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Genetics continues to play a crucial part in furthering our understanding of the basis of disease, from revealing biological pathways involved in pathogenesis to improving knowledge of the relative contributions of various genetic and environmental factors. The articles in this series focus on genetic studies of specific diseases or specific processes in pathogenesis.
Aneuploidy contributes to tumorigenesis, but the underlying processes are not well understood. This Review explains the context dependency of aneuploidy in cancer and discusses its clinical potential as a prognostic marker and a therapeutic target.
This article discusses how integrating different omics data types — such as DNA sequencing, transcriptomics and metabolomics — can provide a rich view of healthy and disease states, including novel clinical diagnoses. The authors discuss the value of the different data types, as well as strategies, considerations and challenges for multi-omic integration in various disease contexts.
DNA repeats are more liable to mutation than other genetic variants, which enables them to mediate genetic plasticity. The expansion of tandem repeats can cause a range of monogenic disorders, contribute to the missing heritability of polygenic disorders and regulate gene expression, as well as RNA and protein function, in healthy individuals.
Genomic technologies are providing a clearer picture of how nuclear receptors (NRs) regulate complex transcriptional networks and contribute to the development and progression of cancer. This deeper understanding of NRs will hopefully lead to improved prognostic tools and new therapeutic targets.
Recent large-scale genome-wide association studies have identified numerous variants that are associated with obesity-relevant traits such as body mass index or body fat percentage. Here, the authors explore to what extent this genomic evidence matches the evidence from functional and mechanistic studies.
Recent microbiome genome-wide association studies have identified numerous associations between human genetic variants and the gut microbiome. Here, the authors review how genetic variation in the host can alter the composition of the gut microbiome towards a disease state, with a focus on disorders of immunity and metabolism.
The abundance and heterogeneity of mutations in cancer create challenges for understanding their effects, but such functional characterization will be crucial for optimizing clinical care. In this Review, the authors discuss diverse computational tools and systems biology experimental strategies for elucidating the functional effects of cancer mutations, including consequences on gene regulation, protein structure and local and global perturbations of molecular interaction networks.
The past decade has seen tremendous progress in understanding the genetic architecture of coronary artery disease (CAD). Khera and Kathiresan review research efforts that have improved our understanding of the genetic drivers of CAD, and discuss the promises and challenges of integrating genetic information into routine clinical practice.
In this article, the author reviews the current understanding of the genetic basis for Down syndrome phenotypes, including congenital heart defects, Alzheimer disease and leukaemia. The potential for Down syndrome therapies is discussed in light of recent progress in the field.
Many genetic studies focus on germline-inherited genomic variation. However, there is increasing realization that mutations occurring during our lifetime are so frequent and pervasive that, in all likelihood, no two of our cells are truly genetically identical. In this Review, the authors describe the detection, molecular nature and dynamics of this under-appreciated post-zygotic variation, and discuss the implications for normal human physiology and disease.
Disruption to the epigenome is increasingly appreciated as a major contributor to the development of cancer. The authors discuss how conceptualizing genes affecting the epigenome as epigenetic modulators, epigenetic modifiers or epigenetic mediators provides a valuable framework for understanding diverse aspects of the causes and consequences of epigenome alteration in cancer.
Recent studies have revealed a ubiquitous role for genome architecture in the formation of structural variants at a given locus, both in DNA recombination-based and in DNA replication-based processes. These reports showcase the influence of repeat sequences on genomic stability and structural variant complexity and the tremendous plasticity and dynamic nature of our genome.
Genome-wide approaches have advanced the study into mechanisms triggering autoimmunity. This Review illustrates how this has been achieved for twelve common autoimmune diseases, and discusses recent functional genomics approaches that have the potential to help define key immune molecular traits, cell types and cell states.
Complex and intricate RNA splicing mechanisms are crucial for gene regulation and for maximizing proteomic diversity. This Review discusses how alterations to splicing mechanisms — such as mutations in pre-mRNAs, or mutations and dysregulation of core spliceosome proteins and other RNA-binding proteins — results in diverse molecular consequences and various diseases. Opportunities for therapeutic correction of these defects are also explored.
The study of the genetic basis of neurodevelopmental disorders and neurodegenerative diseases has progressed through recent large-scale association studies as well as the application of a range of high-throughput molecular methods. In this Review, the authors examine systems biology approaches and demonstrate how gene networks provide an organizing framework to integrate the analysis of large-scale genetic and molecular profiling data sets to characterize the genetic basis of phenotypes that affect the central nervous system.
Mendelian conditions, which are caused by dysfunction of a single gene, illustrate how the availability of the human genome sequence and tools for interrogating individual genomes can provide insights into disease. In this Review, cystic fibrosis is presented as an example of how genetics can continuously inform clinical research and practice.
Understanding disease pathogenesis and developing potential therapies require accurate and genetically tractable models. This Review discusses how human stem cells — including embryonic stem cells, adult stem cells and induced pluripotent stem cells — can provide informative models of diverse human diseases. Such methods can also be extended through gene editing, co-culture or infectious agent approaches.
Among rodent species, there is a wide diversity in lifespans and cancer susceptibilities, which makes comparative studies of rodents an attractive strategy for identifying molecular mechanisms that underlie ageing and cancer. This Review describes the various biological insights provided by comparative rodent genomics, including those from whole-genome sequencing of long-lived and highly cancer-resistant species. Such progress has potential implications for understanding and modulating human disease.
Imprinted genes influence a wide range of biological processes, the effects of which extend from prenatal stages to adulthood. This Review discusses the role of imprinted genes, with a focus on postnatal and adult phenotypes, and their contribution to common diseases such as intrauterine growth restriction, obesity, psychiatric disorders and cancer.
This Review describes how genomic technologies are providing novel insights intoMycobacterium tuberculosis, which is the causative agent of human tuberculosis. There has been progress in understanding the ancient evolutionary history of human-adapted M. tuberculosis, mutations underlying strain diversity and drug resistance, and the host–pathogen molecular interactions.
In the past few years, there have been rapid advances in the identification of the genetic components of autism spectrum disorders, particularly in the form ofde novomutations. Here, the authors review these developments in light of genetic models for autism spectrum disorders.
There is an increasing realization of epigenetic dysregulation in cancer, which comprises both the mutation of genes encoding epigenetic regulators and the broader disruptions to chromatin states of the epigenome. This Review discusses our latest understanding of these phenomena, their convergence and the implications for cancer biology and therapeutics.
Research into the genetics of immune and inflammatory disease has experienced major recent advances owing to the availability of a custom single-nucleotide polymorphism (SNP) genotyping array — the Immunochip — developed specifically to investigate these disorders. In this Analysis, the authors assess findings from studies that have used this platform, and explore the shared and phenotype-specific genetic associations among several immune-mediated diseases.
Mosaicism refers to genetic heterogeneity within an organism that arises from postzygotic mutational events. This Review describes our latest understanding of the diverse types and widespread nature of mosaicism that underlies normal human variation and, in particular, a wide range of clinical diseases.
This Review discusses the roles of mitochondrial DNA (mtDNA) mutations in human disease. In addition to many primary mitochondrial diseases, there is emerging — and sometimes controversial — evidence that mutations in mtDNA are involved in complex traits such as neurodegeneration, ageing and cancer.
Telomeres have long been implicated in processes of cellular ageing. This Review discusses how a diverse range of human diseases are now known to be caused by mutations that result in defective telomere maintenance and shortened telomeres. It describes the unique inheritance patterns of telomere defects and how telomere biology sheds light into several disease mechanisms.
This Review considers recent findings — from genome-wide association studies, structural variant studies and exome sequencing — about the genetics of nine psychiatric disorders. The authors evaluate the implications of our current picture of the genetic architectures of these conditions for future research strategies.
Genome-wide association studies have recently furthered the understanding of the genetics of osteoporosis. The authors here present the major findings from these studies, the pathways that have been highlighted in the progress of the disease and strategies for future diagnosis and therapy development.
Aneuploidy — an abnormal number of chromosomes — typically has a detrimental effect on viability. Somewhat paradoxically, it is a remarkably common feature of cancer. This Review discusses how aneuploidy occurs, the cellular responses to aneuploidy and how aneuploidy can provide particular selective advantages during tumorigenesis.
The role of non-coding RNAs (ncRNAs) in disease is best understood for microRNAs in cancer. However, there is increasing interest in the disease-related roles of other ncRNAs — including piRNAs, snoRNAs, T-UCRs and lncRNAs — and in using this knowledge for therapy.
Various genetic and functional studies have enhanced the understanding of type 1 diabetes susceptibility genes, including their roles in the underlying immune dysfunction. This Review summarizes the current understanding of type 1 diabetes genetics from the identification of novel susceptibility loci to functional characterization of new and established risk loci.
Genetic and genomic approaches — including high-throughput sequence analysis and transcriptomics experiments — are revealing a clearer picture of the pathophysiological steps underlying the different forms of heart failure (genetic and acquired) and the genomic responses to cardiac overload.
Clefts of the lip and/or palate are common and have a complex genetic and environmental basis. Recent work on these birth defects illustrates the value of combining genome-wide association studies, animal models and improved clinical phenotyping. Future work may also address gene–environment interactions.
Chronic stress is increasingly implicated as a contributing factor in common diseases, including cancer, cardiovascular disease and diabetes. This Opinion article brings together evidence supporting the idea that stress can induce epigenetic changes that alter cell behaviour and thereby lead to disease.
Expansions of repeat sequences cause some of the most common inherited neurological diseases. But how do repeats in DNA lead to pathogenesis? This Review considers the diverse mechanisms that are now emerging, including aberrant splicing, post-translational modification and autophagy.
Retinal degeneration due to photoreceptor cell death is a major cause of visual impairment in adults. Over one hundred genes have been implicated, so how does this genetic heterogeneity converge on a shared phenotype? The emerging insights have implications for therapy.
