Articles

sgBE: a structure-guided design of sgRNA architecture specifies base editing window and enables simultaneous conversion of cytosine and adenosine

We present a base editing system, in which base editors are attached to different sites of sgRNA scaffold (sgBE). Each independent sgBE has its own specific editing pattern for a given target site. Among teste...

Authors: Yanhong Wang, Lifang Zhou, Rui Tao, Nan Liu, Jie Long, Fengming Qin, Wenling Tang, Yang Yang, Qiang Chen and Shaohua Yao

Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference

DNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation. Here, we identify 818 genes that affect DNA methylati...

Authors: Paul J. Hop, René Luijk, Lucia Daxinger, Maarten van Iterson, Koen F. Dekkers, Rick Jansen, Joyce B. J. van Meurs, Peter A. C. ’t Hoen, M. Arfan Ikram, Marleen M. J. van Greevenbroek, Dorret I. Boomsma, P. Eline Slagboom, Jan H. Veldink, Erik W. van Zwet and Bastiaan T. Heijmans

3DeFDR: statistical methods for identifying cell type-specific looping interactions in 5C and Hi-C data

An important unanswered question in chromatin biology is the extent to which long-range looping interactions change across developmental models, genetic perturbations, drug treatments, and disease states. Comp...

Authors: Lindsey R. Fernandez, Thomas G. Gilgenast and Jennifer E. Phillips-Cremins

A systematic evaluation of single-cell RNA-sequencing imputation methods

The rapid development of single-cell RNA-sequencing (scRNA-seq) technologies has led to the emergence of many methods for removing systematic technical noises, including imputation methods, which aim to addres...

Authors: Wenpin Hou, Zhicheng Ji, Hongkai Ji and Stephanie C. Hicks

PSCAN: Spatial scan tests guided by protein structures improve complex disease gene discovery and signal variant detection

Germline disease-causing variants are generally more spatially clustered in protein 3-dimensional structures than benign variants. Motivated by this tendency, we develop a fast and powerful protein-structure-b...

Authors: Zheng-Zheng Tang, Gregory R. Sliwoski, Guanhua Chen, Bowen Jin, William S. Bush, Bingshan Li and John A. Capra

Transcriptional regulatory networks of tumor-associated macrophages that drive malignancy in mesenchymal glioblastoma

Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal phenotype up...

Authors: Jason K. Sa, Nakho Chang, Hye Won Lee, Hee Jin Cho, Michele Ceccarelli, Luigi Cerulo, Jinlong Yin, Sung Soo Kim, Francesca P. Caruso, Mijeong Lee, Donggeon Kim, Young Taek Oh, Yeri Lee, Nam-Gu Her, Byeongkwi Min, Hye-Jin Kim…

Improved reference genome of the arboviral vector Aedes albopictus

The Asian tiger mosquito Aedes albopictus is globally expanding and has become the main vector for human arboviruses in Europe. With limited antiviral drugs and vaccines available, vector control is the primary a...

Authors: Umberto Palatini, Reem A. Masri, Luciano V. Cosme, Sergey Koren, Françoise Thibaud-Nissen, James K. Biedler, Flavia Krsticevic, J. Spencer Johnston, Rebecca Halbach, Jacob E. Crawford, Igor Antoshechkin, Anna-Bella Failloux, Elisa Pischedda, Michele Marconcini, Jay Ghurye, Arang Rhie…

Author Correction: SMURF-seq: efficient copy number profiling on long-read sequencers

An amendment to this paper has been published and can be accessed via the original article.

Authors: Rishvanth K. Prabakar, Liya Xu, James Hicks and Andrew D. Smith

Long-read individual-molecule sequencing reveals CRISPR-induced genetic heterogeneity in human ESCs

Quantifying the genetic heterogeneity of a cell population is essential to understanding of biological systems. We develop a universal method to label individual DNA molecules for single-base-resolution haplot...

Authors: Chongwei Bi, Lin Wang, Baolei Yuan, Xuan Zhou, Yu Li, Sheng Wang, Yuhong Pang, Xin Gao, Yanyi Huang and Mo Li

Tuning parameters of dimensionality reduction methods for single-cell RNA-seq analysis

Many computational methods have been developed recently to analyze single-cell RNA-seq (scRNA-seq) data. Several benchmark studies have compared these methods on their ability for dimensionality reduction, clu...

Authors: Felix Raimundo, Celine Vallot and Jean-Philippe Vert

GBAT: a gene-based association test for robust detection of trans-gene regulation

The observation that disease-associated genetic variants typically reside outside of exons has inspired widespread investigation into the genetic basis of transcriptional regulation. While associations between...

Authors: Xuanyao Liu, Joel A. Mefford, Andrew Dahl, Yuan He, Meena Subramaniam, Alexis Battle, Alkes L. Price and Noah Zaitlen

DNA polymerase stalling at structured DNA constrains the expansion of short tandem repeats

Short tandem repeats (STRs) contribute significantly to de novo mutagenesis, driving phenotypic diversity and genetic disease. Although highly diverse, their repetitive sequences induce DNA polymerase slippage...

Authors: Pierre Murat, Guillaume Guilbaud and Julian E. Sale

Cis and trans effects differentially contribute to the evolution of promoters and enhancers

Gene expression differences between species are driven by both cis and trans effects. Whereas cis effects are caused by genetic variants located on the same DNA molecule as the target gene, trans effects are due ...

Authors: Kaia Mattioli, Winona Oliveros, Chiara Gerhardinger, Daniel Andergassen, Philipp G. Maass, John L. Rinn and Marta Melé

CRISPR and transposon in vivo screens for cancer drivers and therapeutic targets

Human cancers harbor substantial genetic, epigenetic, and transcriptional changes, only some of which drive oncogenesis at certain times during cancer evolution. Identifying the cancer-driver alterations among...

Authors: Imran Noorani, Allan Bradley and Jorge de la Rosa

Methods for copy number aberration detection from single-cell DNA-sequencing data

Copy number aberrations (CNAs), which are pathogenic copy number variations (CNVs), play an important role in the initiation and progression of cancer. Single-cell DNA-sequencing (scDNAseq) technologies produc...

Authors: Xian F. Mallory, Mohammadamin Edrisi, Nicholas Navin and Luay Nakhleh

DiMSum: an error model and pipeline for analyzing deep mutational scanning data and diagnosing common experimental pathologies

Deep mutational scanning (DMS) enables multiplexed measurement of the effects of thousands of variants of proteins, RNAs, and regulatory elements. Here, we present a customizable pipeline, DiMSum, that represe...

Authors: Andre J. Faure, Jörn M. Schmiedel, Pablo Baeza-Centurion and Ben Lehner

Correction to: PiggyBac mutagenesis and exome sequencing identify genetic driver landscapes and potential therapeutic targets of EGFR-mutant gliomas

An amendment to this paper has been published and can be accessed via the original article.

Authors: Imran Noorani, Jorge de la Rosa, Yoon Ha Choi, Alexander Strong, Hannes Ponstingl, M. S. Vijayabaskar, Jusung Lee, Eunmin Lee, Angela Richard-Londt, Mathias Friedrich, Federica Furlanetto, Rocio Fuente, Ruby Banerjee, Fengtang Yang, Frances Law, Colin Watts…

Sc3.0: revamping and minimizing the yeast genome

Authors: Junbiao Dai, Jef D. Boeke, Zhouqing Luo, Shuangying Jiang and Yizhi Cai

Spatial patterns of CTCF sites define the anatomy of TADs and their boundaries

Topologically associating domains (TADs) are genomic regions of self-interaction. Additionally, it is known that TAD boundaries are enriched in CTCF binding sites. In turn, CTCF sites are known to be asymmetri...

Authors: Luca Nanni, Stefano Ceri and Colin Logie

The asynchronous establishment of chromatin 3D architecture between in vitro fertilized and uniparental preimplantation pig embryos

Pigs are important animals for agricultural and biomedical research, and improvement is needed for use of the assisted reproductive technologies. Determining underlying mechanisms of epigenetic reprogramming i...

Authors: Feifei Li, Danyang Wang, Ruigao Song, Chunwei Cao, Zhihua Zhang, Yu Wang, Xiaoli Li, Jiaojiao Huang, Qiang Liu, Naipeng Hou, Bingxiang Xu, Xiao Li, Xiaomeng Gao, Yan Jia, Jianguo Zhao and Yanfang Wang

An evolutionary driver of interspersed segmental duplications in primates

The complex interspersed pattern of segmental duplications in humans is responsible for rearrangements associated with neurodevelopmental disease, including the emergence of novel genes important in human brai...

Authors: Stuart Cantsilieris, Susan M. Sunkin, Matthew E. Johnson, Fabio Anaclerio, John Huddleston, Carl Baker, Max L. Dougherty, Jason G. Underwood, Arvis Sulovari, PingHsun Hsieh, Yafei Mao, Claudia Rita Catacchio, Maika Malig, AnneMarie E. Welch, Melanie Sorensen, Katherine M. Munson…

A seventeenth-century Mycobacterium tuberculosis genome supports a Neolithic emergence of the Mycobacterium tuberculosis complex

Although tuberculosis accounts for the highest mortality from a bacterial infection on a global scale, questions persist regarding its origin. One hypothesis based on modern Mycobacterium tuberculosis complex (MT...

Authors: Susanna Sabin, Alexander Herbig, Åshild J. Vågene, Torbjörn Ahlström, Gracijela Bozovic, Caroline Arcini, Denise Kühnert and Kirsten I. Bos

The chromosome-level wintersweet (Chimonanthus praecox) genome provides insights into floral scent biosynthesis and flowering in winter

Wintersweet (Chimonanthus praecox), an important ornamental plant, has evolved unique fragrant aroma and winter-flowering properties, which are critical for its successful sexual reproduction. However, the molecu...

Authors: Junzhong Shang, Jingpu Tian, Huihui Cheng, Qiaomu Yan, Lai Li, Abbas Jamal, Zhongping Xu, Lin Xiang, Christopher A. Saski, Shuangxia Jin, Kaige Zhao, Xiuqun Liu and Longqing Chen

ContamLD: estimation of ancient nuclear DNA contamination using breakdown of linkage disequilibrium

We report a method called ContamLD for estimating autosomal ancient DNA (aDNA) contamination by measuring the breakdown of linkage disequilibrium in a sequenced individual due to the introduction of contaminan...

Authors: Nathan Nakatsuka, Éadaoin Harney, Swapan Mallick, Matthew Mah, Nick Patterson and David Reich

Integrative analyses of single-cell transcriptome and regulome using MAESTRO

We present Model-based AnalysEs of Transcriptome and RegulOme (MAESTRO), a comprehensive open-source computational workflow (http://​github.​com/​liulab-dfci/​MAESTRO)...

Authors: Chenfei Wang, Dongqing Sun, Xin Huang, Changxin Wan, Ziyi Li, Ya Han, Qian Qin, Jingyu Fan, Xintao Qiu, Yingtian Xie, Clifford A. Meyer, Myles Brown, Ming Tang, Henry Long, Tao Liu and X. Shirley Liu

Demystifying “drop-outs” in single-cell UMI data

Many existing pipelines for scRNA-seq data apply pre-processing steps such as normalization or imputation to account for excessive zeros or “drop-outs." Here, we extensively analyze diverse UMI data sets to sh...

Authors: Tae Hyun Kim, Xiang Zhou and Mengjie Chen

The RNA-binding protein SERBP1 functions as a novel oncogenic factor in glioblastoma by bridging cancer metabolism and epigenetic regulation

RNA-binding proteins (RBPs) function as master regulators of gene expression. Alterations in RBP expression and function are often observed in cancer and influence critical pathways implicated in tumor initiat...

Authors: Adam Kosti, Patricia Rosa de Araujo, Wei-Qing Li, Gabriela D. A. Guardia, Jennifer Chiou, Caihong Yi, Debashish Ray, Fabiana Meliso, Yi-Ming Li, Talia Delambre, Mei Qiao, Suzanne S. Burns, Franziska K. Lorbeer, Fanny Georgi, Markus Flosbach, Sarah Klinnert…

Contiguous and stochastic CHH methylation patterns of plant DRM2 and CMT2 revealed by single-read methylome analysis

Cytosine methylome data is commonly generated through next-generation sequencing, with analyses averaging methylation states of individual reads. We propose an alternative method of analysing single-read methy...

Authors: Keith D. Harris and Assaf Zemach

Insulator-based loops mediate the spreading of H3K27me3 over distant micro-domains repressing euchromatin genes

Chromosomes are subdivided spatially to delimit long-range interactions into topologically associating domains (TADs). TADs are often flanked by chromatin insulators and transcription units that may participat...

Authors: Alexandre Heurteau, Charlène Perrois, David Depierre, Olivier Fosseprez, Jonathan Humbert, Stéphane Schaak and Olivier Cuvier

Elucidating the role of the gastrointestinal microbiota in racial and ethnic health disparities

Authors: Doratha A. Byrd, Tiffany L. Carson, Faustine Williams and Emily Vogtmann

Assessment of statistical methods from single cell, bulk RNA-seq, and metagenomics applied to microbiome data

The correct identification of differentially abundant microbial taxa between experimental conditions is a methodological and computational challenge. Recent work has produced methods to deal with the high spar...

Authors: Matteo Calgaro, Chiara Romualdi, Levi Waldron, Davide Risso and Nicola Vitulo

Knowledge-primed neural networks enable biologically interpretable deep learning on single-cell sequencing data

Deep learning has emerged as a versatile approach for predicting complex biological phenomena. However, its utility for biological discovery has so far been limited, given that generic deep neural networks pro...

Authors: Nikolaus Fortelny and Christoph Bock

Long-read-based human genomic structural variation detection with cuteSV

Long-read sequencing is promising for the comprehensive discovery of structural variations (SVs). However, it is still non-trivial to achieve high yields and performance simultaneously due to the complex SV si...

Authors: Tao Jiang, Yongzhuang Liu, Yue Jiang, Junyi Li, Yan Gao, Zhe Cui, Yadong Liu, Bo Liu and Yadong Wang

GMM-Demux: sample demultiplexing, multiplet detection, experiment planning, and novel cell-type verification in single cell sequencing

Identifying and removing multiplets are essential to improving the scalability and the reliability of single cell RNA sequencing (scRNA-seq). Multiplets create artificial cell types in the dataset. We propose ...

Authors: Hongyi Xin, Qiuyu Lian, Yale Jiang, Jiadi Luo, Xinjun Wang, Carla Erb, Zhongli Xu, Xiaoyi Zhang, Elisa Heidrich-O’Hare, Qi Yan, Richard H. Duerr, Kong Chen and Wei Chen

Population variation in miRNAs and isomiRs and their impact on human immunity to infection

MicroRNAs (miRNAs) are key regulators of the immune system, yet their variation and contribution to intra- and inter-population differences in immune responses is poorly characterized.

Authors: Maxime Rotival, Katherine J. Siddle, Martin Silvert, Julien Pothlichet, Hélène Quach and Lluis Quintana-Murci

PiggyBac mutagenesis and exome sequencing identify genetic driver landscapes and potential therapeutic targets of EGFR-mutant gliomas

Glioma is the most common intrinsic brain tumor and also occurs in the spinal cord. Activating EGFR mutations are common in IDH1 wild-type gliomas. However, the cooperative partners of EGFR driving gliomagenesis ...

Authors: Imran Noorani, Jorge de la Rosa, Yoon Ha Choi, Alexander Strong, Hannes Ponstingl, M. S. Vijayabaskar, Jusung Lee, Eunmin Lee, Angela Richard-Londt, Mathias Friedrich, Federica Furlanetto, Rocio Fuente, Ruby Banerjee, Fengtang Yang, Frances Law, Colin Watts…

RADAR: annotation and prioritization of variants in the post-transcriptional regulome of RNA-binding proteins

RNA-binding proteins (RBPs) play key roles in post-transcriptional regulation and disease. Their binding sites cover more of the genome than coding exons; nevertheless, most noncoding variant prioritization me...

Authors: Jing Zhang, Jason Liu, Donghoon Lee, Jo-Jo Feng, Lucas Lochovsky, Shaoke Lou, Michael Rutenberg-Schoenberg and Mark Gerstein

Splicing-accessible coding 3′UTRs control protein stability and interaction networks

3′-Untranslated regions (3′UTRs) play crucial roles in mRNA metabolism, such as by controlling mRNA stability, translation efficiency, and localization. Intriguingly, in some genes the 3′UTR is longer than the...

Authors: Marco Preussner, Qingsong Gao, Eliot Morrison, Olga Herdt, Florian Finkernagel, Michael Schumann, Eberhard Krause, Christian Freund, Wei Chen and Florian Heyd

Polymorphic mobile element insertions contribute to gene expression and alternative splicing in human tissues

Mobile elements are a major source of structural variants in the human genome, and some mobile elements can regulate gene expression and transcript splicing. However, the impact of polymorphic mobile element i...

Authors: Xiaolong Cao, Yeting Zhang, Lindsay M. Payer, Hannah Lords, Jared P. Steranka, Kathleen H. Burns and Jinchuan Xing

Bovine breed-specific augmented reference graphs facilitate accurate sequence read mapping and unbiased variant discovery

The current bovine genomic reference sequence was assembled from a Hereford cow. The resulting linear assembly lacks diversity because it does not contain allelic variation, a drawback of linear references tha...

Authors: Danang Crysnanto and Hubert Pausch

Bayesian model selection reveals biological origins of zero inflation in single-cell transcriptomics

Single-cell RNA sequencing is a powerful tool for characterizing cellular heterogeneity in gene expression. However, high variability and a large number of zero counts present challenges for analysis and inter...

Authors: Kwangbom Choi, Yang Chen, Daniel A. Skelly and Gary A. Churchill

DNA methylation repels binding of hypoxia-inducible transcription factors to maintain tumor immunotolerance

Hypoxia is pervasive in cancer and other diseases. Cells sense and adapt to hypoxia by activating hypoxia-inducible transcription factors (HIFs), but it is still an outstanding question why cell types differ i...

Authors: Flora D’Anna, Laurien Van Dyck, Jieyi Xiong, Hui Zhao, Rebecca V. Berrens, Junbin Qian, Pawel Bieniasz-Krzywiec, Vikas Chandra, Luc Schoonjans, Jason Matthews, Julie De Smedt, Liesbeth Minnoye, Ricardo Amorim, Sepideh Khorasanizadeh, Qian Yu, Liyun Zhao…

Computational inference of cancer-specific vulnerabilities in clinical samples

Systematic in vitro loss-of-function screens provide valuable resources that can facilitate the discovery of drugs targeting cancer vulnerabilities.

Authors: Kiwon Jang, Min Ji Park, Jae Soon Park, Haeun Hwangbo, Min Kyung Sung, Sinae Kim, Jaeyun Jung, Jong Won Lee, Sei-Hyun Ahn, Suhwan Chang and Jung Kyoon Choi

Producing polished prokaryotic pangenomes with the Panaroo pipeline

Population-level comparisons of prokaryotic genomes must take into account the substantial differences in gene content resulting from horizontal gene transfer, gene duplication and gene loss. However, the auto...

Authors: Gerry Tonkin-Hill, Neil MacAlasdair, Christopher Ruis, Aaron Weimann, Gal Horesh, John A. Lees, Rebecca A. Gladstone, Stephanie Lo, Christopher Beaudoin, R. Andres Floto, Simon D.W. Frost, Jukka Corander, Stephen D. Bentley and Julian Parkhill

Author Correction: Feature selection and dimension reduction for single-cell RNA-Seq based on a multinomial model

An amendment to this paper has been published and can be accessed via the original article.

Authors: F. William Townes, Stephanie C. Hicks, Martin J. Aryee and Rafael A. Irizarry

Single-cell RNA-seq analysis reveals ploidy-dependent and cell-specific transcriptome changes in Arabidopsis female gametophytes

Polyploidy provides new genetic material that facilitates evolutionary novelty, species adaptation, and crop domestication. Polyploidy often leads to an increase in cell or organism size, which may affect tran...

Authors: Qingxin Song, Atsumi Ando, Ning Jiang, Yoko Ikeda and Z. Jeffrey Chen

Approaches for integrating heterogeneous RNA-seq data reveal cross-talk between microbes and genes in asthmatic patients

Sputum induction is a non-invasive method to evaluate the airway environment, particularly for asthma. RNA sequencing (RNA-seq) of sputum samples can be challenging to interpret due to the complex and heteroge...

Authors: Daniel Spakowicz, Shaoke Lou, Brian Barron, Jose L. Gomez, Tianxiao Li, Qing Liu, Nicole Grant, Xiting Yan, Rebecca Hoyd, George Weinstock, Geoffrey L. Chupp and Mark Gerstein

The origins and genomic diversity of American Civil War Era smallpox vaccine strains

Vaccination has transformed public health, most notably including the eradication of smallpox. Despite its profound historical importance, little is known of the origins and diversity of the viruses used in sm...

Authors: Ana T. Duggan, Jennifer Klunk, Ashleigh F. Porter, Anna N. Dhody, Robert Hicks, Geoffrey L. Smith, Margaret Humphreys, Andrea M. McCollum, Whitni B. Davidson, Kimberly Wilkins, Yu Li, Amanda Burke, Hanna Polasky, Lowell Flanders, Debi Poinar, Amogelang R. Raphenya…

Assembly of the threespine stickleback Y chromosome reveals convergent signatures of sex chromosome evolution

Heteromorphic sex chromosomes have evolved repeatedly across diverse species. Suppression of recombination between X and Y chromosomes leads to degeneration of the Y chromosome. The progression of degeneration...

Authors: Catherine L. Peichel, Shaugnessy R. McCann, Joseph A. Ross, Alice F. S. Naftaly, James R. Urton, Jennifer N. Cech, Jane Grimwood, Jeremy Schmutz, Richard M. Myers, David M. Kingsley and Michael A. White

Differential chromatin accessibility landscape reveals structural and functional features of the allopolyploid wheat chromosomes

Our understanding of how the complexity of the wheat genome influences the distribution of chromatin states along the homoeologous chromosomes is limited. Using a differential nuclease sensitivity assay, we in...

Authors: Katherine W. Jordan, Fei He, Monica Fernandez de Soto, Alina Akhunova and Eduard Akhunov