Commentaries

Genetic variation in the Middle East—an opportunity to advance the human genetics field

We highlight the current lack of representation of the Middle East from large genomic studies and emphasize the expected high impact of cataloging its variation. We discuss the limiting factors and possible so...

Authors: Ahmad N. Abou Tayoun and Heidi L. Rehm

Transparency, trust, and community welfare: towards a precision public health ethics framework for the genomics era

Infectious disease control is experiencing a paradigm shift, as pathogen sequencing technologies and digital applications are increasingly implemented for control of diseases such as tuberculosis, Ebola, and C...

Authors: Eric T. Juengst and Annelies Van Rie

Genomics in the era of COVID-19: ethical implications for clinical practice and public health

Genomic studies of patients with COVID-19, or exposed to it, are underway to delineate host factors associated with variability in susceptibility, infectivity, and disease severity. Here, we highlight the ethi...

Authors: Gail Geller, Priya Duggal, Chloe L. Thio, Debra Mathews, Jeffrey P. Kahn, Lisa L. Maragakis and Brian T. Garibaldi

Illuminating the human virome in health and disease

Although the microbiome is established as an important regulator of health and disease, the role of viruses that inhabit asymptomatic humans (collectively, the virome) is less defined. While we are still chara...

Authors: Fatemeh Adiliaghdam and Kate L. Jeffrey

Fecal microbiota transplantation in gastrointestinal disorders: time for precision medicine

Fecal microbiota transplantation (FMT) has demonstrated efficacy in treating inflammatory bowel diseases and irritable bowel syndrome in an increasing number of randomized controlled trials. Recently published...

Authors: Nicolas Benech and Harry Sokol

The Medical Genome Initiative: moving whole-genome sequencing for rare disease diagnosis to the clinic

Clinical whole-genome sequencing (WGS) offers clear diagnostic benefits for patients with rare disease. However, there are barriers to its widespread adoption, including a lack of standards for clinical practi...

Authors: Christian R. Marshall, David Bick, John W. Belmont, Stacie L. Taylor, Euan Ashley, David Dimmock, Vaidehi Jobanputra, Hutton M. Kearney, Shashikant Kulkarni and Heidi Rehm

Clinical impact of splicing in neurodevelopmental disorders

Clinical exome sequencing is frequently used to identify gene-disrupting variants in individuals with neurodevelopmental disorders. While splice-disrupting variants are known to contribute to these disorders, ...

Authors: Stephan J. Sanders, Grace B. Schwartz and Kyle Kai-How Farh

Towards a European health research and innovation cloud (HRIC)

The European Union (EU) initiative on the Digital Transformation of Health and Care (Digicare) aims to provide the conditions necessary for building a secure, flexible, and decentralized digital health infrast...

Authors: F. M. Aarestrup, A. Albeyatti, W. J. Armitage, C. Auffray, L. Augello, R. Balling, N. Benhabiles, G. Bertolini, J. G. Bjaalie, M. Black, N. Blomberg, P. Bogaert, M. Bubak, B. Claerhout, L. Clarke, B. De Meulder…

Keeping up with the genomes: scaling genomic variant interpretation

Authors: Heidi L. Rehm and Douglas M. Fowler

Digital twins to personalize medicine

Personalized medicine requires the integration and processing of vast amounts of data. Here, we propose a solution to this challenge that is based on constructing Digital Twins. These are high-resolution model...

Authors: Bergthor Björnsson, Carl Borrebaeck, Nils Elander, Thomas Gasslander, Danuta R. Gawel, Mika Gustafsson, Rebecka Jörnsten, Eun Jung Lee, Xinxiu Li, Sandra Lilja, David Martínez-Enguita, Andreas Matussek, Per Sandström, Samuel Schäfer, Margaretha Stenmarker, X. F. Sun…

Recommendations for the collection and use of multiplexed functional data for clinical variant interpretation

Variants of uncertain significance represent a massive challenge to medical genetics. Multiplexed functional assays, in which the functional effects of thousands of genomic variants are assessed simultaneously...

Authors: Hannah Gelman, Jennifer N. Dines, Jonathan Berg, Alice H. Berger, Sarah Brnich, Fuki M. Hisama, Richard G. James, Alan F. Rubin, Jay Shendure, Brian Shirts, Douglas M. Fowler and Lea M. Starita

Genomic screening and genomic diagnostic testing—two very different kettles of fish

Genomic testing can be misunderstood as being determinative, when in reality it is the same as all other tests and context is essential for its correct interpretation. Two hypothetical cases of testing for Mar...

Authors: Leslie G. Biesecker

Is ‘likely pathogenic’ really 90% likely? Reclassification data in ClinVar

In 2015, professional guidelines defined the term ‘likely pathogenic’ to mean with a 90% chance of pathogenicity. To determine whether current practice reflects this definition, ClinVar classifications were tr...

Authors: Steven M. Harrison and Heidi L. Rehm

Genetic underpinnings of recovery after stroke: an opportunity for gene discovery, risk stratification, and precision medicine

As the number of stroke survivors continues to increase, identification of therapeutic targets for stroke recovery has become a priority in stroke genomics research. The introduction of high-throughput genotyp...

Authors: Julián N. Acosta, Stacy C. Brown and Guido J. Falcone

The relationship between insomnia and complex diseases—insights from genetic data

Insomnia is a common condition whose pathophysiology is poorly understood. Large genetic studies have provided insights into the etiology of insomnia, highlighting biological pathways that are shared with othe...

Authors: Enda M. Byrne

Advancing cancer immunotherapy: a vision for the field

Authors: Noel F. C. C. de Miranda and Zlatko Trajanoski

The good, the bad, and the ugly: hyperprogression in cancer patients following immune checkpoint therapy

Immune checkpoint blockade therapy can elicit robust and durable responses in a variety of cancer types. While many patients do not respond, recent reports highlight a distinct group of patients whose tumors u...

Authors: Erich Sabio and Timothy A. Chan

Radiation therapy and anti-tumor immunity: exposing immunogenic mutations to the immune system

The expression of antigens that are recognized by self-reactive T cells is essential for immune-mediated tumor rejection by immune checkpoint blockade (ICB) therapy. Growing evidence suggests that mutation-ass...

Authors: Claire Lhuillier, Nils-Petter Rudqvist, Olivier Elemento, Silvia C. Formenti and Sandra Demaria

Mechanisms of immune-related adverse events associated with immune checkpoint blockade: using germline genetics to develop a personalized approach

Personalized care of cancer patients undergoing treatment with immune checkpoint inhibitors will require approaches that can predict their susceptibility to immune-related adverse events. Understanding the rol...

Authors: Zia Khan, Christian Hammer, Ellie Guardino, G. Scott Chandler and Matthew L. Albert

Somatic mutation and clonal expansions in human tissues

Recent sequencing studies on healthy skin and esophagus have found that, as we age, these tissues become colonized by mutant clones of cells carrying driver mutations in traditional cancer genes. This comment ...

Authors: Inigo Martincorena

Dissecting lung development and fibrosis at single-cell resolution

Single-cell transcriptome profiling has enabled high-resolution analysis of cellular populations in tissues during development, health, and disease. Recent studies make innovative use of single-cell RNA sequen...

Authors: Donna L. Farber and Peter A. Sims

Points-to-consider on the return of results in epigenetic research

As epigenetic studies become more common and lead to new insights into health and disease, the return of individual epigenetic results to research participants, in particular in large-scale epigenomic studies,...

Authors: Stephanie O. M. Dyke, Katie M. Saulnier, Charles Dupras, Amy P. Webster, Karen Maschke, Mark Rothstein, Reiner Siebert, Jörn Walter, Stephan Beck, Tomi Pastinen and Yann Joly

Discovery and characterization of actionable tumor antigens

The nature of the tumor antigens that are detectable by T cells remains unclear. In melanoma, T cells were shown to react against major histocompatibility complex (MHC)-associated peptides (MAPs) that are deri...

Authors: Grégory Ehx and Claude Perreault

Designing circulating tumor DNA-based interventional clinical trials in oncology

Circulating tumor (ct) DNA is a powerful tool that can be used to track cancer beyond a single snapshot in space and time. It has potential applications in detecting minimal residual disease and predicting rel...

Authors: Daniel V. Araujo, Scott V. Bratman and Lillian L. Siu

Circular RNAs as promising biomarkers in cancer: detection, function, and beyond

Circular RNAs (circRNAs) are 3′–5′ covalently closed RNA rings produced from back-splicing of precursor mRNA in eukaryotes. Recent studies, using both computational and experimental approaches, have allowed ad...

Authors: Shengli Li and Leng Han

A decade of Genome Medicine: toward precision medicine

Authors: Rabia Begum

Translating genomic medicine to the clinic: challenges and opportunities

Genomic medicine has considerable potential to provide novel diagnostic and therapeutic solutions for patients who have molecularly complex diseases and who are not responding to existing therapies. To bridge ...

Authors: Huan Zhang, Lars Klareskog, Andreas Matussek, Stefan M. Pfister and Mikael Benson

Ten years of Genome Medicine

Authors: Charles Auffray, Julian L. Griffin, Muin J. Khoury, James R. Lupski and Matthias Schwab

From genome integrity to cancer

Authors: Serena Nik-Zainal

Mechanisms of PARP inhibitor resistance in cancer and insights into the DNA damage response

Inhibitors of poly(ADP-ribose) polymerase (PARPi) have entered the clinic for the treatment of patients with cancers that lack homology-directed DNA repair, but drug resistance remains a clinical hurdle. Recen...

Authors: Paola Francica and Sven Rottenberg

Emerging evidence linking the gut microbiome to neurologic disorders

The gut microbiome contributes to the development and function of the immune, metabolic, and nervous systems. Furthermore, commensal bacteria modulate symptoms and pathology in mouse models of neuropsychiatric...

Authors: Jessica A. Griffiths and Sarkis K. Mazmanian

An integrative approach for building personalized gene regulatory networks for precision medicine

Only a small fraction of patients respond to the drug prescribed to treat their disease, which means that most are at risk of unnecessary exposure to side effects through ineffective drugs. This inter-individu...

Authors: Monique G. P. van der Wijst, Dylan H. de Vries, Harm Brugge, Harm-Jan Westra and Lude Franke

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

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

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

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

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

Authors: Julia Simundza

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

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

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

Antifungal immune responses: emerging host–pathogen interactions and translational implications

Understanding the complex and highly dynamic interactions between fungi and host cells in a tissue-specific manner is crucial to facilitate the development of new therapeutic approaches to infections. Here, we...

Authors: Vinod Kumar, Frank L. van de Veerdonk and Mihai G. Netea

Beating the odds: programming proliferation in the mammalian heart

The heart is one of the least regenerative organs in the human body; adult cardiac myocytes divide at extremely low frequency. Therefore, meaningful induction of cardiac regeneration requires in-depth understa...

Authors: Rajan Jain, Andrey Poleshko and Jonathan A. Epstein

Pathogen detection in the CRISPR–Cas era

CRISPR–Cas systems have provided revolutionary tools for genome editing. The discovery of Cas proteins with alternative activities has now enabled sensitive and robust tools for detecting nucleic acids. Recent...

Authors: Dipali G. Sashital

New additions to the cancer precision medicine toolkit

New computational and database-driven tools are emerging to aid in the interpretation of cancer genomic data as its use becomes more common in clinical evidence-based cancer medicine. Two such open source tool...

Authors: Elaine R. Mardis

The emerging roles of exosomes in the modulation of immune responses in cancer

Exosomes are promising tools for improving cancer care, but conversely may also contribute to tumor progression. Here, we highlight recently discovered roles of exosomes in modulating immune responses in cance...

Authors: Paul Kurywchak, Jena Tavormina and Raghu Kalluri

Detection of Creutzfeldt-Jakob disease prions in skin: implications for healthcare

Evidence has recently been reported of prion seeding activity in skin tissue from patients with sporadic Creutzfeldt-Jakob disease (sCJD). This is relevant information for infection control measures during sur...

Authors: Akin Nihat and Simon Mead

Advances in liquid biopsy approaches for early detection and monitoring of cancer

Progress in sensitive analytical approaches has opened new avenues for the detection of cells or products such as circulating cell-free DNA released by tumors. These ‘liquid biopsies’ are being explored in cli...

Authors: Anna Babayan and Klaus Pantel