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Ultra high diversity factorizable libraries for efficient therapeutic discovery Genome Res. (IF 9.043) Pub Date : 2022-06-23 Zheng Dai, Sachit Saksena, Geraldine Horny, Christine Banholzer, Stefan Ewert, David K. Gifford
The successful discovery of novel biological therapeutics by selection requires highly diverse libraries of candidate sequences that contain a high proportion of desirable candidates. Here we propose the use of computationally designed factorizable libraries made of concatenated segment libraries as a method of creating large libraries that meet an objective function at low cost. We show that factorizable
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Genomic analysis of Rad26 and Rad1-Rad10 reveals differences in their dependence on Mediator and RNA polymerase II Genome Res. (IF 9.043) Pub Date : 2022-06-23 Diyavarshini Gopaul, Cyril Denby Wilkes, Arach Goldar, Nathalie Giordanengo Aiach, Marie-Benedicte Barrault, Elizaveta Novikova, Julie Soutourina
Mediator is a conserved coregulator playing a key role in RNA polymerase (Pol) II transcription. Mediator also links transcription and nucleotide excision repair (NER) via a direct contact with Rad2/XPG endonuclease. In this work, we analyzed the genome-wide distribution of Rad26/CSB and Rad1-Rad10/XPF-ERCC1, addressing the question of a potential link of these proteins with Mediator and Pol II in
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Somatic retrotransposition in the developing rhesus macaque brain Genome Res. (IF 9.043) Pub Date : 2022-06-21 Victor Billon, Francisco J Sanchez-Luque, Jay Rasmussen, Gabriela O Bodea, Daniel J Gerhardt, Patricia Gerdes, Seth W Cheetham, Stephanie N Schauer, Prabha Ajjikuttira, Thomas J Meyer, Cora E Layman, Kimberly A Nevonen, Natasha Jansz, Jose L Garcia-Perez, Sandra R Richardson, Adam D Ewing, Lucia Carbone, Geoffrey J Faulkner
The retrotransposon LINE-1 (L1) is central to the recent evolutionary history of the human genome, and continues to drive genetic diversity and germline pathogenesis. However, the spatiotemporal extent and biological significance of somatic L1 activity is poorly defined, and is virtually unexplored in other primates. From a single L1 lineage active at the divergence of apes and Old World monkeys, successive
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Dynamic regulatory module networks for inference of cell type-specific transcriptional networks Genome Res. (IF 9.043) Pub Date : 2022-06-15 Alireza Fotuhi Siahpirani, Sara Knaack, Deborah Chasman, Morten Seirup, Rupa Sridharan, Ron Stewart, James Thomson, Sushmita Roy
Changes in transcriptional regulatory networks can significantly alter cell fate. To gain insight into transcriptional dynamics, several studies have profiled bulk multi-omic datasets with parallel transcriptomic and epigenomic measurements at different stages of a developmental process. However, integrating these data to infer cell type-specific regulatory networks is a major challenge. We present
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HDAC9 structural variants disrupting TWIST1 transcriptional regulation lead to craniofacial and limb malformations Genome Res. (IF 9.043) Pub Date : 2022-06-16 Naama Hirsch, Idit Dahan, Eva D'haene, Matan Avni, Sarah Vergult, Marta Vidal-García, Pamela Magini, Claudio Graziano, Elena Bonora, Anna Maria Nardone, Francesco Brancati, Alberto Fernández-Jaén, Olson J. Rory, Benedikt Hallgrimsson, Ramon Y Birnbaum
Structural variants (SVs) can affect protein-coding sequences as well as gene regulatory elements. However, SVs disrupting protein-coding sequences that also function as cis-regulatory elements remain largely uncharacterized. Here, we show that craniosynostosis patients with SVs containing the Histone deacetylase 9 (HDAC9) protein-coding sequence are associated with disruption of TWIST1 regulatory
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Extensive protein dosage compensation in aneuploid human cancers Genome Res. (IF 9.043) Pub Date : 2022-06-14 Klaske M Schukken, Jason Sheltzer
Aneuploidy is a hallmark of human cancers, but the effects of aneuploidy on protein expression remain poorly understood. To uncover how chromosome copy number changes influence the cancer proteome, we conducted an analysis of hundreds of human cancer cell lines and tumors with matched copy number, RNA expression, and protein expression data. We found that a majority of proteins exhibit dosage compensation
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Epigenomic analysis reveals prevalent contribution of transposable elements to cis-regulatory elements, tissue-specific expression, and alternative promoters in zebrafish Genome Res. (IF 9.043) Pub Date : 2022-06-01 Hyung Joo Lee, Yiran Hou, Ju Heon Maeng, Nakul M. Shah, Yujie Chen, Heather A Lawson, Hongbo Yang, Feng Yue, Ting Wang
Transposable elements (TEs) encode regulatory elements that impact gene expression in multiple species, yet a comprehensive analysis of zebrafish TEs in the context of gene regulation is lacking. Here, we systematically investigate the epigenomic and transcriptomic landscape of TEs across eleven adult zebrafish tissues using multidimensional sequencing data. We find that TEs contribute substantially
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Corrigendum: NicE-C efficiently reveals open chromatin–associated chromosome interactions at high resolution Genome Res. (IF 9.043) Pub Date : 2022-06-01 Zhengyu Luo, Ran Zhang, Tengfei Hu, Yuting Zhu, Yueming Wu, Wenfei Li, Zhi Zhang, Xuebiao Yao, Haiyi Liang, Xiaoyuan Song
Genome Research 32: 534–544 (2022)
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Corrigendum: Precise genotyping of circular mobile elements from metagenomic data uncovers human-associated plasmids with recent common ancestors Genome Res. (IF 9.043) Pub Date : 2022-06-01 Nitan Shalon, David A. Relman, Eitan Yaffe
Genome Research 32: 986–1003 (2022)
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Corrigendum: Enhancer–silencer transitions in the human genome Genome Res. (IF 9.043) Pub Date : 2022-06-01 Di Huang, Ivan Ovcharenko
Genome Research 32: 437–448 (2022)
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Corrigendum: An association test of the spatial distribution of rare missense variants within protein structures identifies Alzheimer's disease–related patterns Genome Res. (IF 9.043) Pub Date : 2022-06-01 Bowen Jin, John A. Capra, Penelope Benchek, Nicholas Wheeler, Adam C. Naj, Kara L. Hamilton-Nelson, John J. Farrell, Yuk Yee Leung, Brian Kunkle, Badri Vadarajan, Gerard D. Schellenberg, Richard Mayeux, Li-San Wang, Lindsay A. Farrer, Margaret A. Pericak-Vance, Eden R. Martin, Jonathan L. Haines, Dana C. Crawford, William S. Bush
Genome Research 32: 778–790 (2022)
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Polishing copy number variant calls on exome sequencing data via deep learning Genome Res. (IF 9.043) Pub Date : 2022-06-01 Furkan Özden, Can Alkan, A. Ercüment Çiçek
Accurate and efficient detection of copy number variants (CNVs) is of critical importance owing to their significant association with complex genetic diseases. Although algorithms that use whole-genome sequencing (WGS) data provide stable results with mostly valid statistical assumptions, copy number detection on whole-exome sequencing (WES) data shows comparatively lower accuracy. This is unfortunate
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Diurnal and eating-associated microbial patterns revealed via high-frequency saliva sampling Genome Res. (IF 9.043) Pub Date : 2022-06-01 Yichen Hu, Amnon Amir, Xiaochang Huang, Yan Li, Shi Huang, Elaine Wolfe, Sophie Weiss, Rob Knight, Zhenjiang Zech Xu
The oral microbiome is linked to oral and systemic health, but its fluctuation under frequent daily activities remains elusive. Here, we sampled saliva at 10- to 60-min intervals to track the high-resolution microbiome dynamics during the course of human activities. This dense time series data showed that eating activity markedly perturbed the salivary microbiota, with tongue-specific Campylobacter
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Precision environmental health monitoring by longitudinal exposome and multi-omics profiling Genome Res. (IF 9.043) Pub Date : 2022-06-01 Peng Gao, Xiaotao Shen, Xinyue Zhang, Chao Jiang, Sai Zhang, Xin Zhou, Sophia Miryam Schüssler-Fiorenza Rose, Michael Snyder
Conventional environmental health studies have primarily focused on limited environmental stressors at the population level, which lacks the power to dissect the complexity and heterogeneity of individualized environmental exposures. Here, as a pilot case study, we integrated deep-profiled longitudinal personal exposome and internal multi-omics to systematically investigate how the exposome shapes
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Snake venom gene expression is coordinated by novel regulatory architecture and the integration of multiple co-opted vertebrate pathways Genome Res. (IF 9.043) Pub Date : 2022-06-01 Blair W. Perry, Siddharth S. Gopalan, Giulia I.M. Pasquesi, Drew R. Schield, Aundrea K. Westfall, Cara F. Smith, Ivan Koludarov, Paul T. Chippindale, Mark W. Pellegrino, Edward B. Chuong, Stephen P. Mackessy, Todd A. Castoe
Understanding how regulatory mechanisms evolve is critical for understanding the processes that give rise to novel phenotypes. Snake venom systems represent a valuable and tractable model for testing hypotheses related to the evolution of novel regulatory networks, yet the regulatory mechanisms underlying venom production remain poorly understood. Here, we use functional genomics approaches to investigate
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Evolution of transcription factor binding through sequence variations and turnover of binding sites Genome Res. (IF 9.043) Pub Date : 2022-06-01 Gat Krieger, Offir Lupo, Patricia Wittkopp, Naama Barkai
Variations in noncoding regulatory sequences play a central role in evolution. Interpreting such variations, however, remains difficult even in the context of defined attributes such as transcription factor (TF) binding sites. Here, we systematically link variations in cis-regulatory sequences to TF binding by profiling the allele-specific binding of 27 TFs expressed in a yeast hybrid, in which two
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Native RNA sequencing in fission yeast reveals frequent alternative splicing isoforms Genome Res. (IF 9.043) Pub Date : 2022-06-01 José Carlos Montañés, Marta Huertas, Simone G. Moro, William R. Blevins, Mercè Carmona, José Ayté, Elena Hidalgo, M. Mar Albà
The unicellular yeast Schizosaccharomyces pombe (fission yeast) retains many of the splicing features observed in humans and is thus an excellent model to study the basic mechanisms of splicing. Nearly half the genes contain introns, but the impact of alternative splicing in gene regulation and proteome diversification remains largely unexplored. Here we leverage Oxford Nanopore Technologies native
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Frequent somatic gene conversion as a mechanism for loss of heterozygosity in tumor suppressor genes Genome Res. (IF 9.043) Pub Date : 2022-06-01 Kazuki K. Takahashi, Hideki Innan
The major processes in carcinogenesis include the inactivation of tumor-suppressor genes (TSGs). Although Knudson's two-hit model requires two independent inactivating mutations, perhaps more frequently, a TSG inactivation can occur through a loss of heterozygosity (LOH) of an inactivating mutation. Deletion and uniparental disomy (UPD) have been well documented as LOH mechanisms, but the role of gene
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Rtt109 promotes nucleosome replacement ahead of the replication fork Genome Res. (IF 9.043) Pub Date : 2022-06-01 Felix Jonas, Gilad Yaakov, Naama Barkai
DNA replication perturbs chromatin by triggering the eviction, replacement, and incorporation of nucleosomes. How this dynamic is orchestrated in time and space is poorly understood. Here, we apply a genetically encoded sensor for histone exchange to follow the time-resolved histone H3 exchange profile in budding yeast cells undergoing slow synchronous replication in nucleotide-limiting conditions
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Profiling the quantitative occupancy of myriad transcription factors across conditions by modeling chromatin accessibility data Genome Res. (IF 9.043) Pub Date : 2022-06-01 Kaixuan Luo, Jianling Zhong, Alexias Safi, Linda K. Hong, Alok K. Tewari, Lingyun Song, Timothy E. Reddy, Li Ma, Gregory E. Crawford, Alexander J. Hartemink
Over a thousand different transcription factors (TFs) bind with varying occupancy across the human genome. Chromatin immunoprecipitation (ChIP) can assay occupancy genome-wide, but only one TF at a time, limiting our ability to comprehensively observe the TF occupancy landscape, let alone quantify how it changes across conditions. We developed TF occupancy profiler (TOP), a Bayesian hierarchical regression
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TP53-inducible putative long noncoding RNAs encode functional polypeptides that suppress cell proliferation Genome Res. (IF 9.043) Pub Date : 2022-06-01 Wenli Xu, Chang Liu, Bing Deng, Penghui Lin, Zhenghua Sun, Anrui Liu, Jiajia Xuan, Yuying Li, Keren Zhou, Xiaoqin Zhang, Qiaojuan Huang, Hui Zhou, Qingyu He, Bin Li, Lianghu Qu, Jianhua Yang
Polypeptides encoded by long noncoding RNAs (lncRNAs) are a novel class of functional molecules. However, whether these hidden polypeptides participate in the TP53 pathway and play a significant biological role is still unclear. Here, we discover that TP53-regulated lncRNAs can encode peptides, two of which are functional in various human cell lines. Using ribosome profiling and RNA-seq approaches
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Automated annotation of human centromeres with HORmon Genome Res. (IF 9.043) Pub Date : 2022-06-01 Olga Kunyavskaya, Tatiana Dvorkina, Andrey V. Bzikadze, Ivan A. Alexandrov, Pavel A. Pevzner
Recent advances in long-read sequencing opened a possibility to address the long-standing questions about the architecture and evolution of human centromeres. They also emphasized the need for centromere annotation (partitioning human centromeres into monomers and higher-order repeats [HORs]). Although there was a half-century-long series of semi-manual studies of centromere architecture, a rigorous
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Rapid evolution and strain turnover in the infant gut microbiome Genome Res. (IF 9.043) Pub Date : 2022-06-01 Daisy W. Chen, Nandita R. Garud
Although the ecological dynamics of the infant gut microbiome have been intensely studied, relatively little is known about evolutionary dynamics in the infant gut microbiome. Here we analyze longitudinal fecal metagenomic data from more than 700 infants and their mothers over the first year of life and find that the evolutionary dynamics in infant gut microbiomes are distinct from those of adults
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Gene prediction in the immunoglobulin loci Genome Res. (IF 9.043) Pub Date : 2022-06-01 Vikram Sirupurapu, Yana Safonova, Pavel A. Pevzner
The V(D)J recombination process rearranges the variable (V), diversity (D), and joining (J) genes in the immunoglobulin (IG) loci to generate antibody repertoires. Annotation of these loci across various species and predicting the V, D, and J genes (IG genes) are critical for studies of the adaptive immune system. However, because the standard gene finding algorithms are not suitable for predicting
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Transposable element accumulation drives size differences among polymorphic Y Chromosomes in Drosophila Genome Res. (IF 9.043) Pub Date : 2022-06-01 Alison H. Nguyen, Weixiang Wang, Emily Chong, Kamalakar Chatla, Doris Bachtrog
Y Chromosomes of many species are gene poor and show low levels of nucleotide variation, yet they often display high amounts of structural diversity. Dobzhansky cataloged several morphologically distinct Y Chromosomes in Drosophila pseudoobscura that differ in size and shape, but the molecular causes of their large size differences are unclear. Here we use cytogenetics and long-read sequencing to study
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Genetic, epigenetic, and environmental mechanisms govern allele-specific gene expression Genome Res. (IF 9.043) Pub Date : 2022-06-01 Celine L. St. Pierre, Juan F. Macias-Velasco, Jessica P. Wayhart, Li Yin, Clay F. Semenkovich, Heather A. Lawson
Allele-specific expression (ASE) is a phenomenon in which one allele is preferentially expressed over the other. Genetic and epigenetic factors cause ASE by altering the final composition of a gene's product, leading to expression imbalances that can have functional consequences on phenotypes. Environmental signals also impact allele-specific expression, but how they contribute to this cross talk remains
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Multiple Pristionchus pacificus genomes reveal distinct evolutionary dynamics between de novo candidates and duplicated genes Genome Res. (IF 9.043) Pub Date : 2022-05-26 Neel Prabh, Christian Roedelsperger
The birth of new genes is a major molecular innovation driving phenotypic diversity across all domains of life. Although repurposing of existing protein-coding material by duplication is considered the main process of new gene formation, recent studies have discovered thousands of transcriptionally active sequences as a rich source of new genes. However, differential loss rates have to be assumed to
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Lossless indexing with counting de Bruijn graphs Genome Res. (IF 9.043) Pub Date : 2022-05-24 Mikhail Karasikov, Harun Mustafa, Gunnar Rätsch, Andre Kahles
Sequencing data is rapidly accumulating in public repositories. Making this resource accessible for interactive analysis at scale requires efficient approaches for its storage and indexing. There have recently been advances in building compressed representations of annotated (or colored) de Bruijn graphs for efficiently indexing k-mer sets. Approaches for representing quantitative attributes such as
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Corrigendum: Low-input RNase footprinting for simultaneous quantification of cytosolic and mitochondrial translation Genome Res. (IF 9.043) Pub Date : 2022-05-01 Qianru Li, Haiwang Yang, Emily K. Stroup, Hongbin Wang, Zhe Ji
Genome Research 32: 545–557 (2022)
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Early embryonic mutations reveal dynamics of somatic and germ cell lineages in mice Genome Res. (IF 9.043) Pub Date : 2022-05-01 Arikuni Uchimura, Hirotaka Matsumoto, Yasunari Satoh, Yohei Minakuchi, Sayaka Wakayama, Teruhiko Wakayama, Mayumi Higuchi, Masakazu Hashimoto, Ryutaro Fukumura, Atsushi Toyoda, Yoichi Gondo, Takeshi Yagi
De novo mutations accumulate with zygotic cell divisions. However, the occurrence of these mutations and the way they are inherited by somatic cells and germ cells remain unclear. Here, we present a novel method to reconstruct cell lineages. We identified mosaic mutations in mice using deep whole-genome sequencing and reconstructed embryonic cell lineages based on the variant allele frequencies of
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A complete pedigree-based graph workflow for rare candidate variant analysis Genome Res. (IF 9.043) Pub Date : 2022-05-01 Charles Markello, Charles Huang, Alex Rodriguez, Andrew Carroll, Pi-Chuan Chang, Jordan Eizenga, Thomas Markello, David Haussler, Benedict Paten
Methods that use a linear genome reference for genome sequencing data analysis are reference-biased. In the field of clinical genetics for rare diseases, a resulting reduction in genotyping accuracy in some regions has likely prevented the resolution of some cases. Pangenome graphs embed population variation into a reference structure. Although pangenome graphs have helped to reduce reference mapping
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Genome-wide promoter assembly in E. coli measured at single-base resolution Genome Res. (IF 9.043) Pub Date : 2022-05-01 Jordan John, Javaid Jabbar, Nitika Badjatia, Matthew J. Rossi, William K.M. Lai, B. Franklin Pugh
When detected at single-base-pair resolution, the genome-wide location, occupancy level, and structural organization of DNA-binding proteins provide mechanistic insights into genome regulation. Here we use ChIP-exo to provide a near-base-pair resolution view of the epigenomic organization of the Escherichia coli transcription machinery and nucleoid structural proteins at the time when cells are growing
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Precise genotyping of circular mobile elements from metagenomic data uncovers human-associated plasmids with recent common ancestors Genome Res. (IF 9.043) Pub Date : 2022-05-01 Nitan Shalon, David A. Relman, Eitan Yaffe
Mobile genetic elements with circular genomes play a key role in the evolution of microbial communities. Their circular genomes correspond to circular walks in metagenome graphs, and yet, assemblies derived from natural microbial communities produce graphs riddled with spurious cycles, complicating the accurate reconstruction of circular genomes. We present DomCycle, an algorithm that reconstructs
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Relative contributions of sex hormones, sex chromosomes, and gonads to sex differences in tissue gene regulation Genome Res. (IF 9.043) Pub Date : 2022-05-01 Montgomery Blencowe, Xuqi Chen, Yutian Zhao, Yuichiro Itoh, Caden N. McQuillen, Yanjie Han, Benjamin L. Shou, Rebecca McClusky, Karen Reue, Arthur P. Arnold, Xia Yang
Sex differences in physiology and disease in mammals result from the effects of three classes of factors that are inherently unequal in males and females: reversible (activational) effects of gonadal hormones, permanent (organizational) effects of gonadal hormones, and cell-autonomous effects of sex chromosomes, as well as genes driven by these classes of factors. Often, these factors act together
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Chromatin interaction–aware gene regulatory modeling with graph attention networks Genome Res. (IF 9.043) Pub Date : 2022-05-01 Alireza Karbalayghareh, Merve Sahin, Christina S. Leslie
Linking distal enhancers to genes and modeling their impact on target gene expression are longstanding unresolved problems in regulatory genomics and critical for interpreting noncoding genetic variation. Here, we present a new deep learning approach called GraphReg that exploits 3D interactions from chromosome conformation capture assays to predict gene expression from 1D epigenomic data or genomic
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H3K36 dimethylation shapes the epigenetic interaction landscape by directing repressive chromatin modifications in embryonic stem cells Genome Res. (IF 9.043) Pub Date : 2022-05-01 Haifen Chen, Bo Hu, Cynthia Horth, Eric Bareke, Phillip Rosenbaum, Sin Young Kwon, Jacinthe Sirois, Daniel N. Weinberg, Faith M. Robison, Benjamin A. Garcia, Chao Lu, William A. Pastor, Jacek Majewski
Epigenetic modifications on the chromatin do not occur in isolation. Chromatin-associated proteins and their modification products form a highly interconnected network, and disturbing one component may rearrange the entire system. We see this increasingly clearly in epigenetically dysregulated cancers. It is important to understand the rules governing epigenetic interactions. Here, we use the mouse
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Long-read sequencing of 111 rice genomes reveals significantly larger pan-genomes Genome Res. (IF 9.043) Pub Date : 2022-05-01 Fan Zhang, Hongzhang Xue, Xiaorui Dong, Min Li, Xiaoming Zheng, Zhikang Li, Jianlong Xu, Wensheng Wang, Chaochun Wei
The concept of pan-genome, which is the collection of all genomes from a population, has shown a great potential in genomics study, especially for crop sciences. The rice pan-genome constructed from the second-generation sequencing (SGS) data is about 270 Mb larger than Nipponbare, the rice reference genome (NipRG), but it is still disadvantaged by incompleteness and loss of genomic contexts. The third-generation
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Extensive sampling of Saccharomyces cerevisiae in Taiwan reveals ecology and evolution of predomesticated lineages Genome Res. (IF 9.043) Pub Date : 2022-05-01 Tracy Jiaye Lee, Yu-Ching Liu, Wei-An Liu, Yu-Fei Lin, Hsin-Han Lee, Huei-Mien Ke, Jen-Pan Huang, Mei-Yeh Jade Lu, Chia-Lun Hsieh, Kuo-Fang Chung, Gianni Liti, Isheng Jason Tsai
The ecology and genetic diversity of the model yeast Saccharomyces cerevisiae before human domestication remain poorly understood. Taiwan is regarded as part of this yeast's geographic birthplace, where the most divergent natural lineage was discovered. Here, we extensively sampled the broadleaf forests across this continental island to probe the ancestral species’ diversity. We found that S. cerevisiae
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Classification and clustering of RNA crosslink-ligation data reveal complex structures and homodimers Genome Res. (IF 9.043) Pub Date : 2022-05-01 Minjie Zhang, Irena T. Hwang, Kongpan Li, Jianhui Bai, Jian-Fu Chen, Tsachy Weissman, James Y. Zou, Zhipeng Lu
The recent development and application of methods based on the general principle of “crosslinking and proximity ligation” (crosslink-ligation) are revolutionizing RNA structure studies in living cells. However, extracting structure information from such data presents unique challenges. Here, we introduce a set of computational tools for the systematic analysis of data from a wide variety of crosslink-ligation
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Global mapping of RNA homodimers in living cells Genome Res. (IF 9.043) Pub Date : 2022-05-01 Marta M. Gabryelska, Andrew P. Badrock, Jian You Lau, Raymond T. O'Keefe, Yanick J. Crow, Grzegorz Kudla
RNA homodimerization is important for various physiological processes, including the assembly of membraneless organelles, RNA subcellular localization, and packaging of viral genomes. However, understanding RNA dimerization has been hampered by the lack of systematic in vivo detection methods. Here, we show that CLASH, PARIS, and other RNA proximity ligation methods detect RNA homodimers transcriptome-wide
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A general calculus of fitness landscapes finds genes under selection in cancers Genome Res. (IF 9.043) Pub Date : 2022-05-01 Teng-Kuei Hsu, Jennifer Asmussen, Amanda Koire, Byung-Kwon Choi, Mayur A. Gadhikar, Eunna Huh, Chih-Hsu Lin, Daniel M. Konecki, Young Won Kim, Curtis R. Pickering, Marek Kimmel, Lawrence A. Donehower, Mitchell J. Frederick, Jeffrey N. Myers, Panagiotis Katsonis, Olivier Lichtarge
Genetic variants drive the evolution of traits and diseases. We previously modeled these variants as small displacements in fitness landscapes and estimated their functional impact by differentiating the evolutionary relationship between genotype and phenotype. Conversely, here we integrate these derivatives to identify genes steering specific traits. Over cancer cohorts, integration identified 460
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A general framework for identifying oligogenic combinations of rare variants in complex disorders Genome Res. (IF 9.043) Pub Date : 2022-05-01 Vijay Kumar Pounraja, Santhosh Girirajan
Genetic studies of complex disorders such as autism and intellectual disability (ID) are often based on enrichment of individual rare variants or their aggregate burden in affected individuals compared to controls. However, these studies overlook the influence of combinations of rare variants that may not be deleterious on their own due to statistical challenges resulting from rarity and combinatorial
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A curated collection of Klebsiella metabolic models reveals variable substrate usage and gene essentiality Genome Res. (IF 9.043) Pub Date : 2022-05-01 Jane Hawkey, Ben Vezina, Jonathan M. Monk, Louise M. Judd, Taylor Harshegyi, Sebastián López-Fernández, Carla Rodrigues, Sylvain Brisse, Kathryn E. Holt, Kelly L. Wyres
The Klebsiella pneumoniae species complex (KpSC) is a set of seven Klebsiella taxa that are found in a variety of niches and are an important cause of opportunistic health care–associated infections in humans. Because of increasing rates of multi-drug resistance within the KpSC, there is a growing interest in better understanding the biology and metabolism of these organisms to inform novel control
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Genome-wide transcript and protein analysis highlights the role of protein homeostasis in the aging mouse heart Genome Res. (IF 9.043) Pub Date : 2022-05-01 Isabela Gerdes Gyuricza, Joel M. Chick, Gregory R. Keele, Andrew G. Deighan, Steven C. Munger, Ron Korstanje, Steven P. Gygi, Gary A. Churchill
Investigation of the molecular mechanisms of aging in the human heart is challenging because of confounding factors, such as diet and medications, as well as limited access to tissues from healthy aging individuals. The laboratory mouse provides an ideal model to study aging in healthy individuals in a controlled environment. However, previous mouse studies have examined only a narrow range of the
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Erratum: Genome biology of the darkedged splitfin, Girardinichthys multiradiatus, and the evolution of sex chromosomes and placentation Genome Res. (IF 9.043) Pub Date : 2022-04-01
Genome Research 32: 583–594 (2022)
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Haig H. Kazazian, Jr. (1937–2022) Genome Res. (IF 9.043) Pub Date : 2022-04-01 Stylianos E. Antonarakis, Stuart H. Orkin
Dr. Haig H. Kazazian, Jr. passed away on January 20, 2022 in Baltimore, Maryland. He was a towering figure in human molecular genetics, and his research contributions and academic mentorship transformed our understanding of the causative role of the genetic variation in phenotypic variation.
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Variations in antibody repertoires correlate with vaccine responses Genome Res. (IF 9.043) Pub Date : 2022-04-01 Yana Safonova, Sung Bong Shin, Luke Kramer, James Reecy, Corey T. Watson, Timothy P.L. Smith, Pavel A. Pevzner
An important challenge in vaccine development is to figure out why a vaccine succeeds in some individuals and fails in others. Although antibody repertoires hold the key to answering this question, there have been very few personalized immunogenomics studies so far aimed at revealing how variations in immunoglobulin genes affect a vaccine response. We conducted an immunosequencing study of 204 calves
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Short arms of human acrocentric chromosomes and the completion of the human genome sequence Genome Res. (IF 9.043) Pub Date : 2022-04-01 Stylianos E. Antonarakis
The complete, ungapped sequence of the short arms of human acrocentric chromosomes (SAACs) is still unknown almost 20 years after the near completion of the Human Genome Project. Yet these short arms of Chromosomes 13, 14, 15, 21, and 22 contain the ribosomal DNA (rDNA) genes, which are of paramount importance for human biology. The sequences of SAACs show an extensive variation in the copy number
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The genetics and epigenetics of satellite centromeres Genome Res. (IF 9.043) Pub Date : 2022-04-01 Paul B. Talbert, Steven Henikoff
Centromeres, the chromosomal loci where spindle fibers attach during cell division to segregate chromosomes, are typically found within satellite arrays in plants and animals. Satellite arrays have been difficult to analyze because they comprise megabases of tandem head-to-tail highly repeated DNA sequences. Much evidence suggests that centromeres are epigenetically defined by the location of nucleosomes
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Implications of the first complete human genome assembly Genome Res. (IF 9.043) Pub Date : 2022-04-01
The Telomere-to-Telomere (T2T) Consortium has recently announced the assembly and analysis of the first complete human genome assembly. The use of the functionally haploid CHM13hTERT cell line (CHM13), originally isolated from a hydatidiform mole, as well as ultra-long Oxford Nanopore Technologies (ONT) and Pacific Biosciences (PacBio) high-fidelity (HiFi) data, has resulted in the gapless assemblies
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The role of insulators and transcription in 3D chromatin organization of flies Genome Res. (IF 9.043) Pub Date : 2022-04-01 Keerthi T. Chathoth, Liudmila A. Mikheeva, Gilles Crevel, Jareth C. Wolfe, Ioni Hunter, Saskia Beckett-Doyle, Sue Cotterill, Hongsheng Dai, Andrew Harrison, Nicolae Radu Zabet
The DNA in many organisms, including humans, is shown to be organized in topologically associating domains (TADs). In Drosophila, several architectural proteins are enriched at TAD borders, but it is still unclear whether these proteins play a functional role in the formation and maintenance of TADs. Here, we show that depletion of BEAF-32, Cp190, Chro, and Dref leads to changes in TAD organization
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A hidden layer of structural variation in transposable elements reveals potential genetic modifiers in human disease-risk loci Genome Res. (IF 9.043) Pub Date : 2022-04-01 Elisabeth J. van Bree, Rita L.F.P. Guimarães, Mischa Lundberg, Elena R. Blujdea, Jimi L. Rosenkrantz, Fred T.G. White, Josse Poppinga, Paula Ferrer-Raventós, Anne-Fleur E. Schneider, Isabella Clayton, David Haussler, Marcel J.T. Reinders, Henne Holstege, Adam D. Ewing, Colette Moses, Frank M.J. Jacobs
Genome-wide association studies (GWAS) have been highly informative in discovering disease-associated loci but are not designed to capture all structural variations in the human genome. Using long-read sequencing data, we discovered widespread structural variation within SINE-VNTR-Alu (SVA) elements, a class of great ape-specific transposable elements with gene-regulatory roles, which represents a
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Sequencing of individual barcoded cDNAs using Pacific Biosciences and Oxford Nanopore Technologies reveals platform-specific error patterns Genome Res. (IF 9.043) Pub Date : 2022-04-01 Alla Mikheenko, Andrey D. Prjibelski, Anoushka Joglekar, Hagen U. Tilgner
Long-read transcriptomics require understanding error sources inherent to technologies. Current approaches cannot compare methods for an individual RNA molecule. Here, we present a novel platform-comparison method that combines barcoding strategies and long-read sequencing to sequence cDNA copies representing an individual RNA molecule on both Pacific Biosciences (PacBio) and Oxford Nanopore Technologies
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Broad domains of histone marks in the highly compact Paramecium macronuclear genome Genome Res. (IF 9.043) Pub Date : 2022-04-01 Franziska Drews, Abdulrahman Salhab, Sivarajan Karunanithi, Miriam Cheaib, Martin Jung, Marcel H. Schulz, Martin Simon
The unicellular ciliate Paramecium contains a large vegetative macronucleus with several unusual characteristics, including an extremely high coding density and high polyploidy. As macronculear chromatin is devoid of heterochromatin, our study characterizes the functional epigenomic organization necessary for gene regulation and proper Pol II activity. Histone marks (H3K4me3, H3K9ac, H3K27me3) reveal
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GC content, but not nucleosome positioning, directly contributes to intron splicing efficiency in Paramecium Genome Res. (IF 9.043) Pub Date : 2022-04-01 Stefano Gnan, Mélody Matelot, Marion Weiman, Olivier Arnaiz, Frédéric Guérin, Linda Sperling, Mireille Bétermier, Claude Thermes, Chun-Long Chen, Sandra Duharcourt
Eukaryotic genes are interrupted by introns that must be accurately spliced from mRNA precursors. With an average length of 25 nt, the more than 90,000 introns of Paramecium tetraurelia stand among the shortest introns reported in eukaryotes. The mechanisms specifying the correct recognition of these tiny introns remain poorly understood. Splicing can occur cotranscriptionally, and it has been proposed
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Pan-human consensus genome significantly improves the accuracy of RNA-seq analyses Genome Res. (IF 9.043) Pub Date : 2022-04-01 Benjamin Kaminow, Sara Ballouz, Jesse Gillis, Alexander Dobin
The Human Reference Genome serves as the foundation for modern genomic analyses. However, in its present form, it does not adequately represent the vast genetic diversity of the human population. In this study, we explored the consensus genome as a potential successor of the current reference genome and assessed its effect on the accuracy of RNA-seq read alignment. To find the best haploid genome representation
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An association test of the spatial distribution of rare missense variants within protein structures identifies Alzheimer's disease–related patterns Genome Res. (IF 9.043) Pub Date : 2022-04-01 Bowen Jin, John A. Capra, Penelope Benchek, Nicholas Wheeler, Adam C. Naj, Kara L. Hamilton-Nelson, John J. Farrell, Yuk Yee Leung, Brian Kunkle, Badri Vadarajan, Gerard D. Schellenberg, Richard Mayeux, Li-San Wang, Lindsay A. Farrer, Margaret A. Pericak-Vance, Eden R. Martin, Jonathan L. Haines, Dana C. Crawford, William S. Bush
More than 90% of genetic variants are rare in most modern sequencing studies, such as the Alzheimer's Disease Sequencing Project (ADSP) whole-exome sequencing (WES) data. Furthermore, 54% of the rare variants in ADSP WES are singletons. However, both single variant and unit-based tests are limited in their statistical power to detect an association between rare variants and phenotypes. To best use
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A framework to score the effects of structural variants in health and disease Genome Res. (IF 9.043) Pub Date : 2022-04-01 Philip Kleinert, Martin Kircher
Although technological advances improved the identification of structural variants (SVs) in the human genome, their interpretation remains challenging. Several methods utilize individual mechanistic principles like the deletion of coding sequence or 3D genome architecture disruptions. However, a comprehensive tool using the broad spectrum of available annotations is missing. Here, we describe CADD-SV
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Identification of phenotype-specific networks from paired gene expression–cell shape imaging data Genome Res. (IF 9.043) Pub Date : 2022-04-01 Charlie George Barker, Eirini Petsalaki, Girolamo Giudice, Julia Sero, Emmanuel Nsa Ekpenyong, Chris Bakal, Evangelia Petsalaki
The morphology of breast cancer cells is often used as an indicator of tumor severity and prognosis. Additionally, morphology can be used to identify more fine-grained, molecular developments within a cancer cell, such as transcriptomic changes and signaling pathway activity. Delineating the interface between morphology and signaling is important to understand the mechanical cues that a cell processes
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Somatic structural variant formation is guided by and influences genome architecture Genome Res. (IF 9.043) Pub Date : 2022-04-01 Nikos Sidiropoulos, Balca R. Mardin, F. Germán Rodríguez-González, Ivan D. Bochkov, Shilpa Garg, Adrian M. Stütz, Jan O. Korbel, Erez Lieberman Aiden, Joachim Weischenfeldt
The occurrence and formation of genomic structural variants (SVs) is known to be influenced by the 3D chromatin architecture, but the extent and magnitude have been challenging to study. Here, we apply Hi-C to study chromatin organization before and after induction of chromothripsis in human cells. We use Hi-C to manually assemble the derivative chromosomes following the occurrence of massive complex