Articles

Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing

Studies have shown that complex structural variants (cxSVs) contribute to human genomic variation and can cause Mendelian disease. We aimed to identify cxSVs relevant to Mendelian disease using short-read whol...

Authors: Alba Sanchis-Juan, Jonathan Stephens, Courtney E. French, Nicholas Gleadall, Karyn Mégy, Christopher Penkett, Olga Shamardina, Kathleen Stirrups, Isabelle Delon, Eleanor Dewhurst, Helen Dolling, Marie Erwood, Detelina Grozeva, Luca Stefanucci, Gavin Arno, Andrew R. Webster…

Integrated proteotranscriptomics of breast cancer reveals globally increased protein-mRNA concordance associated with subtypes and survival

Transcriptome analysis of breast cancer discovered distinct disease subtypes of clinical significance. However, it remains a challenge to define disease biology solely based on gene expression because tumor bi...

Authors: Wei Tang, Ming Zhou, Tiffany H. Dorsey, DaRue A. Prieto, Xin W. Wang, Eytan Ruppin, Timothy D. Veenstra and Stefan Ambs

Identification of Jun loss promotes resistance to histone deacetylase inhibitor entinostat through Myc signaling in luminal breast cancer

Based on promising phase II data, the histone deacetylase inhibitor entinostat is in phase III trials for patients with metastatic estrogen receptor-positive breast cancer. Predictors of sensitivity and resist...

Authors: Maki Tanioka, Kevin R. Mott, Daniel P. Hollern, Cheng Fan, David B. Darr and Charles M. Perou

Genomics of response to immune checkpoint therapies for cancer: implications for precision medicine

Immune checkpoint blockade (ICB) therapies, which potentiate the body’s natural immune response against tumor cells, have shown immense promise in the treatment of various cancers. Currently, tumor mutational ...

Authors: Jake R. Conway, Eric Kofman, Shirley S. Mo, Haitham Elmarakeby and Eliezer Van Allen

Time series analysis of neoadjuvant chemotherapy and bevacizumab-treated breast carcinomas reveals a systemic shift in genomic aberrations

Chemotherapeutic agents such as anthracyclines and taxanes are commonly used in the neoadjuvant setting. Bevacizumab is an antibody which binds to vascular endothelial growth factor A (VEGFA) and inhibits its ...

Authors: Elen Kristine Höglander, Silje Nord, David C. Wedge, Ole Christian Lingjærde, Laxmi Silwal-Pandit, Hedda vdL Gythfeldt, Hans Kristian Moen Vollan, Thomas Fleischer, Marit Krohn, Ellen Schlitchting, Elin Borgen, Øystein Garred, Marit M. Holmen, Erik Wist, Bjørn Naume, Peter Van Loo…

Inactivation of DNA repair—prospects for boosting cancer immune surveillance

The emergence of drug resistance depends on the ability of the genome of cancer cells to constantly mutate and evolve under selective pressures. The generation of new mutations is accelerated when genes involv...

Authors: Anna Truini, Giovanni Germano and Alberto Bardelli

A role for the unfolded protein response stress sensor ERN1 in regulating the response to MEK inhibitors in KRAS mutant colon cancers

Mutations in KRAS are frequent in human cancer, yet effective targeted therapeutics for these cancers are still lacking. Attempts to drug the MEK kinases downstream of KRAS have had limited success in clinical tr...

Authors: Tonći Šuštić, Sake van Wageningen, Evert Bosdriesz, Robert J. D. Reid, John Dittmar, Cor Lieftink, Roderick L. Beijersbergen, Lodewyk F. A. Wessels, Rodney Rothstein and René Bernards

The ins and outs of telomere crisis in cancer

Telomere crisis is linked with many of the genomic alterations found in cancer genomes. A new understanding of how these alterations arise points towards an active role for innate immune sensors during crisis ...

Authors: Patrick von Morgen and John Maciejowski

Early life immunity in the era of systems biology: understanding development and disease

Systems immunology has the potential to offer invaluable insights into the development of the immune system. Two recent studies offer an in-depth view of both the dynamics of immune system development and the ...

Authors: Steven Schaffert and Purvesh Khatri

Acquired mechanisms of immune escape in cancer following immunotherapy

Immunotherapy has revolutionized the management of numerous cancers; however, a substantial proportion that initially respond subsequently acquire means of immune escape and relapse. Analysis of recent clinica...

Authors: J. Bryan Iorgulescu, David Braun, Giacomo Oliveira, Derin B. Keskin and Catherine J. Wu

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis

There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potent...

Authors: Markus Mayrhofer, Bram De Laere, Tom Whitington, Peter Van Oyen, Christophe Ghysel, Jozef Ampe, Piet Ost, Wim Demey, Lucien Hoekx, Dirk Schrijvers, Barbara Brouwers, Willem Lybaert, Els Everaert, Daan De Maeseneer, Michiel Strijbos, Alain Bols…

Footprints of antigen processing boost MHC class II natural ligand predictions

Major histocompatibility complex class II (MHC-II) molecules present peptide fragments to T cells for immune recognition. Current predictors for peptide to MHC-II binding are trained on binding affinity data, ...

Authors: Carolina Barra, Bruno Alvarez, Sinu Paul, Alessandro Sette, Bjoern Peters, Massimo Andreatta, Søren Buus and Morten Nielsen

Computational analysis reveals histotype-dependent molecular profile and actionable mutation effects across cancers

Comprehensive mutational profiling data now available on all major cancers have led to proposals of novel molecular tumor classifications that modify or replace the established organ- and tissue-based tumor ty...

Authors: Daniel Heim, Grégoire Montavon, Peter Hufnagl, Klaus-Robert Müller and Frederick Klauschen

Whole-genome epidemiology, characterisation, and phylogenetic reconstruction of Staphylococcus aureus strains in a paediatric hospital

Staphylococcus aureus is an opportunistic pathogen and a leading cause of nosocomial infections. It can acquire resistance to all the antibiotics that entered the clinics to date, and the World Health Organizatio...

Authors: Serena Manara, Edoardo Pasolli, Daniela Dolce, Novella Ravenni, Silvia Campana, Federica Armanini, Francesco Asnicar, Alessio Mengoni, Luisa Galli, Carlotta Montagnani, Elisabetta Venturini, Omar Rota-Stabelli, Guido Grandi, Giovanni Taccetti and Nicola Segata

Distinct microbes, metabolites, and ecologies define the microbiome in deficient and proficient mismatch repair colorectal cancers

Links between colorectal cancer (CRC) and the gut microbiome have been established, but the specific microbial species and their role in carcinogenesis remain an active area of inquiry. Our understanding would...

Authors: Vanessa L. Hale, Patricio Jeraldo, Jun Chen, Michael Mundy, Janet Yao, Sambhawa Priya, Gary Keeney, Kelly Lyke, Jason Ridlon, Bryan A. White, Amy J. French, Stephen N. Thibodeau, Christian Diener, Osbaldo Resendis-Antonio, Jaime Gransee, Tumpa Dutta…

Recent advances in immunotherapies: from infection and autoimmunity, to cancer, and back again

For at least 300 years the immune system has been targeted to improve human health. Decades of work advancing immunotherapies against infection and autoimmunity paved the way for the current explosion in cance...

Authors: Samantha L. Bucktrout, Jeffrey A. Bluestone and Fred Ramsdell

Landscape of genomic alterations in high-grade serous ovarian cancer from exceptional long- and short-term survivors

Patients diagnosed with high-grade serous ovarian cancer (HGSOC) who received initial debulking surgery followed by platinum-based chemotherapy can experience highly variable clinical responses. A small percen...

Authors: S. Y. Cindy Yang, Stephanie Lheureux, Katherine Karakasis, Julia V. Burnier, Jeffery P. Bruce, Derek L. Clouthier, Arnavaz Danesh, Rene Quevedo, Mark Dowar, Youstina Hanna, Tiantian Li, Lin Lu, Wei Xu, Blaise A. Clarke, Pamela S. Ohashi, Patricia A. Shaw…

Targeting the microbiome: from probiotics to fecal microbiota transplantation

The modern techniques of microbiome science can be applied to the development and evaluation of all microbiota-directed products, including probiotics and fecal microbiota transplantation.

Authors: Alexander Khoruts

Tracking key virulence loci encoding aerobactin and salmochelin siderophore synthesis in Klebsiella pneumoniae

Klebsiella pneumoniae is a recognised agent of multidrug-resistant (MDR) healthcare-associated infections; however, individual strains vary in their virulence potential due to the presence of mobile accessory gen...

Authors: Margaret M. C. Lam, Kelly L. Wyres, Louise M. Judd, Ryan R. Wick, Adam Jenney, Sylvain Brisse and Kathryn E. Holt

Genome-wide analyses reveal the IRE1a-XBP1 pathway promotes T helper cell differentiation by resolving secretory stress and accelerating proliferation

The IRE1a-XBP1 pathway is a conserved adaptive mediator of the unfolded protein response. The pathway is indispensable for the development of secretory cells by facilitating protein folding and enhancing secre...

Authors: Jhuma Pramanik, Xi Chen, Gozde Kar, Johan Henriksson, Tomás Gomes, Jong-Eun Park, Kedar Natarajan, Kerstin B. Meyer, Zhichao Miao, Andrew N. J. McKenzie, Bidesh Mahata and Sarah A. Teichmann

Genotype effects contribute to variation in longitudinal methylome patterns in older people

DNA methylation levels change along with age, but few studies have examined the variation in the rate of such changes between individuals.

Authors: Qian Zhang, Riccardo E Marioni, Matthew R Robinson, Jon Higham, Duncan Sproul, Naomi R Wray, Ian J Deary, Allan F McRae and Peter M Visscher

T cell dynamics and response of the microbiota after gene therapy to treat X-linked severe combined immunodeficiency

Mutation of the IL2RG gene results in a form of severe combined immune deficiency (SCID-X1), which has been treated successfully with hematopoietic stem cell gene therapy. SCID-X1 gene therapy results in reconsti...

Authors: Erik L. Clarke, A. Jesse Connell, Emmanuelle Six, Nadia A. Kadry, Arwa A. Abbas, Young Hwang, John K. Everett, Casey E. Hofstaedter, Rebecca Marsh, Myriam Armant, Judith Kelsen, Luigi D. Notarangelo, Ronald G. Collman, Salima Hacein-Bey-Abina, Donald B. Kohn, Marina Cavazzana…

Clinical exome sequencing for fetuses with ultrasound abnormalities and a suspected Mendelian disorder

Exome sequencing is now being incorporated into clinical care for pediatric and adult populations, but its integration into prenatal diagnosis has been more limited. One reason for this is the paucity of infor...

Authors: Elizabeth A. Normand, Alicia Braxton, Salma Nassef, Patricia A. Ward, Francesco Vetrini, Weimin He, Vipulkumar Patel, Chunjing Qu, Lauren E. Westerfield, Samantha Stover, Avinash V. Dharmadhikari, Donna M. Muzny, Richard A. Gibbs, Hongzheng Dai, Linyan Meng, Xia Wang…

Advanced model systems and tools for basic and translational human immunology

There are fundamental differences between humans and the animals we typically use to study the immune system. We have learned much from genetically manipulated and inbred animal models, but instances in which ...

Authors: Lisa E. Wagar, Robert M. DiFazio and Mark M. Davis

Infection and immunity: insights and therapeutic strategies through genomic analysis of the host, pathogen, and host–pathogen interaction

Authors: Julia Simundza

Single-cell transcriptomics reveal that PD-1 mediates immune tolerance by regulating proliferation of regulatory T cells

We have previously reported an antigen-specific protocol to induce transplant tolerance and linked suppression to human embryonic stem cell (hESC)-derived tissues in immunocompetent mice through coreceptor and...

Authors: Cherry S. Leung, Kevin Y. Yang, Xisheng Li, Vicken W. Chan, Manching Ku, Herman Waldmann, Shohei Hori, Jason C. H. Tsang, Yuk Ming Dennis Lo and Kathy O. Lui

Exome-wide analysis of bi-allelic alterations identifies a Lynch phenotype in The Cancer Genome Atlas

Cancer susceptibility germline variants generally require somatic alteration of the remaining allele to drive oncogenesis and, in some cases, tumor mutational profiles. Whether combined germline and somatic bi...

Authors: Alexandra R. Buckley, Trey Ideker, Hannah Carter, Olivier Harismendy and Nicholas J. Schork

Increased DNA methylation variability in rheumatoid arthritis-discordant monozygotic twins

Rheumatoid arthritis is a common autoimmune disorder influenced by both genetic and environmental factors. Epigenome-wide association studies can identify environmentally mediated epigenetic changes such as al...

Authors: Amy P. Webster, Darren Plant, Simone Ecker, Flore Zufferey, Jordana T. Bell, Andrew Feber, Dirk S. Paul, Stephan Beck, Anne Barton, Frances M. K. Williams and Jane Worthington

Comprehensive antibiotic-linked mutation assessment by resistance mutation sequencing (RM-seq)

Mutation acquisition is a major mechanism of bacterial antibiotic resistance that remains insufficiently characterised. Here we present RM-seq, a new amplicon-based deep sequencing workflow based on a molecula...

Authors: Romain Guérillot, Lucy Li, Sarah Baines, Brian Howden, Mark B. Schultz, Torsten Seemann, Ian Monk, Sacha J. Pidot, Wei Gao, Stefano Giulieri, Anders Gonçalves da Silva, Anthony D’Agata, Takehiro Tomita, Anton Y. Peleg, Timothy P. Stinear and Benjamin P. Howden

Exploring the pre-immune landscape of antigen-specific T cells

Adaptive immune responses to newly encountered pathogens depend on the mobilization of antigen-specific clonotypes from a vastly diverse pool of naive T cells. Using recent advances in immune repertoire sequen...

Authors: Mikhail V. Pogorelyy, Alla D. Fedorova, James E. McLaren, Kristin Ladell, Dmitri V. Bagaev, Alexey V. Eliseev, Artem I. Mikelov, Anna E. Koneva, Ivan V. Zvyagin, David A. Price, Dmitry M. Chudakov and Mikhail Shugay

Genomic exploration of sequential clinical isolates reveals a distinctive molecular signature of persistent Staphylococcus aureus bacteraemia

Large-scale genomic studies of within-host diversity in Staphylococcus aureus bacteraemia (SAB) are needed to understanding bacterial adaptation underlying persistence and thus refining the role of genomics in ma...

Authors: Stefano G. Giulieri, Sarah L. Baines, Romain Guerillot, Torsten Seemann, Anders Gonçalves da Silva, Mark Schultz, Ruth C. Massey, Natasha E. Holmes, Timothy P. Stinear and Benjamin P. Howden

Cross-genetic determination of maternal and neonatal immune mediators during pregnancy

The immune system plays a fundamental role in development during pregnancy and early life. Alterations in circulating maternal and neonatal immune mediators have been associated with pregnancy complications as...

Authors: Michela Traglia, Lisa A. Croen, Karen L. Jones, Luke S. Heuer, Robert Yolken, Martin Kharrazi, Gerald N. DeLorenze, Paul Ashwood, Judy Van de Water and Lauren A. Weiss

p53 activation: a checkpoint for precision genome editing?

Recent work has reported that the activation of the p53 pathway in primary cells hampers the efficiency of genome editing by CRISPR/Cas9 via induction of apoptosis or cell cycle arrest. These findings highligh...

Authors: Anastasia Conti and Raffaella Di Micco

A genome-wide siRNA screen identifies a druggable host pathway essential for the Ebola virus life cycle

The 2014–2016 Ebola virus (EBOV) outbreak in West Africa highlighted the need for improved therapeutic options against this virus. Approaches targeting host factors/pathways essential for the virus are advanta...

Authors: Scott Martin, Abhilash I. Chiramel, Marie Luisa Schmidt, Yu-Chi Chen, Nadia Whitt, Ari Watt, Eric C. Dunham, Kyle Shifflett, Shelby Traeger, Anne Leske, Eugen Buehler, Cynthia Martellaro, Janine Brandt, Lisa Wendt, Andreas Müller, Stephanie Peitsch…

Exploring the OncoGenomic Landscape of cancer

The widespread incorporation of next-generation sequencing into clinical oncology has yielded an unprecedented amount of molecular data from thousands of patients. A main current challenge is to find out relia...

Authors: Lidia Mateo, Oriol Guitart-Pla, Miquel Duran-Frigola and Patrick Aloy

Causality in dietary interventions—building a case for gut microbiota

We provide a conceptual framework to establish a causal link between diet, gut microbiota, and health. Identifying the key strains that mediate microbe–host interactions and understanding the mechanisms involv...

Authors: Yan Y. Lam, Chenhong Zhang and Liping Zhao

Human genetic variants and age are the strongest predictors of humoral immune responses to common pathogens and vaccines

Humoral immune responses to infectious agents or vaccination vary substantially among individuals, and many of the factors responsible for this variability remain to be defined. Current evidence suggests that ...

Authors: Petar Scepanovic, Cécile Alanio, Christian Hammer, Flavia Hodel, Jacob Bergstedt, Etienne Patin, Christian W. Thorball, Nimisha Chaturvedi, Bruno Charbit, Laurent Abel, Lluis Quintana-Murci, Darragh Duffy, Matthew L. Albert and Jacques Fellay

Integrative omics analyses broaden treatment targets in human cancer

Although large-scale, next-generation sequencing (NGS) studies of cancers hold promise for enabling precision oncology, challenges remain in integrating NGS with clinically validated biomarkers.

Authors: Sohini Sengupta, Sam Q. Sun, Kuan-lin Huang, Clara Oh, Matthew H. Bailey, Rajees Varghese, Matthew A. Wyczalkowski, Jie Ning, Piyush Tripathi, Joshua F. McMichael, Kimberly J. Johnson, Cyriac Kandoth, John Welch, Cynthia Ma, Michael C. Wendl, Samuel H. Payne…

Single-cell transcriptome analysis of lineage diversity in high-grade glioma

Despite extensive molecular characterization, we lack a comprehensive understanding of lineage identity, differentiation, and proliferation in high-grade gliomas (HGGs).

Authors: Jinzhou Yuan, Hanna Mendes Levitin, Veronique Frattini, Erin C. Bush, Deborah M. Boyett, Jorge Samanamud, Michele Ceccarelli, Athanassios Dovas, George Zanazzi, Peter Canoll, Jeffrey N. Bruce, Anna Lasorella, Antonio Iavarone and Peter A. Sims

Rare variants in SOX17 are associated with pulmonary arterial hypertension with congenital heart disease

Pulmonary arterial hypertension (PAH) is a rare disease characterized by distinctive changes in pulmonary arterioles that lead to progressive pulmonary arterial pressures, right-sided heart failure, and a high...

Authors: Na Zhu, Carrie L. Welch, Jiayao Wang, Philip M. Allen, Claudia Gonzaga-Jauregui, Lijiang Ma, Alejandra K. King, Usha Krishnan, Erika B. Rosenzweig, D. Dunbar Ivy, Eric D. Austin, Rizwan Hamid, Michael W. Pauciulo, Katie A. Lutz, William C. Nichols, Jeffrey G. Reid…

Functional and genomic analyses reveal therapeutic potential of targeting β-catenin/CBP activity in head and neck cancer

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy characterized by tumor heterogeneity, locoregional metastases, and resistance to existing treatments. Although a number of genomic and ...

Authors: Vinay K. Kartha, Khalid A. Alamoud, Khikmet Sadykov, Bach-Cuc Nguyen, Fabrice Laroche, Hui Feng, Jina Lee, Sara I. Pai, Xaralabos Varelas, Ann Marie Egloff, Jennifer E. Snyder-Cappione, Anna C. Belkina, Manish V. Bais, Stefano Monti and Maria A. Kukuruzinska

Epigenomic profiling of non-small cell lung cancer xenografts uncover LRP12 DNA methylation as predictive biomarker for carboplatin resistance

Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related deaths worldwide and is primarily treated with radiation, surgery, and platinum-based drugs like cisplatin and carboplatin. The maj...

Authors: Sabrina Grasse, Matthias Lienhard, Steffen Frese, Martin Kerick, Anne Steinbach, Christina Grimm, Michelle Hussong, Jana Rolff, Michael Becker, Felix Dreher, Uwe Schirmer, Stefan Boerno, Anna Ramisch, Gunda Leschber, Bernd Timmermann, Christian Grohé…

Prioritization and functional assessment of noncoding variants associated with complex diseases

Unraveling functional noncoding variants associated with complex diseases is still a great challenge. We present a novel algorithm, Prioritization And Functional Assessment (PAFA), that prioritizes and assesse...

Authors: Lin Zhou and Fangqing Zhao

Exploration of Plasmodium vivax transmission dynamics and recurrent infections in the Peruvian Amazon using whole genome sequencing

Plasmodium vivax poses a significant challenge to malaria elimination due to its ability to cause relapsed infections from reactivation of dormant liver parasites called hypnozoites. We analyzed 69 P. vivax whole...

Authors: Annie N. Cowell, Hugo O. Valdivia, Danett K. Bishop and Elizabeth A. Winzeler

INSaFLU: an automated open web-based bioinformatics suite “from-reads” for influenza whole-genome-sequencing-based surveillance

A new era of flu surveillance has already started based on the genetic characterization and exploration of influenza virus evolution at whole-genome scale. Although this has been prioritized by national and in...

Authors: Vítor Borges, Miguel Pinheiro, Pedro Pechirra, Raquel Guiomar and João Paulo Gomes

Red blood cell indices and anaemia as causative factors for cognitive function deficits and for Alzheimer’s disease

Studies have shown that low haemoglobin and anaemia are associated with poor cognition, and anaemia is known to be associated with Alzheimer’s disease (AD), but the mechanism of this risk is unknown. Here, we ...

Authors: Laura M. Winchester, John Powell, Simon Lovestone and Alejo J. Nevado-Holgado

Disease-specific regulation of gene expression in a comparative analysis of juvenile idiopathic arthritis and inflammatory bowel disease

The genetic and immunological factors that contribute to differences in susceptibility and progression between sub-types of inflammatory and autoimmune diseases continue to be elucidated. Inflammatory bowel di...

Authors: Angela Mo, Urko M. Marigorta, Dalia Arafat, Lai Hin Kimi Chan, Lori Ponder, Se Ryeong Jang, Jarod Prince, Subra Kugathasan, Sampath Prahalad and Greg Gibson

Therapy-induced stress response is associated with downregulation of pre-mRNA splicing in cancer cells

Abnormal pre-mRNA splicing regulation is common in cancer, but the effects of chemotherapy on this process remain unclear.

Authors: Ksenia S. Anufrieva, Victoria О. Shender, Georgij P. Arapidi, Marat S. Pavlyukov, Michail I. Shakhparonov, Polina V. Shnaider, Ivan O. Butenko, Maria A. Lagarkova and Vadim M. Govorun

Genomic surveillance of avian-origin influenza A viruses causing human disease

Avian influenza A viruses (AIVs) pose a threat to global health because of their sporadic zoonotic transmission and potential to cause pandemics. Genomic surveillance of AIVs has become a powerful, cost-effect...

Authors: Tommy T. Lam and Oliver G. Pybus

Developing Zika vaccines: the lessons for disease X

There is an urgent need to develop vaccines against emerging diseases, including those caused by pathogens that are currently unknown to cause human disease, termed ‘disease X’. Here, Zika virus infection is c...

Authors: Alan D. T. Barrett