Annual Review of Genomics and Human Genetics - Volume 14, 2013
Volume 14, 2013
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The Role of the Inherited Disorders of Hemoglobin, the First “Molecular Diseases,” in the Future of Human Genetics
Vol. 14 (2013), pp. 1–24More LessAlthough the inherited hemoglobin disorders were the first genetic diseases to be explored at the molecular level, they still have important messages for the future of medical genetics. In particular, they can offer a better understanding of the evolutionary and population biology of genetic disease, the mechanisms that underlie the phenotypic diversity of monogenic disease, and how, by developing appropriate partnerships, richer countries can help low-income countries to evolve programs for the control and management of these diseases where, in many cases, they are particularly common.
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Genetic Analysis of Hypoxia Tolerance and Susceptibility in Drosophila and Humans
Vol. 14 (2013), pp. 25–43More LessOxygen is essential for metazoans' life on earth. Oxygen deprivation, or hypoxia, contributes significantly to the pathophysiology of many human diseases. A better understanding of the fundamental molecular and genetic basis for adaptation to low-oxygen environments will help us develop therapeutic strategies to prevent or treat diseases that have hypoxia as a major part of their pathogenesis. Different cells and organisms have evolved different ways to cope with this life-threatening challenge, and the molecular and genetic mechanisms remain largely unknown. The current revolution of genomic technology has advanced our understanding of the genetic basis of many diseases and conditions, including hypoxia tolerance and susceptibility. In this review, we highlight the progress made in understanding the molecular responses to hypoxia in an animal model organism (Drosophila melanogaster) and genetic adaptation to high-altitude hypoxia in humans.
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The Genomics of Memory and Learning in Songbirds
Vol. 14 (2013), pp. 45–65More LessSongbirds have unique value as a model for memory and learning. In their natural social life, they communicate through vocalizations that they must learn to produce and recognize. Song communication elicits abrupt changes in gene expression in regions of the forebrain responsible for song perception and production—what is the functional significance of this genomic response? For 20 years, the focus of research was on just a few genes [primarily ZENK, now known as egr1 (early gene response 1)]. Recently, however, DNA microarrays have been developed and applied to songbird behavioral research, and in 2010 the initial draft assembly of the zebra finch genome was published. Together, these new data reveal that the genomic involvement in song processing is far more complex than anticipated. The concepts of neurogenomic computation and biological embedding are introduced as frameworks for future research.
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The Spatial Organization of the Human Genome
Vol. 14 (2013), pp. 67–84More LessIn vivo, the human genome functions as a complex, folded, three-dimensional chromatin polymer. Understanding how the human genome is spatially organized and folded inside the cell nucleus is therefore central to understanding how genes are regulated in normal development and dysregulated in disease. Established light microscopy–based approaches and more recent molecular chromosome conformation capture methods are now combining to give us unprecedented insight into this fascinating aspect of human genomics.
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X Chromosome Inactivation and Epigenetic Responses to Cellular Reprogramming
Vol. 14 (2013), pp. 85–110More LessReprogramming somatic cells to derive induced pluripotent stem cells (iPSCs) has provided a new method to model disease and holds great promise for regenerative medicine. Although genetically identical to their donor somatic cells, iPSCs undergo substantial changes in the epigenetic landscape during reprogramming. One such epigenetic process, X chromosome inactivation (XCI), has recently been shown to vary widely in human female iPSCs and embryonic stem cells (ESCs). XCI is a form of dosage compensation whose chief regulator is the noncoding RNA Xist. In mouse iPSCs and ESCs, Xist expression and XCI strictly correlate with the pluripotent state, but no such correlation exists in humans. Lack of XIST expression in human cells is linked to reduced developmental potential and an altered transcriptional profile, including upregulation of genes associated with cancer, which has therefore led to concerns about the safety of pluripotent stem cells for use in regenerative medicine. In this review, we describe how different states of XIST expression define three classes of female human pluripotent stem cells and explore progress in discovering the reasons for these variations and how they might be countered.
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Genetic Interaction Networks: Toward an Understanding of Heritability
Vol. 14 (2013), pp. 111–133More LessUnderstanding the relationship between the genotypes and phenotypes of individuals is key for identifying genetic variants responsible for disease and developing successful therapeutic strategies. Mapping the phenotypic effects of individual genetic variants and their combinations in human populations presents numerous practical and statistical challenges. However, model organisms, such as the budding yeast Saccharomyces cerevisiae, provide an incredible set of molecular tools and advanced technologies that should be able to efficiently perform this task. In particular, large-scale genetic interaction screens in yeast and other model systems have revealed common properties of genetic interaction networks, many of which appear to be maintained over extensive evolutionary distances. Indeed, despite relatively low conservation of individual genes and their pairwise interactions, the overall topology of genetic interaction networks and the connections between broad biological processes may be similar in most organisms. Taking advantage of these general principles should provide a fundamental basis for mapping and predicting genetic interaction networks in humans.
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Genome Engineering at the Dawn of the Golden Age
Vol. 14 (2013), pp. 135–158More LessGenome engineering—the ability to precisely alter the DNA information in living cells—is beginning to transform human genetics and genomics. Advances in tools and methods have enabled genetic modifications ranging from the “scarless” correction of a single base pair to the deletion of entire chromosomes. Targetable nucleases are leading the advances in this field, providing the tools to modify any gene in seemingly any organism with high efficiency. Targeted gene alterations have now been reported in more than 30 diverse species, ending the reign of mice as the exclusive model of mammalian genetics, and targetable nucleases have been used to modify more than 150 human genes and loci. A nuclease has also already entered clinical trials, signaling the beginning of genome engineering as therapy. The recent dramatic increase in the number of investigators using these techniques signifies a transition away from methods development toward a new age of exciting applications.
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Cellular Assays for Drug Discovery in Genetic Disorders of Intracellular Trafficking
Vol. 14 (2013), pp. 159–190More LessIntracellular membrane trafficking is essential for organelle biogenesis, structure, and function; the exchange of material between organelles; and communication between the cell and its external environment. Genetic disorders affecting intracellular trafficking can lead to a variety of human diseases, but specific therapies for these diseases are notably lacking. In this article, we focus on how current knowledge about genetic disorders that affect intracellular trafficking can be used to develop strategies for cell-based assays in order to identify drugs using high-content screening approaches.
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The Genetic Landscapes of Autism Spectrum Disorders
Vol. 14 (2013), pp. 191–213More LessThe autism spectrum disorders (ASD) are characterized by impairments in social interaction and stereotyped behaviors. For the majority of individuals with ASD, the causes of the disorder remain unknown; however, in up to 25% of cases, a genetic cause can be identified. Chromosomal rearrangements as well as rare and de novo copy-number variants are present in ∼10–20% of individuals with ASD, compared with 1–2% in the general population and/or unaffected siblings. Rare and de novo coding-sequence mutations affecting neuronal genes have also been identified in ∼5–10% of individuals with ASD. Common variants such as single-nucleotide polymorphisms seem to contribute to ASD susceptibility, but, taken individually, their effects appear to be small. Despite a heterogeneous genetic landscape, the genes implicated thus far—which are involved in chromatin remodeling, metabolism, mRNA translation, and synaptic function—seem to converge in common pathways affecting neuronal and synaptic homeostasis. Animal models developed to study these genes should lead to a better understanding of the diversity of the genetic landscapes of ASD.
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The Genetic Theory of Infectious Diseases: A Brief History and Selected Illustrations
Vol. 14 (2013), pp. 215–243More LessUntil the mid-nineteenth century, life expectancy at birth averaged 20 years worldwide, owing mostly to childhood fevers. The germ theory of diseases then gradually overcame the belief that diseases were intrinsic. However, around the turn of the twentieth century, asymptomatic infection was discovered to be much more common than clinical disease. Paradoxically, this observation barely challenged the newly developed notion that infectious diseases were fundamentally extrinsic. Moreover, interindividual variability in the course of infection was typically explained by the emerging immunological (or somatic) theory of infectious diseases, best illustrated by the impact of vaccination. This powerful explanation is, however, best applicable to reactivation and secondary infections, particularly in adults; it can less easily account for interindividual variability in the course of primary infection during childhood. Population and clinical geneticists soon proposed a complementary hypothesis, a germline genetic theory of infectious diseases. Over the past century, this idea has gained some support, particularly among clinicians and geneticists, but has also encountered resistance, particularly among microbiologists and immunologists. We present here the genetic theory of infectious diseases and briefly discuss its history and the challenges encountered during its emergence in the context of the apparently competing but actually complementary microbiological and immunological theories. We also illustrate its recent achievements by highlighting inborn errors of immunity underlying eight life-threatening infectious diseases of children and young adults. Finally, we consider the far-reaching biological and clinical implications of the ongoing human genetic dissection of severe infectious diseases.
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The Genetics of Common Degenerative Skeletal Disorders: Osteoarthritis and Degenerative Disc Disease
Vol. 14 (2013), pp. 245–256More LessDegenerative skeletal disorders are common and serious problems worldwide, especially in aging populations. They are polygenic diseases influenced by both genetic and environmental factors, and hence the identification of susceptibility genes may provide clues to their etiology and pathogenesis, although this is still in its early stages. This review focuses on genetic studies of two representative degenerative skeletal disorders: osteoarthritis and degenerative disc disease. Genetic studies of these two diseases share common features and face similar problems, although their current statuses are very different. The two diseases have common susceptibility alleles—namely, the GDF5 rs143383 single-nucleotide polymorphism and the asporin D14 triplet repeat—which provides hints on how to investigate their genetic factors. The future success of genetic studies of these diseases will depend on accurate and reliable diagnostics, large-scale interpopulation association studies and replications, and consideration of environmental effects and related diseases with similar phenotypes.
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The Genetics of Melanoma: Recent Advances*
Vol. 14 (2013), pp. 257–279More LessCutaneous malignant melanoma results from the interplay of genetic, host, and environmental factors. Genetic factors implicated in melanoma etiology include inherited high-, intermediate-, and low-risk susceptibility genes as well as numerous somatic mutations in melanoma tumors. CDKN2A is the major high-risk melanoma susceptibility gene identified to date. Recent identification of low-risk loci has been accomplished predominantly through genome-wide association studies. Whole-exome and whole-genome studies have identified numerous genes somatically altered in melanoma tumors and highlighted a higher mutation load in melanoma tumors compared with those in other cancers. This higher load is believed to be attributable to the preponderance of cytosine-to-thymine nucleotide substitutions as a result of UV radiation exposure. Technological advances, particularly next-generation sequencing, have increased the opportunities for germline and somatic gene discovery in melanoma and are opening up new avenues for understanding melanoma pathogenesis as well as leading to new opportunities for treatment.
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The Genomics of Emerging Pathogens
Vol. 14 (2013), pp. 281–300More LessGlobalization and industrialization have dramatically altered the vulnerability of human and animal populations to emerging and reemerging infectious diseases while shifting both the scale and pace of disease outbreaks. Fortunately, the advent of high-throughput DNA sequencing platforms has also increased the speed with which such pathogens can be detected and characterized as part of an outbreak response effort. It is now possible to sequence the genome of a pathogen rapidly, inexpensively, and with high sensitivity, transforming the fields of diagnostics, surveillance, forensic analysis, and pathogenesis. Here, we review advances in methods for microbial discovery and characterization, as well as strategies for testing the clinical and public health significance of microbe-disease associations. Finally, we discuss how genetic data can inform our understanding of the general process of pathogen emergence.
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Major Histocompatibility Complex Genomics and Human Disease
Vol. 14 (2013), pp. 301–323More LessOver several decades, various forms of genomic analysis of the human major histocompatibility complex (MHC) have been extremely successful in picking up many disease associations. This is to be expected, as the MHC region is one of the most gene-dense and polymorphic stretches of human DNA. It also encodes proteins critical to immunity, including several controlling antigen processing and presentation. Single-nucleotide polymorphism genotyping and human leukocyte antigen (HLA) imputation now permit the screening of large sample sets, a technique further facilitated by high-throughput sequencing. These methods promise to yield more precise contributions of MHC variants to disease. However, interpretation of MHC-disease associations in terms of the functions of variants has been problematic. Most studies confirm the paramount importance of class I and class II molecules, which are key to resistance to infection. Infection is likely driving the extreme variation of these genes across the human population, but this has been difficult to demonstrate. In contrast, many associations with autoimmune conditions have been shown to be specific to certain class I and class II alleles. Interestingly, conditions other than infections and autoimmunity are also associated with the MHC, including some cancers and neuropathies. These associations could be indirect, owing, for example, to the infectious history of a particular individual and selective pressures operating at the population level.
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Mapping of Immune-Mediated Disease Genes
Vol. 14 (2013), pp. 325–353More LessGenetic studies in immune-mediated diseases have yielded a large number of disease-associated loci. Here we review the progress being made in 12 such diseases, for which 199 independently associated non-HLA loci have been identified by genome-wide association studies since 2007. It is striking that many of the loci are not unique to a single disease but shared between different immune-mediated diseases. The challenge now is to understand how the unique and shared genetic factors can provide insight into the underlying disease biology. We annotated disease-associated variants using the Encyclopedia of DNA Elements (ENCODE) database and demonstrate that, of the predisposing disease variants, the majority have the potential to be regulatory. We also demonstrate that many of these variants affect the expression of nearby genes. Furthermore, we summarize results from the Immunochip, a custom array, which allows a detailed comparison between five of the diseases that have so far been analyzed using this platform.
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The RASopathies
Vol. 14 (2013), pp. 355–369More LessThe RASopathies are a clinically defined group of medical genetic syndromes caused by germline mutations in genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) pathway. These disorders include neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with multiple lentigines, capillary malformation–arteriovenous malformation syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, and Legius syndrome. Because of the common underlying Ras/MAPK pathway dysregulation, the RASopathies exhibit numerous overlapping phenotypic features. The Ras/MAPK pathway plays an essential role in regulating the cell cycle and cellular growth, differentiation, and senescence, all of which are critical to normal development. Therefore, it is not surprising that Ras/MAPK pathway dysregulation has profound deleterious effects on both embryonic and later stages of development. The Ras/MAPK pathway has been well studied in cancer and is an attractive target for small-molecule inhibition to treat various malignancies. The use of these molecules to ameliorate developmental defects in the RASopathies is under consideration.
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Translational Genetics for Diagnosis of Human Disorders of Sex Development
Vol. 14 (2013), pp. 371–392More LessDisorders of sex development (DSDs) are congenital conditions with discrepancies between the chromosomal, gonadal, and phenotypic sex of the individual. Such disorders have historically been difficult to diagnose and cause great stress to patients and their families. Genetic analysis of human samples has been instrumental in elucidating the molecules and pathways involved in the development of the bipotential gonad into a functioning testis or ovary. However, many DSD patients still do not receive a genetic diagnosis. New genetic and genomic technologies are expanding our knowledge of the underlying mechanism of DSDs and opening new avenues for clinical diagnosis. We review the genetic technologies that have elucidated the genes that are well established in sex determination in humans, discuss findings from more recent genomic technologies, and propose a new paradigm for clinical diagnosis of DSDs.
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Marsupials in the Age of Genomics
Vol. 14 (2013), pp. 393–420More LessMarsupials are “alternative mammals” that differ from eutherians most spectacularly in their mode of reproduction and sexual differentiation. They represent a 160-million-year-old isolate from the more numerous eutherians, making them particularly valuable for comparative genome studies that enlarge and enhance our understanding of the function and evolution of the mammalian genome. The genomes of three sequenced marsupial species are similar in size to those of mice and humans but show informative differences in base composition and repetitive elements. Small differences in gene sets and gene families between marsupials and eutherians may relate to physiological and environmental differences. Marsupial karyotypes are highly conserved in chromosome numbers, sizes, and G-banding patterns, and an ancestor with a 2n = 14 karyotype can be deduced. Marsupial sex chromosomes, partly homologous to those of eutherians, represent the ancestral therian XY pair. Epigenetic regulation of X inactivation in marsupials differs markedly from that of eutherians and has apparently retained an ancient silencing mechanism. Genomic imprinting of a smaller set of genes occurs in the marsupial placenta and, uniquely, in the mammary gland.
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Dissecting Quantitative Traits in Mice
Vol. 14 (2013), pp. 421–439More LessProgress in complex trait mapping in mice has been accelerated by the development of new populations suited to high-resolution mapping and by statistical methodologies that control for population structure. When combined with newly acquired catalogs of sequence variation in inbred strains, the genetic architecture of these new populations makes it possible to dissect complex traits down to the level of single variants. These analyses have shown not only that complex traits are caused by multiple contributing loci but also that each locus is likely due to the combined effects of multiple causal DNA variants. In combination with new rapid methods for producing transgenic mice that make it efficient to test candidate genes and variants, these advances significantly enhance the mouse genetics toolbox for dissecting quantitative traits.
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The Power of Meta-Analysis in Genome-Wide Association Studies
Vol. 14 (2013), pp. 441–465More LessMeta-analysis of multiple genome-wide association (GWA) studies has become common practice over the past few years. The main advantage of this technique is the maximization of power to detect subtle genetic effects for common traits. Moreover, one can use meta-analysis to probe and identify heterogeneity in the effect sizes across the combined studies. In this review, we systematically appraise and evaluate the characteristics of GWA meta-analyses with 10,000 or more subjects published up to June 2012. We provide an overview of the current landscape of variants discovered by GWA meta-analyses, and we discuss and assess with extrapolations from empirical data the value of larger meta-analyses for the discovery of additional genetic associations and new biology in the future. Finally, we discuss some emerging logistical and practical issues related to the conduct of meta-analysis of GWA studies.
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Previous Volumes
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Volume 25 (2024)
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Volume 24 (2023)
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Volume 23 (2022)
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Volume 22 (2021)
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Volume 21 (2020)
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Volume 20 (2019)
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Volume 19 (2018)
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Volume 18 (2017)
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Volume 17 (2016)
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Volume 16 (2015)
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Volume 15 (2014)
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Volume 14 (2013)
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Volume 13 (2012)
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Volume 12 (2011)
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Volume 11 (2010)
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Volume 10 (2009)
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Volume 9 (2008)
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Volume 8 (2007)
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Volume 7 (2006)
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Volume 6 (2005)
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Volume 5 (2004)
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Volume 4 (2003)
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Volume 3 (2002)
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Volume 2 (2001)
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Volume 1 (2000)
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Volume 0 (1932)