Annual Review of Genomics and Human Genetics - Volume 17, 2016

It is my great pleasure to have been asked by the Editorial Committee of the Annual Review of Genomics and Human Genetics to write a short autobiography of my life in genetics over the past 70 years. It has been a great adventure. I came both to America and to human genetics by a circuitous and ultimately very fortunate route. I hope the next generation of geneticists will enjoy reading about it.

Genome function, replication, integrity, and propagation rely on the dynamic structural organization of chromosomes during the cell cycle. Genome folding in interphase provides regulatory segmentation for appropriate transcriptional control, facilitates ordered genome replication, and contributes to genome integrity by limiting illegitimate recombination. Here, we review recent high-resolution chromosome conformation capture and functional studies that have informed models of the spatial and regulatory compartmentalization of mammalian genomes, and discuss mechanistic models for how CTCF and cohesin control the functional architecture of mammalian chromosomes.

As a species, we possess unique biological features that distinguish us from other primates. Here, we review recent efforts to identify changes in gene regulation that drove the evolution of novel human phenotypes. We discuss genotype-directed comparisons of human and nonhuman primate genomes to identify human-specific genetic changes that may encode new regulatory functions. We also review phenotype-directed approaches, which use comparisons of gene expression or regulatory function in homologous human and nonhuman primate cells and tissues to identify changes in expression levels or regulatory activity that may be due to genetic changes in humans. Together, these studies are beginning to reveal the landscape of regulatory innovation in human evolution and point to specific regulatory changes for further study. Finally, we highlight two novel strategies to model human-specific regulatory functions in vivo: primate induced pluripotent stem cells and the generation of humanized mice by genome editing.

Beyond coding for proteins, RNA molecules have well-established functions in the posttranscriptional regulation of gene expression. Less clear are the upstream roles of RNA in regulating transcription and chromatin-based processes in the nucleus. RNA is transcribed in the nucleus, so it is logical that RNA could play diverse and broad roles that would impact human physiology. Indeed, this idea is supported by well-established examples of noncoding RNAs that affect chromatin structure and function. There has been dramatic growth in studies focused on the nuclear roles of long noncoding RNAs (lncRNAs). Although little is known about the biochemical mechanisms of these lncRNAs, there is a developing consensus regarding the challenges of defining lncRNA function and mechanism. In this review, we examine the definition, discovery, functions, and mechanisms of lncRNAs. We emphasize areas where challenges remain and where consensus among laboratories has underscored the exciting ways in which human lncRNAs may affect chromatin biology.

The term next-generation sequencing is almost a decade old, but it remains the colloquial way to describe highly parallel or high-output sequencing methods that produce data at or beyond the genome scale. Since the introduction of these technologies, the number of applications and methods that leverage the power of genome-scale sequencing has increased at an exponential pace. This review highlights recent concepts, technologies, and methods from next-generation sequencing to illustrate the breadth and depth of the applications and research areas that are driving progress in genomics.

Over the past few years, interest in the identification of rare variants that influence human phenotype has led to the development of many statistical methods for testing for association between sets of rare variants and binary or quantitative traits. Here, I review some of the most important ideas that underlie these methods and the most relevant issues when choosing a method for analysis. In addition to the tests for association, I review crucial issues in performing a rare variant study, from experimental design to interpretation and validation. I also discuss the many challenges of these studies, some of their limitations, and future research directions.

The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system, a versatile RNA-guided DNA targeting platform, has been revolutionizing our ability to modify, manipulate, and visualize the human genome, which greatly advances both biological research and therapeutics development. Here, we review the current development of CRISPR/Cas9 technologies for gene editing, transcription regulation, genome imaging, and epigenetic modification. We discuss the broad application of this system to the study of functional genomics, especially genome-wide genetic screening, and to therapeutics development, including establishing disease models, correcting defective genetic mutations, and treating diseases.

Cystic fibrosis (CF) is the most common life-shortening autosomal recessive disorder in the Caucasian population and occurs in many other ethnicities worldwide. The daily treatment burden is substantial for CF patients even when they are well, with numerous pharmacologic and physical therapies targeting lung disease requiring the greatest time commitment. CF treatments continue to advance with greater understanding of factors influencing long-term morbidity and mortality. In recent years, in-depth understanding of genetic and protein structure-function relationships has led to the introduction of targeted therapies for patients with specific CF genotypes. With these advances, CF has become a model of personalized or precision medicine. The near future will see greater access to targeted therapies for most patients carrying common mutations, which will mandate individualized bench-to-bedside methodologies for those with rare genotypes.

The perinatal period is a window of susceptibility for later life disease. Recent epigenetic findings are beginning to increase our understanding of the molecular mechanisms that may contribute to the programming of obesity. This review summarizes recent evidence that supports the role of epigenetically mediated early life programming in the later onset of obesity. Establishing such links between environmental exposures and modifiable molecular changes ultimately holds promise to inform interventional efforts toward alleviating the environmentally mediated onset of obesity.

The emergence and reemergence of rapidly evolving RNA viruses—particularly those responsible for respiratory diseases, such as influenza viruses and coronaviruses—pose a significant threat to global health, including the potential of major pandemics. Importantly, recent advances in high-throughput genome sequencing enable researchers to reveal the genomic diversity of these viral pathogens at much lower cost and with much greater precision than they could before. In particular, the genome sequence data generated allow inferences to be made on the molecular basis of viral emergence, evolution, and spread in human populations in real time. In this review, we introduce recent computational methods that analyze viral genomic data, particularly in combination with metadata such as sampling time, geographic location, and virulence. We then outline the insights these analyses have provided into the fundamental patterns and processes of evolution and emergence in human respiratory RNA viruses, as well as the major challenges in such genomic analyses.

Some de novo human mutations arise at frequencies far exceeding the genome average mutation rate. Examples include the common mutations at one or a few sites in the genes that cause achondroplasia, Apert syndrome, multiple endocrine neoplasia type 2B, and Noonan syndrome. These mutations are recurrent, provide a gain of function, are paternally derived, and are more likely to be transmitted as the father ages. Recent experiments have tested whether the high mutation frequencies are due to an elevated mutation rate per cell division, as expected, or to an advantage of the mutant spermatogonial stem cells over wild-type stem cells. The evidence, which includes the surprising discovery of testis mutation clusters, rules out the former model but not the latter. We propose how the mutations might alter spermatogonial stem cell function and discuss how germline selection contributes to the paternal age effect, the human mutational load, and adaptive evolution.

Autoinflammatory diseases are inborn disorders of the innate immune system characterized by episodes of systemic inflammation that are mediated largely by myeloid cells. The field of autoinflammatory diseases has been established since 1999, following the identification of the first genes underlying periodic fever syndromes. This review focuses on developments that have transformed the field in the last two years. We discuss three newly described monogenic autoinflammatory diseases [deficiency of adenosine deaminase 2 (DADA2), a subtype of macrophage activation syndrome (MAS), and stimulator of interferon genes (STING)–associated vasculopathy with onset in infancy (SAVI)], discuss the possibilities of somatic mosaicism and digenic inheritance, and give an update on new concepts in pathways involved in familial Mediterranean fever (FMF). Finally, the new monogenic autoinflammatory disease haploinsufficiency of A20 (HA20) underscores the placement of monogenic diseases in the firmament of common autoinflammatory phenotypes. The advances in the last two years have shed light on the pathophysiology of several autoinflammatory diseases and have elucidated new pathways that play a role in innate immunity.

Rheumatoid arthritis (RA) is the most common inflammatory arthritis and exhibits genetic overlap with other autoimmune and inflammatory disorders. Although predominant associations with the HLA-DRB1 locus have been known for decades, recent data have revealed additional insight into the likely causative variants within HLA-DRB1 as well as within other HLA loci that contribute to disease risk. In addition, more than 100 common variants in non-HLA loci have been implicated in disease susceptibility. Genetic factors are involved not only in the development of RA, but also with various disease subphenotypes, including production and circulating levels of autoantibodies and joint destruction. The major current challenge is to integrate these new data into a precise understanding of disease pathogenesis, including the critical cell types and molecular networks involved as well as interactions with environmental factors. We predict that delineating the functional effects of genetic variants is likely to drive new diagnostic and therapeutic approaches to the disease.

As with all fields of medicine, the first step toward medical management of genetic disorders is obtaining an accurate diagnosis, which often requires testing at the molecular level. Unfortunately, given the large number of genetic conditions without a specific intervention, only rarely does a genetic diagnosis alter patient management—which raises the question, what is the added value of obtaining a molecular diagnosis? Given the fast-paced advancement of genomic technologies, this is an important question to address in the context of genome-scale testing. Here, we address the value of establishing a diagnosis using genome-scale testing and highlight the benefits and drawbacks of such testing. We also review and compare recent major studies implementing genome-scale sequencing methods to identify a molecular diagnosis in cohorts manifesting a broad range of Mendelian monogenic disorders. Finally, we discuss potential future applications of genomic sequencing, such as screening for rare conditions.

Ebola virus (EBOV) emerged in West Africa in 2014 to devastating effect, and demonstrated that infection can cause a broad range of severe disease manifestations. As the virus itself was genetically similar to other Zaire ebolaviruses, the spectrum of pathology likely resulted from variable responses to infection in a large and genetically diverse population. This review comprehensively summarizes current knowledge of the host response to EBOV infection, including pathways hijacked by the virus to facilitate replication, host processes that contribute directly to pathogenesis, and host-pathogen interactions involved in subverting or antagonizing host antiviral immunity.

Beginning in the early 2000s, the accumulation of biospecimens linked to electronic health records (EHRs) made possible genome-phenome studies (i.e., comparative analyses of genetic variants and phenotypes) using only data collected as a by-product of typical health care. In addition to disease and trait genetics, EHRs proved a valuable resource for analyzing pharmacogenetic traits and developing reverse genetics approaches such as phenome-wide association studies (PheWASs). PheWASs are designed to survey which of many phenotypes may be associated with a given genetic variant. PheWAS methods have been validated through replication of hundreds of known genotype-phenotype associations, and their use has differentiated between true pleiotropy and clinical comorbidity, added context to genetic discoveries, and helped define disease subtypes, and may also help repurpose medications. PheWAS methods have also proven to be useful with research-collected data. Future efforts that integrate broad, robust collection of phenotype data (e.g., EHR data) with purpose-collected research data in combination with a greater understanding of EHR data will create a rich resource for increasingly more efficient and detailed genome-phenome analysis to usher in new discoveries in precision medicine.

Genomic research and biobanking are increasingly being conducted in the context of collaborations between researchers in high-income countries and those in low- and middle-income countries. Although these scientific advancements have presented unique opportunities for researchers to contribute to cutting-edge scientific projects and address important health problems, they have also challenged existing ethical and regulatory frameworks, particularly in sub-Saharan Africa. Broad consent is a model that allows the use of human biological samples and associated data in future research that may be unrelated to the original study. Drawing on emerging perspectives in low- and middle-income countries, we argue that broad consent is equivalent to consent to governance and that a robust governance framework for genomics and biobanking should seek to promote global health and research equity and take into account five key elements: respect, authentic community engagement and trust building, the preservation of privacy and confidentiality, feedback of results, and capacity strengthening.

Human biospecimens have played a crucial role in scientific and medical advances. Although the ethical and policy issues associated with biospecimen research have long been the subject of scholarly debate, the story of Henrietta Lacks, her family, and the creation of HeLa cells captured the attention of a much broader audience. The story has been a catalyst for policy change, including major regulatory changes proposed in the United States surrounding informed consent. These proposals are premised in part on public opinion data, necessitating a closer look at what such data tell us. The development of biospecimen policy should be informed by many considerations—one of which is public input, robustly gathered, on acceptable approaches that optimize shared interests, including access for all to the benefits of research. There is a need for consent approaches that are guided by realistic aspirations and a balanced view of autonomy within an expanded ethical framework.