Showing papers in "Annual Review of Genomics and Human Genetics in 2019"

Thinking About the Evolution of Complex Traits in the Era of Genome-Wide Association Studies

Abstract: Many traits of interest are highly heritable and genetically complex, meaning that much of the variation they exhibit arises from differences at numerous loci in the genome. Complex traits and their evolution have been studied for more than a century, but only in the last decade have genome-wide association studies (GWASs) in humans begun to reveal their genetic basis. Here, we bring these threads of research together to ask how findings from GWASs can further our understanding of the processes that give rise to heritable variation in complex traits and of the genetic basis of complex trait evolution in response to changing selection pressures (i.e., of polygenic adaptation). Conversely, we ask how evolutionary thinking helps us to interpret findings from GWASs and informs related efforts of practical importance.

The Causes and Consequences of Genetic Interactions (Epistasis)

Abstract: The same mutation can have different effects in different individuals. One important reason for this is that the outcome of a mutation can depend on the genetic context in which it occurs. This dep...

Advances in the Genetic Basis and Pathogenesis of Sarcomere Cardiomyopathies.

Abstract: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are common heart muscle disorders that are caused by pathogenic variants in sarcomere protein genes. HCM is characterized by unexplained cardiac hypertrophy (increased chamber wall thickness) that is accompanied by enhanced cardiac contractility and impaired relaxation. DCM is defined as increased ventricular chamber volume with contractile impairment. In this review, we discuss recent analyses that provide new insights into the molecular mechanisms that cause these conditions. HCM studies have uncovered the critical importance of conformational changes that occur during relaxation and enable energy conservation, which are frequently disturbed by HCM mutations. DCM studies have demonstrated the considerable prevalence of truncating variants in titin and have discerned that these variants reduce contractile function by impairing sarcomerogenesis. These new pathophysiologic mechanisms open exciting opportunities to identify new pharmacological targets and develop future cardioprotective strategies.

Massively Parallel Assays and Quantitative Sequence–Function Relationships

Abstract: Over the last decade, a rich variety of massively parallel assays have revolutionized our understanding of how biological sequences encode quantitative molecular phenotypes. These assays include deep mutational scanning, high-throughput SELEX, and massively parallel reporter assays. Here, we review these experimental methods and how the data they produce can be used to quantitatively model sequence-function relationships. In doing so, we touch on a diverse range of topics, including the identification of clinically relevant genomic variants, the modeling of transcription factor binding to DNA, the functional and evolutionary landscapes of proteins, and cis-regulatory mechanisms in both transcription and mRNA splicing. We further describe a unified conceptual framework and a core set of mathematical modeling strategies that studies in these diverse areas can make use of. Finally, we highlight key aspects of experimental design and mathematical modeling that are important for the results of such studies to be interpretable and reproducible.

Genomic Research Through an Indigenous Lens: Understanding the Expectations.

Abstract: Indigenous scholars are leading initiatives to improve access to genetic and genomic research and health care based on their unique cultural contexts and within sovereign-based governance models cr...

The Genetics of Human Skin and Hair Pigmentation.

Abstract: Human skin and hair color are visible traits that can vary dramatically within and across ethnic populations. The genetic makeup of these traits-including polymorphisms in the enzymes and signaling proteins involved in melanogenesis, and the vital role of ion transport mechanisms operating during the maturation and distribution of the melanosome-has provided new insights into the regulation of pigmentation. A large number of novel loci involved in the process have been recently discovered through four large-scale genome-wide association studies in Europeans, two large genetic studies of skin color in Africans, one study in Latin Americans, and functional testing in animal models. The responsible polymorphisms within these pigmentation genes appear at different population frequencies, can be used as ancestry-informative markers, and provide insight into the evolutionary selective forces that have acted to create this human diversity.

Genetic Etiologies, Diagnosis, and Treatment of Tuberous Sclerosis Complex.

Abstract: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems due to an inactivating variant in either TSC1 or TSC2, resulting in the hyperactivation of the mechanistic target of rapamycin (mTOR) pathway. Dysregulated mTOR signaling results in increased cell growth and proliferation. Clinically, TSC patients exhibit great phenotypic variability, but the neurologic and neuropsychiatric manifestations of the disease have the greatest morbidity and mortality. TSC-associated epilepsy occurs in nearly all patients and is often difficult to treat because it is refractory to multiple antiseizure medications. The advent of mTOR inhibitors offers great promise in the treatment of TSC-associated epilepsy and other neurodevelopmental manifestations of the disease; however, the optimal timing of therapeutic intervention is not yet fully understood.

tRNA Metabolism and Neurodevelopmental Disorders.

Abstract: tRNAs are short noncoding RNAs required for protein translation. The human genome includes more than 600 putative tRNA genes, many of which are considered redundant. tRNA transcripts are subject to tightly controlled, multistep maturation processes that lead to the removal of flanking sequences and the addition of nontemplated nucleotides. Furthermore, tRNAs are highly structured and posttranscriptionally modified. Together, these unique features have impeded the adoption of modern genomics and transcriptomics technologies for tRNA studies. Nevertheless, it has become apparent from human neurogenetic research that many tRNA biogenesis proteins cause brain abnormalities and other neurological disorders when mutated. The cerebral cortex, cerebellum, and peripheral nervous system show defects, impairment, and degeneration upon tRNA misregulation, suggesting that they are particularly sensitive to changes in tRNA expression or function. An integrated approach to identify tRNA species and contextually characterize tRNA function will be imperative to drive future tool development and novel therapeutic design for tRNA-associated disorders.

Measuring Clonal Evolution in Cancer with Genomics

Abstract: Cancers originate from somatic cells in the human body that have accumulated genetic alterations. These mutations modify the phenotype of the cells, allowing them to escape the homeostatic regulation that maintains normal cell number. Viewed through the lens of evolutionary biology, the transformation of normal cells into malignant cells is evolution in action. Evolution continues throughout cancer growth, progression, treatment resistance, and disease relapse, driven by adaptation to changes in the cancer's environment, and intratumor heterogeneity is an inevitable consequence of this evolutionary process. Genomics provides a powerful means to characterize tumor evolution, enabling quantitative measurement of evolving clones across space and time. In this review, we discuss concepts and approaches to quantify and measure this evolutionary process in cancer using genomics.

Lynch Syndrome: From Screening to Diagnosis to Treatment in the Era of Modern Molecular Oncology.

Abstract: Lynch syndrome is a hereditary cancer predisposition syndrome caused by germline alterations in the mismatch repair genes and is the most common etiology of hereditary colorectal cancer. While Lync...

The Genetics and Epigenetics of Facioscapulohumeral Muscular Dystrophy.

Abstract: Facioscapulohumeral muscular dystrophy (FSHD), a progressive myopathy that afflicts individuals of all ages, provides a powerful model of the complex interplay between genetic and epigenetic mechan...

Early Lessons from the Implementation of Genomic Medicine Programs.

Abstract: Massively parallel sequencing is emerging from research settings into clinical practice, helping the vision of precision medicine to become a reality. The most successful applications are using the...

Consanguinity and Inbreeding in Health and Disease in North African Populations.

Abstract: North Africa is defined as the geographical region separated from the rest of the continent by the Sahara and from Europe by the Mediterranean Sea. The main demographic features of North African populations are their familial structure and high rates of familial and geographic endogamy, which have a proven impact on health, particularly the occurrence of genetic diseases, with a greater effect on the frequency and spectrum of the rarest forms of autosomal recessive genetic diseases. More than 500 different genetic diseases have been reported in this region, most of which are autosomal recessive. During the last few decades, there has been great interest in the molecular investigation of large consanguineous North African families. The development of local capacities has brought a substantial improvement in the molecular characterization of these diseases, but the genetic bases of half of them remain unknown. Diseases of known molecular etiology are characterized by their genetic and mutational heterogeneity, although some founder mutations are encountered relatively frequently. Some founder mutations are specific to a single country or a specific ethnic or geographic group, and others are shared by all North African countries or worldwide. The impact of consanguinity on common multifactorial diseases is less evident.

The Future of Genomic Studies Must Be Globally Representative: Perspectives from PAGE.

Abstract: The past decade has seen a technological revolution in human genetics that has empowered population-level investigations into genetic associations with phenotypes. Although these discoveries rely on genetic variation across individuals, association studies have overwhelmingly been performed in populations of European descent. In this review, we describe limitations faced by single-population studies and provide an overview of strategies to improve global representation in existing data sets and future human genomics research via diversity-focused, multiethnic studies. We highlight the successes of individual studies and meta-analysis consortia that have provided unique knowledge. Additionally, we outline the approach taken by the Population Architecture Using Genomics and Epidemiology (PAGE) study to develop best practices for performing genetic epidemiology in multiethnic contexts. Finally, we discuss how limiting investigations to single populations impairs findings in the clinical domain for both rare-variant identification and genetic risk prediction.

Gene and Induced Pluripotent Stem Cell Therapy for Retinal Diseases.

Abstract: Given the importance of visual information to many daily activities, retinal degenerative diseases-which include both inherited conditions (such as retinitis pigmentosa) and acquired conditions (such as age-related macular degeneration)-can have a dramatic impact on human lives. The therapeutic options for these diseases remain limited. Since the discovery of the first causal gene for retinitis pigmentosa almost three decades ago, more than 250 genes have been identified, and gene therapies have been rapidly developed. Simultaneously, stem cell technologies such as induced pluripotent stem cell-based transplantation have advanced and have been applied to the treatment of retinal degenerative diseases. Here, we review recent progress in these expanding fields and discuss the potential for precision medicine in ophthalmic care.

Genetic Predisposition to Childhood Cancer in the Genomic Era.

Abstract: Developments over the past five years have significantly advanced our ability to use genome-scale analyses—including high-density genotyping, transcriptome sequencing, exome sequencing, and genome ...

Epigenetic Regulation and Risk Factors During the Development of Human Gametes and Early Embryos

Abstract: Drastic epigenetic reprogramming occurs during human gametogenesis and early embryo development. Advances in low-input and single-cell epigenetic techniques have provided powerful tools to dissect the genome-wide dynamics of different epigenetic molecular layers in these processes. In this review, we focus mainly on the most recent progress in understanding the dynamics of DNA methylation, chromatin accessibility, and histone modifications in human gametogenesis and early embryo development. Deficiencies in remodeling of the epigenomes can cause severe developmental defects, infertility, and long-term health issues in offspring. Aspects of the external environment, including assisted reproductive technology procedures, parental diets, and unhealthy parental habits, may disturb the epigenetic reprogramming processes and lead to an aberrant epigenome in the offspring. Here, we review the current knowledge of the potential risk factors of aberrant epigenomes in humans.

The Status and Impact of Clinical Tumor Genome Sequencing.

Abstract: Since the discovery that DNA alterations initiate tumorigenesis, scientists and clinicians have been exploring ways to counter these changes with targeted therapeutics. The sequencing of tumor DNA ...

Pregnancy Immunogenetics and Genomics: Implications for Pregnancy-Related Complications and Autoimmune Disease.

Abstract: Pregnancy presents a singular physiological scenario during which the maternal immune system must accommodate the semiallogeneic fetus. Fluctuations between pro- and anti-inflammatory states are required throughout gestation to facilitate uterine tissue remodeling, fetal growth and development, and finally birth. Tolerance for the fetus must be established and maintained without fundamentally compromising the maternal immune system function, so that both the mother and fetus are protected from foreign insults. Here, we review our current understanding of how genetic variation at both maternal and fetal loci affects implantation and placenta formation, thereby determining the likelihood of a successful pregnancy outcome or the development of pregnancy-related complications. We also consider the impact of pregnancy on both the maternal and fetal systemic immune systems and the related implications for modulating ongoing autoimmune diseases and triggering their development.

Roles of Extracellular Vesicles in High-Grade Gliomas: Tiny Particles with Outsized Influence

Abstract: High-grade gliomas, particularly glioblastomas (grade IV), are devastating diseases with dismal prognoses; afflicted patients seldom live longer than 15 months, and their quality of life suffers immensely. Our current standard-of-care therapy has remained essentially unchanged for almost 15 years, with little new therapeutic progress. We desperately need a better biologic understanding of these complicated tumors in a complicated organ. One area of rejuvenated study relates to extracellular vesicles (EVs)-membrane-enclosed nano- or microsized particles that originate from the endosomal system or are shed from the plasma membrane. EVs contribute to tumor heterogeneity (including the maintenance of glioma stem cells or their differentiation), the impacts of hypoxia (angiogenesis and coagulopathies), interactions amid the tumor microenvironment (concerning the survival of astrocytes, neurons, endothelial cells, blood vessels, the blood-brain barrier, and the ensuing inflammation), and influences on the immune system (both stimulatory and suppressive). This article reviews glioma EVs and the ways that EVs manifest themselves as autocrine, paracrine, and endocrine factors in proximal and distal intra- and intercellular communications. The reader should note that there is much controversy, and indeed confusion, in the field over the exact roles for EVs in many biological processes, and we will engage some of these difficulties herein.

The Development of Human Genetics at the National Research Centre, Cairo, Egypt: A Story of 50 Years

Abstract: This article describes my experiences over more than 50 years in initiating and maintaining research on human genetics and genomics at the National Research Centre in Cairo, Egypt, from its beginni...

International Divergence in Gene Patenting.

Abstract: This review explores the recent divergence in international patent law relating to genes and associated subject matter. This divergence stems primarily from decisions of the highest courts in the United States and Australia on the eligibility of patent claims relating to the BRCA gene sequences. Patent offices, courts, and policy makers have struggled for many years to clearly articulate the bounds of patent claims on isolated and synthetic DNA and related products and processes, including methods for their use in genetic diagnostics. This review provides context to the current divergence by mapping key events in the gene patent journey from the early 1980s onward in five key jurisdictions: the United States, the member states of the European Patent Convention, Australia, Canada, and China. Early approaches to gene patenting had some commonalities across jurisdictions, which makes exploration of the recent divergence all the more interesting.There is insufficient empirical evidence to date to confidently predict the consequences of this recent divergence. However, it could potentially have a significant effect on local industry and on consumer access.