzygotic mosaic variants from prezygotic de novos. Diagnostic variants were established by LRS in 11 probands, with diverse underlying genetic causes including de novo and compound heterozygous variants, large-scale SVs, and epigenetic modifications. Our study demonstrates LRS's potential to enhance diagnostic yield for rare monogenic diseases, implying utility in future clinical genomics workflows.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"428-449"},"PeriodicalIF":8.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035843","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}
引用次数: 0
Design and implementation of an action plan for justice, equity, diversity, and inclusion within the Clinical Genome Resource. 在临床基因组资源中设计和实施正义、公平、多样性和包容性的行动计划。
IF 8.1 1区 生物学
American journal of human genetics Pub Date : 2025-02-06 Epub Date: 2025-01-09 DOI: 10.1016/j.ajhg.2024.12.009
Alice B Popejoy, Deborah I Ritter, Danielle Azzariti, Jonathan S Berg, Joanna E Bulkley, Mildred Cho, Claudia Gonzaga-Jauregui, Teri E Klein, Daphne O Martschenko, Akinyemi Oni-Orisan, Erin M Ramos, Heidi L Rehm, Erin R Riggs, Matthew W Wright, Michael Yudell, Sharon E Plon, Joannella Morales
{"title":"Design and implementation of an action plan for justice, equity, diversity, and inclusion within the Clinical Genome Resource.","authors":"Alice B Popejoy, Deborah I Ritter, Danielle Azzariti, Jonathan S Berg, Joanna E Bulkley, Mildred Cho, Claudia Gonzaga-Jauregui, Teri E Klein, Daphne O Martschenko, Akinyemi Oni-Orisan, Erin M Ramos, Heidi L Rehm, Erin R Riggs, Matthew W Wright, Michael Yudell, Sharon E Plon, Joannella Morales","doi":"10.1016/j.ajhg.2024.12.009","DOIUrl":"10.1016/j.ajhg.2024.12.009","url":null,"abstract":"<p><p>How might members of a large, multi-institutional research and resource consortium foster justice, equity, diversity, and inclusion as central to its mission, goals, governance, and culture? These four principles, often referred to as JEDI, can be aspirational-but to be operationalized, they must be supported by concrete actions, investments, and a persistent long-term commitment to the principles themselves, which often requires self-reflection and course correction. We present here the iterative design process implemented across the Clinical Genome Resource (ClinGen) that led to the development of an action plan to operationalize JEDI principles across three major domains, with specific deliverables and commitments dedicated to each. Active involvement of consortium leadership, buy-in from its members at all levels, and support from NIH program staff at pivotal stages were essential to the success of this effort. The ClinGen JEDI action plan that resulted from our process is a living document and roadmap whose target goals and deliverables will continue to evolve. Here, we offer a transparent account of how a large, multi-site biomedical research consortium achieved this, as well as the challenges and opportunities we encountered on this first step in our journey toward enacting JEDI principles in our sphere of influence. We hope that others seeking to engage in this work will gain valuable insights from our process, experience, and lessons learned.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"215-223"},"PeriodicalIF":8.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963503","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}
引用次数: 0
Genomic and phenotypic correlates of mosaic loss of chromosome Y in blood. 血液中Y染色体镶嵌缺失的基因组和表型相关性。
IF 8.1 1区 生物学
American journal of human genetics Pub Date : 2025-02-06 Epub Date: 2025-01-13 DOI: 10.1016/j.ajhg.2024.12.014
Yasminka A Jakubek, Xiaolong Ma, Adrienne M Stilp, Fulong Yu, Jason Bacon, Justin W Wong, Francois Aguet, Kristin Ardlie, Donna K Arnett, Kathleen Barnes, Joshua C Bis, Tom Blackwell, Lewis C Becker, Eric Boerwinkle, Russell P Bowler, Matthew J Budoff, April P Carson, Jiawen Chen, Michael H Cho, Josef Coresh, Nancy J Cox, Paul S de Vries, Dawn L DeMeo, David W Fardo, Myriam Fornage, Xiuqing Guo, Michael E Hall, Nancy Heard-Costa, Bertha Hidalgo, Marguerite Ryan Irvin, Andrew D Johnson, Eric Jorgenson, Eimear E Kenny, Michael D Kessler, Daniel Levy, Yun Li, Joao A C Lima, Yongmei Liu, Adam E Locke, Ruth J F Loos, Mitchell J Machiela, Rasika A Mathias, Braxton D Mitchell, Joanne M Murabito, Josyf C Mychaleckyj, Kari E North, Peter Orchard, Stephen C J Parker, Yash Pershad, Patricia A Peyser, Katherine A Pratte, Bruce M Psaty, Laura M Raffield, Susan Redline, Stephen S Rich, Jerome I Rotter, Sanjiv J Shah, Jennifer A Smith, Aaron P Smith, Albert Smith, Margaret A Taub, Hemant K Tiwari, Russell Tracy, Bjoernar Tuftin, Alexander G Bick, Vijay G Sankaran, Alexander P Reiner, Paul Scheet, Paul L Auer
{"title":"Genomic and phenotypic correlates of mosaic loss of chromosome Y in blood.","authors":"Yasminka A Jakubek, Xiaolong Ma, Adrienne M Stilp, Fulong Yu, Jason Bacon, Justin W Wong, Francois Aguet, Kristin Ardlie, Donna K Arnett, Kathleen Barnes, Joshua C Bis, Tom Blackwell, Lewis C Becker, Eric Boerwinkle, Russell P Bowler, Matthew J Budoff, April P Carson, Jiawen Chen, Michael H Cho, Josef Coresh, Nancy J Cox, Paul S de Vries, Dawn L DeMeo, David W Fardo, Myriam Fornage, Xiuqing Guo, Michael E Hall, Nancy Heard-Costa, Bertha Hidalgo, Marguerite Ryan Irvin, Andrew D Johnson, Eric Jorgenson, Eimear E Kenny, Michael D Kessler, Daniel Levy, Yun Li, Joao A C Lima, Yongmei Liu, Adam E Locke, Ruth J F Loos, Mitchell J Machiela, Rasika A Mathias, Braxton D Mitchell, Joanne M Murabito, Josyf C Mychaleckyj, Kari E North, Peter Orchard, Stephen C J Parker, Yash Pershad, Patricia A Peyser, Katherine A Pratte, Bruce M Psaty, Laura M Raffield, Susan Redline, Stephen S Rich, Jerome I Rotter, Sanjiv J Shah, Jennifer A Smith, Aaron P Smith, Albert Smith, Margaret A Taub, Hemant K Tiwari, Russell Tracy, Bjoernar Tuftin, Alexander G Bick, Vijay G Sankaran, Alexander P Reiner, Paul Scheet, Paul L Auer","doi":"10.1016/j.ajhg.2024.12.014","DOIUrl":"10.1016/j.ajhg.2024.12.014","url":null,"abstract":"<p><p>Mosaic loss of Y (mLOY) is the most common somatic chromosomal alteration detected in human blood. The presence of mLOY is associated with altered blood cell counts and increased risk of Alzheimer disease, solid tumors, and other age-related diseases. We sought to gain a better understanding of genetic drivers and associated phenotypes of mLOY through analyses of whole-genome sequencing (WGS) of a large set of genetically diverse males from the Trans-Omics for Precision Medicine (TOPMed) program. We show that haplotype-based calling methods can be used with WGS data to successfully identify mLOY events. This approach enabled us to identify differences in mLOY frequencies across populations defined by genetic similarity, revealing a higher frequency of mLOY in the European (EUR) ancestry group compared to other ancestries. We identify multiple loci associated with mLOY susceptibility and show that subsets of human hematopoietic stem cells are enriched for the activity of mLOY susceptibility variants. Finally, we found that certain alleles on chromosome Y are more likely to be lost than others in detectable mLOY clones.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"276-290"},"PeriodicalIF":8.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982410","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}
引用次数: 0
Multivariate proteome-wide association study to identify causal proteins for Alzheimer disease. 多变量蛋白质组关联研究确定阿尔茨海默病的致病蛋白。
IF 8.1 1区 生物学
American journal of human genetics Pub Date : 2025-02-06 Epub Date: 2025-01-09 DOI: 10.1016/j.ajhg.2024.12.010
Lei Fang, Haoran Xue, Zhaotong Lin, Wei Pan
{"title":"Multivariate proteome-wide association study to identify causal proteins for Alzheimer disease.","authors":"Lei Fang, Haoran Xue, Zhaotong Lin, Wei Pan","doi":"10.1016/j.ajhg.2024.12.010","DOIUrl":"10.1016/j.ajhg.2024.12.010","url":null,"abstract":"<p><p>Alzheimer disease (AD) is a complex and progressive neurodegenerative disorder that accounts for the majority of individuals with dementia. Here, we aim to identify causal plasma proteins for AD, shedding light on the etiology of AD. We utilized the latest large-scale plasma proteomic data from the UK Biobank Pharma Proteomics Project (UKB-PPP) and AD genome-wide association study (GWAS) summary data from the International Genomics of Alzheimer's Project (IGAP). Via a robust univariate instrumental variable (IV) regression method, we identified causal proteins through cis-protein quantitative trait loci (pQTLs) and (both cis- and trans-)pQTLs. To further reduce potential false positives due to high linkage disequilibrium (LD) of some pQTLs and high correlations among some proteins, we developed a robust multivariate IV regression method, called two-stage constrained maximum likelihood (MV-2ScML), to distinguish direct and confounding/mediating effects of proteins; some key features of the method include its robustness to invalid IVs and applicability to GWAS summary data. Our work highlights some differences between using cis-pQTLs and trans-pQTLs and critical values of multivariate analysis for fine-mapping causal proteins, providing insights into plasma protein pathways to AD.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"291-300"},"PeriodicalIF":8.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142963433","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}
引用次数: 0
HiFi long-read genomes for difficult-to-detect, clinically relevant variants. 高保真长读基因组难以检测,临床相关的变异。
IF 8.1 1区 生物学
American journal of human genetics Pub Date : 2025-02-06 Epub Date: 2025-01-13 DOI: 10.1016/j.ajhg.2024.12.013
Wolfram Höps, Marjan M Weiss, Ronny Derks, Jordi Corominas Galbany, Amber den Ouden, Simone van den Heuvel, Raoul Timmermans, Jos Smits, Tom Mokveld, Egor Dolzhenko, Xiao Chen, Arthur van den Wijngaard, Michael A Eberle, Helger G Yntema, Alexander Hoischen, Christian Gilissen, Lisenka E L M Vissers
{"title":"HiFi long-read genomes for difficult-to-detect, clinically relevant variants.","authors":"Wolfram Höps, Marjan M Weiss, Ronny Derks, Jordi Corominas Galbany, Amber den Ouden, Simone van den Heuvel, Raoul Timmermans, Jos Smits, Tom Mokveld, Egor Dolzhenko, Xiao Chen, Arthur van den Wijngaard, Michael A Eberle, Helger G Yntema, Alexander Hoischen, Christian Gilissen, Lisenka E L M Vissers","doi":"10.1016/j.ajhg.2024.12.013","DOIUrl":"10.1016/j.ajhg.2024.12.013","url":null,"abstract":"<p><p>Clinical short-read exome and genome sequencing approaches have positively impacted diagnostic testing for rare diseases. Yet, technical limitations associated with short reads challenge their use for the detection of disease-associated variation in complex regions of the genome. Long-read sequencing (LRS) technologies may overcome these challenges, potentially qualifying as a first-tier test for all rare diseases. To test this hypothesis, we performed LRS (30× high-fidelity [HiFi] genomes) for 100 samples with 145 known clinically relevant germline variants that are challenging to detect using short-read sequencing and necessitate a broad range of complementary test modalities in diagnostic laboratories. We show that relevant variant callers readily re-identified the majority of variants (120/145, 83%), including ∼90% of structural variants, SNVs/insertions or deletions (indels) in homologous sequences, and expansions of short tandem repeats. Another 10% (n = 14) was visually apparent in the data but not automatically detected. Our analyses also identified systematic challenges for the remaining 7% (n = 11) of variants, such as the detection of AG-rich repeat expansions. Titration analysis showed that 90% of all automatically called variants could also be identified using 15-fold coverage. Long-read genomes thus identified 93% of challenging pathogenic variants from our dataset. Even with reduced coverage, the vast majority of variants remained detectable, possibly enhancing cost-effective diagnostic implementation. Most importantly, we show the potential to use a single technology to accurately identify all types of clinically relevant variants.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"450-456"},"PeriodicalIF":8.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982420","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}
引用次数: 0
CIROZ is dispensable in ancestral vertebrates but essential for left-right patterning in humans. CIROZ在祖先脊椎动物中是可有可无的,但在人类的左右模式中却是必不可少的。
IF 8.1 1区 生物学
American journal of human genetics Pub Date : 2025-02-06 Epub Date: 2025-01-02 DOI: 10.1016/j.ajhg.2024.12.006
Emmanuelle Szenker-Ravi, Tim Ott, Amirah Yusof, Maya Chopra, Muznah Khatoo, Beatrice Pak, Wei Xuan Goh, Anja Beckers, Angela F Brady, Lisa J Ewans, Nabila Djaziri, Naif A M Almontashiri, Malak Ali Alghamdi, Essa Alharby, Majed Dasouki, Lindsay Romo, Wen-Hann Tan, Sateesh Maddirevula, Fowzan S Alkuraya, Jessica L Giordano, Anna Alkelai, Ronald J Wapner, Karen Stals, Majid Alfadhel, Abdulrahman Faiz Alswaid, Susanne Bogusch, Anna Schafer-Kosulya, Sebastian Vogel, Philipp Vick, Axel Schweickert, Matthew Wakeling, Anne Moreau de Bellaing, Aisha M Alshamsi, Damien Sanlaville, Hamdi Mbarek, Chadi Saad, Sian Ellard, Frank Eisenhaber, Kornelia Tripolszki, Christian Beetz, Peter Bauer, Achim Gossler, Birgit Eisenhaber, Martin Blum, Patrice Bouvagnet, Aida Bertoli-Avella, Jeanne Amiel, Christopher T Gordon, Bruno Reversade
{"title":"CIROZ is dispensable in ancestral vertebrates but essential for left-right patterning in humans.","authors":"Emmanuelle Szenker-Ravi, Tim Ott, Amirah Yusof, Maya Chopra, Muznah Khatoo, Beatrice Pak, Wei Xuan Goh, Anja Beckers, Angela F Brady, Lisa J Ewans, Nabila Djaziri, Naif A M Almontashiri, Malak Ali Alghamdi, Essa Alharby, Majed Dasouki, Lindsay Romo, Wen-Hann Tan, Sateesh Maddirevula, Fowzan S Alkuraya, Jessica L Giordano, Anna Alkelai, Ronald J Wapner, Karen Stals, Majid Alfadhel, Abdulrahman Faiz Alswaid, Susanne Bogusch, Anna Schafer-Kosulya, Sebastian Vogel, Philipp Vick, Axel Schweickert, Matthew Wakeling, Anne Moreau de Bellaing, Aisha M Alshamsi, Damien Sanlaville, Hamdi Mbarek, Chadi Saad, Sian Ellard, Frank Eisenhaber, Kornelia Tripolszki, Christian Beetz, Peter Bauer, Achim Gossler, Birgit Eisenhaber, Martin Blum, Patrice Bouvagnet, Aida Bertoli-Avella, Jeanne Amiel, Christopher T Gordon, Bruno Reversade","doi":"10.1016/j.ajhg.2024.12.006","DOIUrl":"10.1016/j.ajhg.2024.12.006","url":null,"abstract":"<p><p>Four genes-DAND5, PKD1L1, MMP21, and CIROP-form a genetic module that has specifically evolved in vertebrate species that harbor motile cilia in their left-right organizer (LRO). We find here that CIROZ (previously known as C1orf127) is also specifically expressed in the LRO of mice, frogs, and fish, where it encodes a protein with a signal peptide followed by 3 zona pellucida N domains, consistent with extracellular localization. We report 16 individuals from 10 families with bi-allelic CIROZ inactivation variants, which cause heterotaxy with congenital heart defects. While the knockout of Ciroz in mice also leads to situs anomalies, we unexpectedly find that its targeted inactivation in zebrafish and Xenopus does not lead to observable LR anomalies. Moreover, CIROZ is absent or obsolete in select animals with motile cilia at their LRO, including Carnivora, Atherinomorpha fish, or jawless vertebrates. In summary, this evo-devo study identifies CIROZ as an essential gene for breaking bilateral embryonic symmetry in humans and mice, whereas we witness its contemporary pseudogenization in discrete vertebrate species.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"353-373"},"PeriodicalIF":8.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926203","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}
引用次数: 0
Characterizing substructure via mixture modeling in large-scale genetic summary statistics. 大尺度遗传汇总统计中混合建模表征子结构。
IF 8.1 1区 生物学
American journal of human genetics Pub Date : 2025-02-06 Epub Date: 2025-01-16 DOI: 10.1016/j.ajhg.2024.12.007
Hayley R Stoneman, Adelle M Price, Nikole Scribner Trout, Riley Lamont, Souha Tifour, Nikita Pozdeyev, Kristy Crooks, Meng Lin, Nicholas Rafaels, Christopher R Gignoux, Katie M Marker, Audrey E Hendricks
{"title":"Characterizing substructure via mixture modeling in large-scale genetic summary statistics.","authors":"Hayley R Stoneman, Adelle M Price, Nikole Scribner Trout, Riley Lamont, Souha Tifour, Nikita Pozdeyev, Kristy Crooks, Meng Lin, Nicholas Rafaels, Christopher R Gignoux, Katie M Marker, Audrey E Hendricks","doi":"10.1016/j.ajhg.2024.12.007","DOIUrl":"10.1016/j.ajhg.2024.12.007","url":null,"abstract":"<p><p>Genetic summary data are broadly accessible and highly useful, including for risk prediction, causal inference, fine mapping, and incorporation of external controls. However, collapsing individual-level data into summary data, such as allele frequencies, masks intra- and inter-sample heterogeneity, leading to confounding, reduced power, and bias. Ultimately, unaccounted-for substructure limits summary data usability, especially for understudied or admixed populations. There is a need for methods to enable the harmonization of summary data where the underlying substructure is matched between datasets. Here, we present Summix2, a comprehensive set of methods and software based on a computationally efficient mixture model to enable the harmonization of genetic summary data by estimating and adjusting for substructure. In extensive simulations and application to public data, we show that Summix2 characterizes finer-scale population structure, identifies ascertainment bias, and scans for potential regions of selection due to local substructure deviation. Summix2 increases the robust use of diverse, publicly available summary data, resulting in improved and more equitable research.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"235-253"},"PeriodicalIF":8.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998473","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}
引用次数: 0
Prenatal gene editing for neurodevelopmental diseases: Ethical considerations.
IF 8.1 1区 生物学
American journal of human genetics Pub Date : 2025-02-06 Epub Date: 2025-01-28 DOI: 10.1016/j.ajhg.2025.01.003
Rami M Major, Eric T Juengst
{"title":"Prenatal gene editing for neurodevelopmental diseases: Ethical considerations.","authors":"Rami M Major, Eric T Juengst","doi":"10.1016/j.ajhg.2025.01.003","DOIUrl":"10.1016/j.ajhg.2025.01.003","url":null,"abstract":"<p><p>Neurodevelopmental diseases (NDDs) are notoriously difficult to treat because clinical symptoms stem from developmental processes that begin before birth. Prenatal gene editing could fill the treatment gap for NDDs by targeting and permanently correcting the genetic variants that underlie these pathogenic developmental processes. At the same time, there is a risk of unintended edits to the fetus or the pregnant person that could result in serious adverse consequences that are difficult, if not impossible, to undo. This raises ethical concerns that make the development of prenatal gene editing especially challenging. To date, there are no frameworks for considering the steps necessary for an ethical path forward for prenatal gene editing specifically. The 60-year history of in utero therapy has included the development of frameworks for other therapies that can provide starting points for addressing the unique issues of prenatal gene editing. We identified 12 themes from 17 ethical frameworks, literature, consensus statements, and government reports on prenatal interventions that could set precedents for prenatal gene editing interventions. In considering these alongside current criteria for postnatal gene therapies for NDDs, we discuss a path forward for prenatal gene editing interventions of NDDs.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"201-214"},"PeriodicalIF":8.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063257","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}
引用次数: 0
Population history and admixture of the Fulani people from the Sahel.
IF 8.1 1区 生物学
American journal of human genetics Pub Date : 2025-02-06 DOI: 10.1016/j.ajhg.2024.12.015
Cesar A Fortes-Lima, Mame Y Diallo, Václav Janoušek, Viktor Černý, Carina M Schlebusch
{"title":"Population history and admixture of the Fulani people from the Sahel.","authors":"Cesar A Fortes-Lima, Mame Y Diallo, Václav Janoušek, Viktor Černý, Carina M Schlebusch","doi":"10.1016/j.ajhg.2024.12.015","DOIUrl":"10.1016/j.ajhg.2024.12.015","url":null,"abstract":"<p><p>The Fulani people, one of the most important pastoralist groups in sub-Saharan Africa, are still largely underrepresented in population genomic research. They speak a Niger-Congo language called Fulfulde or Pulaar and live in scattered locations across the Sahel/Savannah belt, from the Atlantic Ocean to Lake Chad. According to historical records, their ancestors spread from Futa Toro in the Middle Senegal Valley to Futa-Jallon in Guinea and then eastward into the Sahel belt over the past 1,500 years. However, the earlier history of this traditionally pastoral population has not been well studied. To uncover the genetic structure and ancestry of this widespread population, we gathered genome-wide genotype data from 460 individuals across 18 local Fulani populations, along with comparative data from both modern and ancient worldwide populations. This represents a comprehensive geographically wide-scaled genome-wide study of the Fulani. We revealed a genetic component closely associated with all local Fulani populations, suggesting a shared ancestral component possibly linked to the beginning of African pastoralism in the Green Sahara. Comparison to ancient DNA results also identified the presence of an ancient Iberomaurusian-associated component across all Fulani groups, providing additional insights into their deep genetic history. Additionally, our genetic data indicate a later Fulani expansion from the western to the eastern Sahel, characterized by a clinal pattern and admixture with several other African populations north of the equator.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 2","pages":"261-275"},"PeriodicalIF":8.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370136","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}
引用次数: 0
Functional characterization of eQTLs and asthma risk loci with scATAC-seq across immune cell types and contexts. 利用scATAC-seq分析免疫细胞类型和环境中eqtl和哮喘风险位点的功能特征
IF 8.1 1区 生物学
American journal of human genetics Pub Date : 2025-02-06 Epub Date: 2025-01-14 DOI: 10.1016/j.ajhg.2024.12.017
Julong Wei, Justyna A Resztak, Ali Ranjbaran, Adnan Alazizi, Henriette E Mair-Meijers, Richard B Slatcher, Samuele Zilioli, Xiaoquan Wen, Francesca Luca, Roger Pique-Regi
{"title":"Functional characterization of eQTLs and asthma risk loci with scATAC-seq across immune cell types and contexts.","authors":"Julong Wei, Justyna A Resztak, Ali Ranjbaran, Adnan Alazizi, Henriette E Mair-Meijers, Richard B Slatcher, Samuele Zilioli, Xiaoquan Wen, Francesca Luca, Roger Pique-Regi","doi":"10.1016/j.ajhg.2024.12.017","DOIUrl":"10.1016/j.ajhg.2024.12.017","url":null,"abstract":"<p><p>cis-regulatory elements (CREs) control gene transcription dynamics across cell types and in response to the environment. In asthma, multiple immune cell types play an important role in the inflammatory process. Genetic variants in CREs can also affect gene expression response dynamics and contribute to asthma risk. However, the regulatory mechanisms underlying control of transcriptional dynamics across different environmental contexts and cell types at single-cell resolution remain to be elucidated. To resolve this question, we performed single-cell ATAC-seq (scATAC-seq) in peripheral blood mononuclear cells (PBMCs) from 16 children with asthma. PBMCs were activated with phytohemagglutinin (PHA) or lipopolysaccharide (LPS) and treated with dexamethasone (DEX), an anti-inflammatory glucocorticoid. We analyzed changes in chromatin accessibility, measured transcription factor motif activity, and identified treatment- and cell-type-specific transcription factors that drive changes in both gene expression mean and variability. We observed a strong positive linear dependence between motif response and their target gene expression changes but a negative relationship with changes in target gene expression variability. This result suggests that an increase of transcription factor binding tightens the variability of gene expression around the mean. We then annotated genetic variants in chromatin accessibility peaks and response motifs, followed by computational fine-mapping of expression quantitative trait loci (eQTL) from a pediatric asthma cohort. We found that eQTLs were 5-fold enriched in peaks with response motifs and refined the credible set for 410 asthma risk genes, with 191 having the causal variant in response motifs. In conclusion, scATAC-seq enhances the understanding of molecular mechanisms for asthma risk variants mediated by gene expression.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"301-317"},"PeriodicalIF":8.1,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998477","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}
引用次数: 0
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