journal
https://read.qxmd.com/read/37735199/apobec3b-regulates-r-loops-and-promotes-transcription-associated-mutagenesis-in-cancer
#1
JOURNAL ARTICLE
Jennifer L McCann, Agnese Cristini, Emily K Law, Seo Yun Lee, Michael Tellier, Michael A Carpenter, Chiara Beghè, Jae Jin Kim, Anthony Sanchez, Matthew C Jarvis, Bojana Stefanovska, Nuri A Temiz, Erik N Bergstrom, Daniel J Salamango, Margaret R Brown, Shona Murphy, Ludmil B Alexandrov, Kyle M Miller, Natalia Gromak, Reuben S Harris
The single-stranded DNA cytosine-to-uracil deaminase APOBEC3B is an antiviral protein implicated in cancer. However, its substrates in cells are not fully delineated. Here APOBEC3B proteomics reveal interactions with a surprising number of R-loop factors. Biochemical experiments show APOBEC3B binding to R-loops in cells and in vitro. Genetic experiments demonstrate R-loop increases in cells lacking APOBEC3B and decreases in cells overexpressing APOBEC3B. Genome-wide analyses show major changes in the overall landscape of physiological and stimulus-induced R-loops with thousands of differentially altered regions, as well as binding of APOBEC3B to many of these sites...
September 21, 2023: Nature Genetics
https://read.qxmd.com/read/37735198/functional-characterization-of-alzheimer-s-disease-genetic-variants-in-microglia
#2
JOURNAL ARTICLE
Xiaoyu Yang, Jia Wen, Han Yang, Ian R Jones, Xiaodong Zhu, Weifang Liu, Bingkun Li, Claire D Clelland, Wenjie Luo, Man Ying Wong, Xingjie Ren, Xiekui Cui, Michael Song, Hongjiang Liu, Cady Chen, Nicolas Eng, Mirunalini Ravichandran, Yang Sun, David Lee, Eric Van Buren, Min-Zhi Jiang, Candace S Y Chan, Chun Jimmie Ye, Rushika M Perera, Li Gan, Yun Li, Yin Shen
Candidate cis-regulatory elements (cCREs) in microglia demonstrate the most substantial enrichment for Alzheimer's disease (AD) heritability compared to other brain cell types. However, whether and how these genome-wide association studies (GWAS) variants contribute to AD remain elusive. Here we prioritize 308 previously unreported AD risk variants at 181 cCREs by integrating genetic information with microglia-specific 3D epigenome annotation. We further establish the link between functional variants and target genes by single-cell CRISPRi screening in microglia...
September 21, 2023: Nature Genetics
https://read.qxmd.com/read/37726541/author-correction-multiparameter-prediction-of-myeloid-neoplasia-risk
#3
Muxin Gu, Sruthi Cheloor Kovilakam, William G Dunn, Ludovica Marando, Clea Barcena, Irina Mohorianu, Alexandra Smith, Siddhartha P Kar, Margarete A Fabre, Moritz Gerstung, Catherine A Cargo, Luca Malcovati, Pedro M Quiros, George S Vassiliou
No abstract text is available yet for this article.
September 19, 2023: Nature Genetics
https://read.qxmd.com/read/37723264/rice-heterosis-quantitatively-characterized-and-optimized-hybrid-breeding
#4
JOURNAL ARTICLE
(no author information available yet)
No abstract text is available yet for this article.
September 18, 2023: Nature Genetics
https://read.qxmd.com/read/37723263/boosting-the-power-of-genome-wide-association-studies-within-and-across-ancestries-by-using-polygenic-scores
#5
JOURNAL ARTICLE
Adrian I Campos, Shinichi Namba, Shu-Chin Lin, Kisung Nam, Julia Sidorenko, Huanwei Wang, Yoichiro Kamatani, Ling-Hua Wang, Seunggeun Lee, Yen-Feng Lin, Yen-Chen Anne Feng, Yukinori Okada, Peter M Visscher, Loic Yengo
Genome-wide association studies (GWASs) have been mostly conducted in populations of European ancestry, which currently limits the transferability of their findings to other populations. Here, we show, through theory, simulations and applications to real data, that adjustment of GWAS analyses for polygenic scores (PGSs) increases the statistical power for discovery across all ancestries. We applied this method to analyze seven traits available in three large biobanks with participants of East Asian ancestry (n = 340,000 in total) and report 139 additional associations across traits...
September 18, 2023: Nature Genetics
https://read.qxmd.com/read/37723262/molecular-basis-for-maternal-inheritance-of-human-mitochondrial-dna
#6
JOURNAL ARTICLE
William Lee, Angelica Zamudio-Ochoa, Gina Buchel, Petar Podlesniy, Nuria Marti Gutierrez, Margalida Puigròs, Anna Calderon, Hsin-Yao Tang, Li Li, Aleksei Mikhalchenko, Amy Koski, Ramon Trullas, Shoukhrat Mitalipov, Dmitry Temiakov
Uniparental inheritance of mitochondrial DNA (mtDNA) is an evolutionary trait found in nearly all eukaryotes. In many species, including humans, the sperm mitochondria are introduced to the oocyte during fertilization1,2 . The mechanisms hypothesized to prevent paternal mtDNA transmission include ubiquitination of the sperm mitochondria and mitophagy3,4 . However, the causative mechanisms of paternal mtDNA elimination have not been defined5,6 . We found that mitochondria in human spermatozoa are devoid of intact mtDNA and lack mitochondrial transcription factor A (TFAM)-the major nucleoid protein required to protect, maintain and transcribe mtDNA...
September 18, 2023: Nature Genetics
https://read.qxmd.com/read/37709865/somatic-slc30a1-mutations-altering-zinc-transporter-znt1-cause-aldosterone-producing-adenomas-and-primary-aldosteronism
#7
JOURNAL ARTICLE
Juilee Rege, Sascha Bandulik, Kazutaka Nanba, Carla Kosmann, Amy R Blinder, Allein Plain, Pankaj Vats, Chandan Kumar-Sinha, Antonio M Lerario, Tobias Else, Yuto Yamazaki, Fumitoshi Satoh, Hironobu Sasano, Thomas J Giordano, Tracy Ann Williams, Martin Reincke, Adina F Turcu, Aaron M Udager, Richard Warth, William E Rainey
Primary aldosteronism (PA) is the most common form of endocrine hypertension and is characterized by inappropriately elevated aldosterone production via a renin-independent mechanism. Driver somatic mutations for aldosterone excess have been found in approximately 90% of aldosterone-producing adenomas (APAs). Other causes of lateralized adrenal PA include aldosterone-producing nodules (APNs). Using next-generation sequencing, we identified recurrent in-frame deletions in SLC30A1 in four APAs and one APN (p...
September 14, 2023: Nature Genetics
https://read.qxmd.com/read/37709864/genome-wide-association-meta-analysis-identifies-17-loci-associated-with-nonalcoholic-fatty-liver-disease
#8
JOURNAL ARTICLE
Yanhua Chen, Xiaomeng Du, Annapurna Kuppa, Mary F Feitosa, Lawrence F Bielak, Jeffrey R O'Connell, Solomon K Musani, Xiuqing Guo, Bratati Kahali, Vincent L Chen, Albert V Smith, Kathleen A Ryan, Gudny Eirksdottir, Matthew A Allison, Donald W Bowden, Matthew J Budoff, John Jeffrey Carr, Yii-Der I Chen, Kent D Taylor, Antonino Oliveri, Adolfo Correa, Breland F Crudup, Sharon L R Kardia, Thomas H Mosley, Jill M Norris, James G Terry, Jerome I Rotter, Lynne E Wagenknecht, Brian D Halligan, Kendra A Young, John E Hokanson, George R Washko, Vilmundur Gudnason, Michael A Province, Patricia A Peyser, Nicholette D Palmer, Elizabeth K Speliotes
Nonalcoholic fatty liver disease (NAFLD) is common and partially heritable and has no effective treatments. We carried out a genome-wide association study (GWAS) meta-analysis of imaging (n = 66,814) and diagnostic code (3,584 cases versus 621,081 controls) measured NAFLD across diverse ancestries. We identified NAFLD-associated variants at torsin family 1 member B (TOR1B), fat mass and obesity associated (FTO), cordon-bleu WH2 repeat protein like 1 (COBLL1)/growth factor receptor-bound protein 14 (GRB14), insulin receptor (INSR), sterol regulatory element-binding transcription factor 1 (SREBF1) and patatin-like phospholipase domain-containing protein 2 (PNPLA2), as well as validated NAFLD-associated variants at patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), apolipoprotein E (APOE), glucokinase regulator (GCKR), tribbles homolog 1 (TRIB1), glycerol-3-phosphate acyltransferase (GPAM), mitochondrial amidoxime-reducing component 1 (MARC1), microsomal triglyceride transfer protein large subunit (MTTP), alcohol dehydrogenase 1B (ADH1B), transmembrane channel like 4 (TMC4)/membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and receptor-type tyrosine-protein phosphatase δ (PTPRD)...
September 14, 2023: Nature Genetics
https://read.qxmd.com/read/37709863/mismatch-repair-deficiency-is-not-sufficient-to-elicit-tumor-immunogenicity
#9
JOURNAL ARTICLE
Peter M K Westcott, Francesc Muyas, Haley Hauck, Olivia C Smith, Nathan J Sacks, Zackery A Ely, Alex M Jaeger, William M Rideout, Daniel Zhang, Arjun Bhutkar, Mary C Beytagh, David A Canner, Grissel C Jaramillo, Roderick T Bronson, Santiago Naranjo, Abbey Jin, J J Patten, Amanda M Cruz, Sean-Luc Shanahan, Isidro Cortes-Ciriano, Tyler Jacks
DNA mismatch repair deficiency (MMRd) is associated with a high tumor mutational burden (TMB) and sensitivity to immune checkpoint blockade (ICB) therapy. Nevertheless, most MMRd tumors do not durably respond to ICB and critical questions remain about immunosurveillance and TMB in these tumors. In the present study, we developed autochthonous mouse models of MMRd lung and colon cancer. Surprisingly, these models did not display increased T cell infiltration or ICB response, which we showed to be the result of substantial intratumor heterogeneity of mutations...
September 14, 2023: Nature Genetics
https://read.qxmd.com/read/37697103/quantifying-fitness-effects-and-mutation-rates-of-mcas-in-blood
#10
JOURNAL ARTICLE
(no author information available yet)
No abstract text is available yet for this article.
September 11, 2023: Nature Genetics
https://read.qxmd.com/read/37697102/mutation-rates-and-fitness-consequences-of-mosaic-chromosomal-alterations-in-blood
#11
JOURNAL ARTICLE
Caroline J Watson, Jamie R Blundell
Mosaic chromosomal alterations (mCAs) are common in cancers and can arise decades before diagnosis. A quantitative understanding of the rate at which these events occur, and their functional consequences, could improve cancer risk prediction and our understanding of somatic evolution. Using mCA clone size estimates from the blood of approximately 500,000 UK Biobank participants, we estimate mutation rates and fitness consequences of acquired gain, loss and copy-neutral loss of heterozygosity events. Most mCAs have moderate to high fitness effects but occur at a low rate, being more than tenfold less common than equivalently fit single-nucleotide variants...
September 11, 2023: Nature Genetics
https://read.qxmd.com/read/37679493/structure-and-function-of-rice-hybrid-genomes-reveal-genetic-basis-and-optimal-performance-of-heterosis
#12
JOURNAL ARTICLE
Zhoulin Gu, Junyi Gong, Zhou Zhu, Zhen Li, Qi Feng, Changsheng Wang, Yan Zhao, Qilin Zhan, Congcong Zhou, Ahong Wang, Tao Huang, Lei Zhang, Qilin Tian, Danlin Fan, Yiqi Lu, Qiang Zhao, Xuehui Huang, Shihua Yang, Bin Han
Exploitation of crop heterosis is crucial for increasing global agriculture production. However, the quantitative genomic analysis of heterosis was lacking, and there is currently no effective prediction tool to optimize cross-combinations. Here 2,839 rice hybrid cultivars and 9,839 segregation individuals were resequenced and phenotyped. Our findings demonstrated that indica-indica hybrid-improving breeding was a process that broadened genetic resources, pyramided breeding-favorable alleles through combinatorial selection and collaboratively improved both parents by eliminating the inferior alleles at negative dominant loci...
September 7, 2023: Nature Genetics
https://read.qxmd.com/read/37666991/single-cell-multi-omics-identifies-chronic-inflammation-as-a-driver-of-tp53-mutant-leukemic-evolution
#13
JOURNAL ARTICLE
Alba Rodriguez-Meira, Ruggiero Norfo, Sean Wen, Agathe L Chédeville, Haseeb Rahman, Jennifer O'Sullivan, Guanlin Wang, Eleni Louka, Warren W Kretzschmar, Aimee Paterson, Charlotte Brierley, Jean-Edouard Martin, Caroline Demeule, Matthew Bashton, Nikolaos Sousos, Daniela Moralli, Lamia Subha Meem, Joana Carrelha, Bishan Wu, Angela Hamblin, Helene Guermouche, Florence Pasquier, Christophe Marzac, François Girodon, William Vainchenker, Mark Drummond, Claire Harrison, J Ross Chapman, Isabelle Plo, Sten Eirik W Jacobsen, Bethan Psaila, Supat Thongjuea, Iléana Antony-Debré, Adam J Mead
Understanding the genetic and nongenetic determinants of tumor protein 53 (TP53)-mutation-driven clonal evolution and subsequent transformation is a crucial step toward the design of rational therapeutic strategies. Here we carry out allelic resolution single-cell multi-omic analysis of hematopoietic stem/progenitor cells (HSPCs) from patients with a myeloproliferative neoplasm who transform to TP53-mutant secondary acute myeloid leukemia (sAML). All patients showed dominant TP53 'multihit' HSPC clones at transformation, with a leukemia stem cell transcriptional signature strongly predictive of adverse outcomes in independent cohorts, across both TP53-mutant and wild-type (WT) AML...
September 4, 2023: Nature Genetics
https://read.qxmd.com/read/37666989/symmetric-inheritance-of-parental-histones-contributes-to-safeguarding-the-fate-of-mouse-embryonic-stem-cells-during-differentiation
#14
JOURNAL ARTICLE
Qing Wen, Jiaqi Zhou, Congcong Tian, Xinran Li, Guibing Song, Yuan Gao, Yaping Sun, Chiyuan Ma, Sitong Yao, Xiaoyan Liang, Xing Kang, Nan Wang, Yuan Yao, Hongbao Wang, Xiaohuan Liang, Jialin Tang, Steven M Offer, Xiaohua Lei, Chuanhe Yu, Xiangyu Liu, Zichuan Liu, Zhiquan Wang, Haiyun Gan
Parental histones, the carriers of posttranslational modifications, are deposited evenly onto the replicating DNA of sister chromatids in a process dependent on the Mcm2 subunit of DNA helicase and the Pole3 subunit of leading-strand DNA polymerase. The biological significance of parental histone propagation remains unclear. Here we show that Mcm2-mutated or Pole3-deleted mouse embryonic stem cells (ESCs) display aberrant histone landscapes and impaired neural differentiation. Mutation of the Mcm2 histone-binding domain causes defects in pre-implantation development and embryonic lethality...
September 4, 2023: Nature Genetics
https://read.qxmd.com/read/37658185/systematic-perturbation-of-chromatin-factors-identifies-regulatory-networks-during-healthy-and-malignant-hematopoiesis
#15
JOURNAL ARTICLE
Llorenç Solé-Boldo, Simon Haas
No abstract text is available yet for this article.
September 1, 2023: Nature Genetics
https://read.qxmd.com/read/37653029/gwas-meta-analysis-of-over-29-000-people-with-epilepsy-identifies-26-risk-loci-and-subtype-specific-genetic-architecture
#16
JOURNAL ARTICLE
(no author information available yet)
Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39...
August 31, 2023: Nature Genetics
https://read.qxmd.com/read/37640880/solanum-americanum-genome-assisted-discovery-of-immune-receptors-that-detect-potato-late-blight-pathogen-effectors
#17
JOURNAL ARTICLE
Xiao Lin, Yuxin Jia, Robert Heal, Maxim Prokchorchik, Maria Sindalovskaya, Andrea Olave-Achury, Moffat Makechemu, Sebastian Fairhead, Azka Noureen, Jung Heo, Kamil Witek, Matthew Smoker, Jodie Taylor, Ram-Krishna Shrestha, Yoonyoung Lee, Chunzhi Zhang, Soon Ju Park, Kee Hoon Sohn, Sanwen Huang, Jonathan D G Jones
Potato (Solanum tuberosum) and tomato (Solanum lycopersicon) crops suffer severe losses to late blight caused by the oomycete pathogen Phytophthora infestans. Solanum americanum, a relative of potato and tomato, is globally distributed and most accessions are highly blight resistant. We generated high-quality reference genomes of four S. americanum accessions, resequenced 52 accessions, and defined a pan-NLRome of S. americanum immune receptor genes. We further screened for variation in recognition of 315P...
August 28, 2023: Nature Genetics
https://read.qxmd.com/read/37626225/author-correction-somatic-mutations-in-facial-skin-from-countries-of-contrasting-skin-cancer-risk
#18
Charlotte King, Joanna C Fowler, Irina Abnizova, Roshan K Sood, Michael W J Hall, Ildikó Szeverényi, Muly Tham, Jingxiang Huang, Stephanie Ming Young, Benjamin A Hall, E Birgitte Lane, Philip H Jones
No abstract text is available yet for this article.
August 25, 2023: Nature Genetics
https://read.qxmd.com/read/37620601/multiparameter-prediction-of-myeloid-neoplasia-risk
#19
JOURNAL ARTICLE
Muxin Gu, Sruthi Cheloor Kovilakam, William G Dunn, Ludovica Marando, Clea Barcena, Irina Mohorianu, Alexandra Smith, Siddhartha P Kar, Margarete A Fabre, Moritz Gerstung, Catherine A Cargo, Luca Malcovati, Pedro M Quiros, George S Vassiliou
The myeloid neoplasms encompass acute myeloid leukemia, myelodysplastic syndromes and myeloproliferative neoplasms. Most cases arise from the shared ancestor of clonal hematopoiesis (CH). Here we analyze data from 454,340 UK Biobank participants, of whom 1,808 developed a myeloid neoplasm 0-15 years after recruitment. We describe the differences in CH mutational landscapes and hematology/biochemistry test parameters among individuals that later develop myeloid neoplasms (pre-MN) versus controls, finding that disease-specific changes are detectable years before diagnosis...
August 24, 2023: Nature Genetics
https://read.qxmd.com/read/37604963/gatk-gcnv-enables-the-discovery-of-rare-copy-number-variants-from-exome-sequencing-data
#20
JOURNAL ARTICLE
Mehrtash Babadi, Jack M Fu, Samuel K Lee, Andrey N Smirnov, Laura D Gauthier, Mark Walker, David I Benjamin, Xuefang Zhao, Konrad J Karczewski, Isaac Wong, Ryan L Collins, Alba Sanchis-Juan, Harrison Brand, Eric Banks, Michael E Talkowski
Copy number variants (CNVs) are major contributors to genetic diversity and disease. While standardized methods, such as the genome analysis toolkit (GATK), exist for detecting short variants, technical challenges have confounded uniform large-scale CNV analyses from whole-exome sequencing (WES) data. Given the profound impact of rare and de novo coding CNVs on genome organization and human disease, we developed GATK-gCNV, a flexible algorithm to discover rare CNVs from sequencing read-depth information, complete with open-source distribution via GATK...
August 21, 2023: Nature Genetics
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