Pub Date : 2024-11-18DOI: 10.1038/s41588-024-01971-9
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
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.
{"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}
Pub Date : 2024-11-15DOI: 10.1038/s41588-024-01977-3
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.
{"title":"Intermediate cells with activated JAK/STAT signaling in prostate regeneration and diseases","authors":"","doi":"10.1038/s41588-024-01977-3","DOIUrl":"https://doi.org/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":"20 1","pages":""},"PeriodicalIF":30.8,"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}
Pub Date : 2024-11-15DOI: 10.1038/s41588-024-02012-1
N. William Rayner, Young-Chan Park, Christian Fuchsberger, Andrei Barysenka, Eleftheria Zeggini
Genomics has the potential to revolutionize healthcare, empowering personalized disease management, including precision prevention. Genome-wide association studies (GWAS) have been instrumental in generating new biological insights into complex human diseases1. The power of GWAS can be increased by increasing sample size through meta-analysis, which requires the imputation and analysis of genotypes that may be untyped across some studies. Imputation relies on the availability of phased haplotype reference panels of whole-genome-sequenced individuals2. These are not amenable to sharing with researchers who need to impute their GWAS data, primarily for reasons of data access and security, dataset size, and scale of computing resources required to enable imputation. Imputation servers have, therefore, been developed to provide a solution: researchers upload their genotyped dataset to the imputation server that hosts the reference panels and imputation machinery, where the data are imputed, and then downloaded back to the researchers’ individual local computing environment. There are a number of imputation servers that serve the global community of researchers, including two based in the USA (University of Michigan, https://imputationserver.sph.umich.edu/index.html and TOPMed, https://imputation.biodatacatalyst.nhlbi.nih.gov/), one based in the UK (Wellcome Sanger Institute, https://imputation.sanger.ac.uk/?about=1) and one based at Kiel University in Germany (https://hybridcomputing.ikmb.uni-kiel.de). Here, we have developed a European Union (EU)-based imputation server serving the community at large, based in Munich, Germany (https://imputationserver.helmholtz-munich.de/), to assist users in complying with their General Data Protection Regulation (GDPR) requirements.
The need for EU-based imputation servers arises from restrictions imposed by GDPR law3, a comprehensive data privacy law in the EU. Genetic data are considered a special category of personal data under GDPR, and hence they are subject to strict data sharing rules and safeguards4. Uploading of genotype data to imputation servers not residing within the EU or covered by an adequacy agreement constitutes a breach of GDPR, unless explicitly covered in informed consent forms for the respective study. Here, we introduce the Helmholtz Munich Imputation Server, designed to provide a cost-free genotype imputation service in a GDPR-compliant manner for EU-based researchers, as well as for researchers globally.
{"title":"Toward GDPR compliance with the Helmholtz Munich genotype imputation server","authors":"N. William Rayner, Young-Chan Park, Christian Fuchsberger, Andrei Barysenka, Eleftheria Zeggini","doi":"10.1038/s41588-024-02012-1","DOIUrl":"https://doi.org/10.1038/s41588-024-02012-1","url":null,"abstract":"<p>Genomics has the potential to revolutionize healthcare, empowering personalized disease management, including precision prevention. Genome-wide association studies (GWAS) have been instrumental in generating new biological insights into complex human diseases<sup>1</sup>. The power of GWAS can be increased by increasing sample size through meta-analysis, which requires the imputation and analysis of genotypes that may be untyped across some studies. Imputation relies on the availability of phased haplotype reference panels of whole-genome-sequenced individuals<sup>2</sup>. These are not amenable to sharing with researchers who need to impute their GWAS data, primarily for reasons of data access and security, dataset size, and scale of computing resources required to enable imputation. Imputation servers have, therefore, been developed to provide a solution: researchers upload their genotyped dataset to the imputation server that hosts the reference panels and imputation machinery, where the data are imputed, and then downloaded back to the researchers’ individual local computing environment. There are a number of imputation servers that serve the global community of researchers, including two based in the USA (University of Michigan, https://imputationserver.sph.umich.edu/index.html and TOPMed, https://imputation.biodatacatalyst.nhlbi.nih.gov/), one based in the UK (Wellcome Sanger Institute, https://imputation.sanger.ac.uk/?about=1) and one based at Kiel University in Germany (https://hybridcomputing.ikmb.uni-kiel.de). Here, we have developed a European Union (EU)-based imputation server serving the community at large, based in Munich, Germany (https://imputationserver.helmholtz-munich.de/), to assist users in complying with their General Data Protection Regulation (GDPR) requirements.</p><p>The need for EU-based imputation servers arises from restrictions imposed by GDPR law<sup>3</sup>, a comprehensive data privacy law in the EU. Genetic data are considered a special category of personal data under GDPR, and hence they are subject to strict data sharing rules and safeguards<sup>4</sup>. Uploading of genotype data to imputation servers not residing within the EU or covered by an adequacy agreement constitutes a breach of GDPR, unless explicitly covered in informed consent forms for the respective study. Here, we introduce the Helmholtz Munich Imputation Server, designed to provide a cost-free genotype imputation service in a GDPR-compliant manner for EU-based researchers, as well as for researchers globally.</p>","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"5 1","pages":""},"PeriodicalIF":30.8,"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}
Pub Date : 2023-10-26DOI: 10.1038/s41588-023-01538-0
Gyda Bjornsdottir, Mona A. Chalmer, Lilja Stefansdottir, Astros Th. Skuladottir, Gudmundur Einarsson, Margret Andresdottir, Doruk Beyter, Egil Ferkingstad, Solveig Gretarsdottir, Bjarni V. Halldorsson, Gisli H. Halldorsson, Anna Helgadottir, Hannes Helgason, Grimur Hjorleifsson Eldjarn, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Ingileif Jonsdottir, Kirk U. Knowlton, Lincoln D. Nadauld, Sigrun H. Lund, Olafur Th. Magnusson, Pall Melsted, Kristjan H. S. Moore, Asmundur Oddsson, Pall I. Olason, Asgeir Sigurdsson, Olafur A. Stefansson, Jona Saemundsdottir, Gardar Sveinbjornsson, Vinicius Tragante, Unnur Unnsteinsdottir, G. Bragi Walters, Florian Zink, Linn Rødevand, Ole A. Andreassen, Jannicke Igland, Rolv T. Lie, Jan Haavik, Karina Banasik, Søren Brunak, Maria Didriksen, Mie T. Bruun, Christian Erikstrup, Lisette J. A. Kogelman, Kaspar R. Nielsen, Erik Sørensen, Ole B. Pedersen, Henrik Ullum, DBDS Genetic Consortium, Gisli Masson, Unnur Thorsteinsdottir, Jes Olesen, Petur Ludvigsson, Olafur Thorarensen, Anna Bjornsdottir, Gudrun R. Sigurdardottir, Olafur A. Sveinsson, Sisse R. Ostrowski, Hilma Holm, Daniel F. Gudbjartsson, Gudmar Thorleifsson, Patrick Sulem, Hreinn Stefansson, Thorgeir E. Thorgeirsson, Thomas F. Hansen, Kari Stefansson
Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes. Genome-wide association analyses of migraine and its subtypes identify new susceptibility loci, including rare variants with large effects implicating PRRT2, SCN11A and KCNK5.
{"title":"Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura","authors":"Gyda Bjornsdottir, Mona A. Chalmer, Lilja Stefansdottir, Astros Th. Skuladottir, Gudmundur Einarsson, Margret Andresdottir, Doruk Beyter, Egil Ferkingstad, Solveig Gretarsdottir, Bjarni V. Halldorsson, Gisli H. Halldorsson, Anna Helgadottir, Hannes Helgason, Grimur Hjorleifsson Eldjarn, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Ingileif Jonsdottir, Kirk U. Knowlton, Lincoln D. Nadauld, Sigrun H. Lund, Olafur Th. Magnusson, Pall Melsted, Kristjan H. S. Moore, Asmundur Oddsson, Pall I. Olason, Asgeir Sigurdsson, Olafur A. Stefansson, Jona Saemundsdottir, Gardar Sveinbjornsson, Vinicius Tragante, Unnur Unnsteinsdottir, G. Bragi Walters, Florian Zink, Linn Rødevand, Ole A. Andreassen, Jannicke Igland, Rolv T. Lie, Jan Haavik, Karina Banasik, Søren Brunak, Maria Didriksen, Mie T. Bruun, Christian Erikstrup, Lisette J. A. Kogelman, Kaspar R. Nielsen, Erik Sørensen, Ole B. Pedersen, Henrik Ullum, DBDS Genetic Consortium, Gisli Masson, Unnur Thorsteinsdottir, Jes Olesen, Petur Ludvigsson, Olafur Thorarensen, Anna Bjornsdottir, Gudrun R. Sigurdardottir, Olafur A. Sveinsson, Sisse R. Ostrowski, Hilma Holm, Daniel F. Gudbjartsson, Gudmar Thorleifsson, Patrick Sulem, Hreinn Stefansson, Thorgeir E. Thorgeirsson, Thomas F. Hansen, Kari Stefansson","doi":"10.1038/s41588-023-01538-0","DOIUrl":"10.1038/s41588-023-01538-0","url":null,"abstract":"Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes. Genome-wide association analyses of migraine and its subtypes identify new susceptibility loci, including rare variants with large effects implicating PRRT2, SCN11A and KCNK5.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"55 11","pages":"1843-1853"},"PeriodicalIF":30.8,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10632135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54230234","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}
Pub Date : 2023-10-26DOI: 10.1038/s41588-023-01545-1
Sigurgeir Olafsson, Elke Rodriguez, Andrew R. J. Lawson, Federico Abascal, Axel Rosendahl Huber, Melike Suembuel, Philip H. Jones, Sascha Gerdes, Iñigo Martincorena, Stephan Weidinger, Peter J. Campbell, Carl A. Anderson
Somatic mutations are hypothesized to play a role in many non-neoplastic diseases. We performed whole-exome sequencing of 1,182 microbiopsies dissected from lesional and nonlesional epidermis from 111 patients with psoriasis to search for evidence that somatic mutations in keratinocytes may influence the disease process. Lesional skin remained highly polyclonal, showing no evidence of large-scale spread of clones carrying potentially pathogenic mutations. The mutation rate of keratinocytes was similarly only modestly affected by the disease. We found evidence of positive selection in previously reported driver genes NOTCH1, NOTCH2, TP53, FAT1 and PPM1D and also identified mutations in four genes (GXYLT1, CHEK2, ZFP36L2 and EEF1A1) that we hypothesize are selected for in squamous epithelium irrespective of disease status. Finally, we describe a mutational signature of psoralens—a class of chemicals previously found in some sunscreens and which are used as part of PUVA (psoralens and ultraviolet-A) photochemotherapy treatment for psoriasis. Analysis of the somatic mutations landscape of 111 patients with psoriasis vulgaris shows that the disease is unlikely to be driven by clonal expansions caused by somatic mutations in keratinocytes. A mutational footprint associated with psoralen treatment was observed and characterized.
{"title":"Effects of psoriasis and psoralen exposure on the somatic mutation landscape of the skin","authors":"Sigurgeir Olafsson, Elke Rodriguez, Andrew R. J. Lawson, Federico Abascal, Axel Rosendahl Huber, Melike Suembuel, Philip H. Jones, Sascha Gerdes, Iñigo Martincorena, Stephan Weidinger, Peter J. Campbell, Carl A. Anderson","doi":"10.1038/s41588-023-01545-1","DOIUrl":"10.1038/s41588-023-01545-1","url":null,"abstract":"Somatic mutations are hypothesized to play a role in many non-neoplastic diseases. We performed whole-exome sequencing of 1,182 microbiopsies dissected from lesional and nonlesional epidermis from 111 patients with psoriasis to search for evidence that somatic mutations in keratinocytes may influence the disease process. Lesional skin remained highly polyclonal, showing no evidence of large-scale spread of clones carrying potentially pathogenic mutations. The mutation rate of keratinocytes was similarly only modestly affected by the disease. We found evidence of positive selection in previously reported driver genes NOTCH1, NOTCH2, TP53, FAT1 and PPM1D and also identified mutations in four genes (GXYLT1, CHEK2, ZFP36L2 and EEF1A1) that we hypothesize are selected for in squamous epithelium irrespective of disease status. Finally, we describe a mutational signature of psoralens—a class of chemicals previously found in some sunscreens and which are used as part of PUVA (psoralens and ultraviolet-A) photochemotherapy treatment for psoriasis. Analysis of the somatic mutations landscape of 111 patients with psoriasis vulgaris shows that the disease is unlikely to be driven by clonal expansions caused by somatic mutations in keratinocytes. A mutational footprint associated with psoralen treatment was observed and characterized.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"55 11","pages":"1892-1900"},"PeriodicalIF":30.8,"publicationDate":"2023-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10632143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54230233","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}
Pub Date : 2023-10-23DOI: 10.1038/s41588-023-01552-2
Changuk Chung, Xiaoxu Yang, Joseph G. Gleeson
Brain somatic mosaicism is linked to several neurological disorders and is thought to arise post-zygotically. A study suggests that pre-zygotic aneuploidy followed by post-zygotic partial reversion leads to a recurrent form of brain mosaicism-related epilepsy.
{"title":"Post-zygotic brain mosaicism as a result of partial reversion of pre-zygotic aneuploidy","authors":"Changuk Chung, Xiaoxu Yang, Joseph G. Gleeson","doi":"10.1038/s41588-023-01552-2","DOIUrl":"10.1038/s41588-023-01552-2","url":null,"abstract":"Brain somatic mosaicism is linked to several neurological disorders and is thought to arise post-zygotically. A study suggests that pre-zygotic aneuploidy followed by post-zygotic partial reversion leads to a recurrent form of brain mosaicism-related epilepsy.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"55 11","pages":"1784-1785"},"PeriodicalIF":30.8,"publicationDate":"2023-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49691536","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}
Pub Date : 2023-10-23DOI: 10.1038/s41588-023-01547-z
Katherine E. Miller, Adithe C. Rivaldi, Noriyuki Shinagawa, Sahib Sran, Jason B. Navarro, Jesse J. Westfall, Anthony R. Miller, Ryan D. Roberts, Yassmine Akkari, Rachel Supinger, Mark E. Hester, Mohammad Marhabaie, Meethila Gade, Jinfeng Lu, Olga Rodziyevska, Meenakshi B. Bhattacharjee, Gretchen K. Von Allmen, Edward Yang, Hart G. W. Lidov, Chellamani Harini, Manish N. Shah, Jeffrey Leonard, Jonathan Pindrik, Ammar Shaikhouni, James E. Goldman, Christopher R. Pierson, Diana L. Thomas, Daniel R. Boué, Adam P. Ostendorf, Elaine R. Mardis, Annapurna Poduri, Daniel C. Koboldt, Erin L. Heinzen, Tracy A. Bedrosian
Somatic mosaicism is a known cause of neurological disorders, including developmental brain malformations and epilepsy. Brain mosaicism is traditionally attributed to post-zygotic genetic alterations arising in fetal development. Here we describe post-zygotic rescue of meiotic errors as an alternate origin of brain mosaicism in patients with focal epilepsy who have mosaic chromosome 1q copy number gains. Genomic analysis showed evidence of an extra parentally derived chromosome 1q allele in the resected brain tissue from five of six patients. This copy number gain is observed only in patient brain tissue, but not in blood or buccal cells, and is strongly enriched in astrocytes. Astrocytes carrying chromosome 1q gains exhibit distinct gene expression signatures and hyaline inclusions, supporting a novel genetic association for astrocytic inclusions in epilepsy. Further, these data demonstrate an alternate mechanism of brain chromosomal mosaicism, with parentally derived copy number gain isolated to brain, reflecting rescue in other tissues during development. Mosaic copy number gains arising from an extra parentally derived chromosome 1q allele are found in brain tissue from five individuals with focal epilepsy. These copy number gains are strongly enriched in astrocytes, indicating somatic rescue in other tissues during development.
{"title":"Post-zygotic rescue of meiotic errors causes brain mosaicism and focal epilepsy","authors":"Katherine E. Miller, Adithe C. Rivaldi, Noriyuki Shinagawa, Sahib Sran, Jason B. Navarro, Jesse J. Westfall, Anthony R. Miller, Ryan D. Roberts, Yassmine Akkari, Rachel Supinger, Mark E. Hester, Mohammad Marhabaie, Meethila Gade, Jinfeng Lu, Olga Rodziyevska, Meenakshi B. Bhattacharjee, Gretchen K. Von Allmen, Edward Yang, Hart G. W. Lidov, Chellamani Harini, Manish N. Shah, Jeffrey Leonard, Jonathan Pindrik, Ammar Shaikhouni, James E. Goldman, Christopher R. Pierson, Diana L. Thomas, Daniel R. Boué, Adam P. Ostendorf, Elaine R. Mardis, Annapurna Poduri, Daniel C. Koboldt, Erin L. Heinzen, Tracy A. Bedrosian","doi":"10.1038/s41588-023-01547-z","DOIUrl":"10.1038/s41588-023-01547-z","url":null,"abstract":"Somatic mosaicism is a known cause of neurological disorders, including developmental brain malformations and epilepsy. Brain mosaicism is traditionally attributed to post-zygotic genetic alterations arising in fetal development. Here we describe post-zygotic rescue of meiotic errors as an alternate origin of brain mosaicism in patients with focal epilepsy who have mosaic chromosome 1q copy number gains. Genomic analysis showed evidence of an extra parentally derived chromosome 1q allele in the resected brain tissue from five of six patients. This copy number gain is observed only in patient brain tissue, but not in blood or buccal cells, and is strongly enriched in astrocytes. Astrocytes carrying chromosome 1q gains exhibit distinct gene expression signatures and hyaline inclusions, supporting a novel genetic association for astrocytic inclusions in epilepsy. Further, these data demonstrate an alternate mechanism of brain chromosomal mosaicism, with parentally derived copy number gain isolated to brain, reflecting rescue in other tissues during development. Mosaic copy number gains arising from an extra parentally derived chromosome 1q allele are found in brain tissue from five individuals with focal epilepsy. These copy number gains are strongly enriched in astrocytes, indicating somatic rescue in other tissues during development.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"55 11","pages":"1920-1928"},"PeriodicalIF":30.8,"publicationDate":"2023-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49691537","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}
Pub Date : 2023-10-19DOI: 10.1038/s41588-023-01528-2
Hiroyuki Hirakawa, Longfei Gao, Daniel Naveed Tavakol, Gordana Vunjak-Novakovic, Lei Ding
Hematopoietic stem cells (HSCs) regenerate after myeloablation, a procedure that adversely disrupts the bone marrow and drives leptin receptor-expressing cells, a key niche component, to differentiate extensively into adipocytes. Regeneration of the bone marrow niche is associated with the resolution of adipocytes, but the mechanisms remain poorly understood. Using Plin1-creER knock-in mice, we followed the fate of adipocytes in the regenerating niche in vivo. We found that bone marrow adipocytes were highly dynamic and dedifferentiated to leptin receptor-expressing cells during regeneration after myeloablation. Bone marrow adipocytes could give rise to osteolineage cells after skeletal injury. The cellular fate of steady-state bone marrow adipocytes was also plastic. Deletion of adipose triglyceride lipase (Atgl) from bone marrow stromal cells, including adipocytes, obstructed adipocyte dedifferentiation and led to severely compromised regeneration of HSCs as well as impaired B lymphopoiesis after myeloablation, but not in the steady state. Thus, the regeneration of HSCs and their niche depends on the cellular plasticity of bone marrow adipocytes. Mouse lineage tracing in regenerating bone marrow after myeloablation shows a dynamic dedifferentiation of mature adipocytes into bone marrow stromal cells. Lipolysis disruption obstructs adipocyte dedifferentiation and hematopoietic stem cell regeneration.
{"title":"Cellular plasticity of the bone marrow niche promotes hematopoietic stem cell regeneration","authors":"Hiroyuki Hirakawa, Longfei Gao, Daniel Naveed Tavakol, Gordana Vunjak-Novakovic, Lei Ding","doi":"10.1038/s41588-023-01528-2","DOIUrl":"10.1038/s41588-023-01528-2","url":null,"abstract":"Hematopoietic stem cells (HSCs) regenerate after myeloablation, a procedure that adversely disrupts the bone marrow and drives leptin receptor-expressing cells, a key niche component, to differentiate extensively into adipocytes. Regeneration of the bone marrow niche is associated with the resolution of adipocytes, but the mechanisms remain poorly understood. Using Plin1-creER knock-in mice, we followed the fate of adipocytes in the regenerating niche in vivo. We found that bone marrow adipocytes were highly dynamic and dedifferentiated to leptin receptor-expressing cells during regeneration after myeloablation. Bone marrow adipocytes could give rise to osteolineage cells after skeletal injury. The cellular fate of steady-state bone marrow adipocytes was also plastic. Deletion of adipose triglyceride lipase (Atgl) from bone marrow stromal cells, including adipocytes, obstructed adipocyte dedifferentiation and led to severely compromised regeneration of HSCs as well as impaired B lymphopoiesis after myeloablation, but not in the steady state. Thus, the regeneration of HSCs and their niche depends on the cellular plasticity of bone marrow adipocytes. Mouse lineage tracing in regenerating bone marrow after myeloablation shows a dynamic dedifferentiation of mature adipocytes into bone marrow stromal cells. Lipolysis disruption obstructs adipocyte dedifferentiation and hematopoietic stem cell regeneration.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"55 11","pages":"1941-1952"},"PeriodicalIF":30.8,"publicationDate":"2023-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49679923","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}
Pub Date : 2023-10-19DOI: 10.1038/s41588-023-01529-1
Hakhamanesh Mostafavi, Jeffrey P. Spence, Sahin Naqvi, Jonathan K. Pritchard
Most signals in genome-wide association studies (GWAS) of complex traits implicate noncoding genetic variants with putative gene regulatory effects. However, currently identified regulatory variants, notably expression quantitative trait loci (eQTLs), explain only a small fraction of GWAS signals. Here, we show that GWAS and cis-eQTL hits are systematically different: eQTLs cluster strongly near transcription start sites, whereas GWAS hits do not. Genes near GWAS hits are enriched in key functional annotations, are under strong selective constraint and have complex regulatory landscapes across different tissue/cell types, whereas genes near eQTLs are depleted of most functional annotations, show relaxed constraint, and have simpler regulatory landscapes. We describe a model to understand these observations, including how natural selection on complex traits hinders discovery of functionally relevant eQTLs. Our results imply that GWAS and eQTL studies are systematically biased toward different types of variant, and support the use of complementary functional approaches alongside the next generation of eQTL studies. This study seeks to explain the poor overlap of genome-wide association study and cis-expression quantitative trait locus variants using a model of differential selective constraint, suggesting that these two study types have biases towards different functional classes of variants.
{"title":"Systematic differences in discovery of genetic effects on gene expression and complex traits","authors":"Hakhamanesh Mostafavi, Jeffrey P. Spence, Sahin Naqvi, Jonathan K. Pritchard","doi":"10.1038/s41588-023-01529-1","DOIUrl":"10.1038/s41588-023-01529-1","url":null,"abstract":"Most signals in genome-wide association studies (GWAS) of complex traits implicate noncoding genetic variants with putative gene regulatory effects. However, currently identified regulatory variants, notably expression quantitative trait loci (eQTLs), explain only a small fraction of GWAS signals. Here, we show that GWAS and cis-eQTL hits are systematically different: eQTLs cluster strongly near transcription start sites, whereas GWAS hits do not. Genes near GWAS hits are enriched in key functional annotations, are under strong selective constraint and have complex regulatory landscapes across different tissue/cell types, whereas genes near eQTLs are depleted of most functional annotations, show relaxed constraint, and have simpler regulatory landscapes. We describe a model to understand these observations, including how natural selection on complex traits hinders discovery of functionally relevant eQTLs. Our results imply that GWAS and eQTL studies are systematically biased toward different types of variant, and support the use of complementary functional approaches alongside the next generation of eQTL studies. This study seeks to explain the poor overlap of genome-wide association study and cis-expression quantitative trait locus variants using a model of differential selective constraint, suggesting that these two study types have biases towards different functional classes of variants.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"55 11","pages":"1866-1875"},"PeriodicalIF":30.8,"publicationDate":"2023-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49679925","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}
Pub Date : 2023-10-19DOI: 10.1038/s41588-023-01525-5
Tiffany Amariuta
The mechanisms of many disease-associated variants are uncertain because of limited power to detect their modest effects on gene expression. This study finds that natural selection leads to preferential detection of disease-associated versus expression-associated variants.
{"title":"The power paradox of detecting disease-associated and gene-expression-associated variants","authors":"Tiffany Amariuta","doi":"10.1038/s41588-023-01525-5","DOIUrl":"10.1038/s41588-023-01525-5","url":null,"abstract":"The mechanisms of many disease-associated variants are uncertain because of limited power to detect their modest effects on gene expression. This study finds that natural selection leads to preferential detection of disease-associated versus expression-associated variants.","PeriodicalId":18985,"journal":{"name":"Nature genetics","volume":"55 11","pages":"1782-1783"},"PeriodicalIF":30.8,"publicationDate":"2023-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49679926","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}
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