Annual Review of Genomics and Human Genetics - Volume 9, 2008
Volume 9, 2008
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Human Telomere Structure and Biology
Vol. 9 (2008), pp. 1–19More LessHuman telomeric DNA is complex and highly variable. Subterminal sequences are associated with cis-acting determinants of allele-specific (TTAGGG)n tract length regulation and may modulate susceptibility of (TTAGGG)n tracts to rapid deletion events. More extensive subtelomeric DNA tracts are filled with segmental duplications and segments that vary in copy number, leading to highly variable subtelomeric allele structures in the human population. RNA transcripts encoded in telomere regions include multicopy protein-encoding gene families and a variety of noncoding RNAs. One recently described family of (UUAGGG)n-containing subterminal RNAs appears to be critical for telomere integrity; these RNAs associate with telomeric chromatin and are regulated by RNA surveillance factors including human homologs of the yeast Est1p protein. An increasingly detailed and complete picture of telomeric DNA sequence organization and structural variation is essential for understanding and tracking allele-specific subterminal and subtelomeric features critical for human biology.
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Infectious Disease in the Genomic Era
Vol. 9 (2008), pp. 21–48More LessAfter half a century of success in combating infectious diseases with vaccination and antibiotics, emerging and reemerging epidemics present a new threat to human health. Meanwhile, the rapid pace of viral and microbial genomics research, largely based on the success of genomics technologies, offers new data-generating platforms and a revolutionary knowledge base for better understanding the diseases and the associated pathogens. Systematic molecular biology studies using genomics information and technologies have helped to elucidate mechanisms of virulence and pathogenicity, whereas genomics-based medical genetic studies have been used to better understand pathogen susceptibility. This progress may lead to the development of effective and safe vaccines in the future. Here we highlight the ongoing historical transition in the field of infectious disease research and clinical practice in the new era of genomics.
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ENU Mutagenesis, a Way Forward to Understand Gene Function
Vol. 9 (2008), pp. 49–69More LessArguably, the main challenge for contemporary genetics is to understand the function of every gene in a mammalian genome. The mouse has emerged as a model for this task because its genome can be manipulated in a number of ways to study gene function or mimic disease states. Two complementary genetic approaches can be used to generate mouse models. A reverse genetics or gene-driven approach (gene to phenotype) starts from a known gene and manipulates the genome to create genetically modified mice, such as knockouts. Alternatively, a forward genetics or phenotype-driven approach (phenotype to gene) involves screening mice for mutant phenotypes without previous knowledge of the genetic basis of the mutation. N-ethyl-N-nitrosourea (ENU) mutagenesis has been widely used for both approaches to generate mouse mutants. Here we review progress in ENU mutagenesis screening, with an emphasis on creating mouse models for human disorders.
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Clinical Utility of Contemporary Molecular Cytogenetics
Vol. 9 (2008), pp. 71–86More LessThe development of microarray-based comparative genomic hybridization (array CGH) methods represents a critical new advance in molecular cytogenetics. This new technology has driven a technical convergence between molecular diagnostics and clinical cytogenetics, questioned our naïve understanding of the complexity of the human genome, revolutionized the practice of medical genetics, challenged conventional wisdom related to the genetic bases of multifactorial and sporadic conditions, and is poised to impact all areas of medicine. The use of contemporary molecular cytogenetic techniques in research and diagnostics has resulted in the identification of many new syndromes, expanded our knowledge about the phenotypic spectrum of recognizable syndromes, elucidated the genomic bases of well-established clinical conditions, and refined our view about the molecular mechanisms of some chromosomal aberrations. Newer methodologies are being developed, which will likely lead to a new understanding of the genome and its relationship to health and disease.
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The Role of Aminoacyl-tRNA Synthetases in Genetic Diseases*
Vol. 9 (2008), pp. 87–107More LessAminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed, essential enzymes responsible for performing the first step of protein synthesis. Specifically, ARSs attach amino acids to their cognate tRNA molecules in the cytoplasm and mitochondria. Recent studies have demonstrated that mutations in genes encoding ARSs can result in neurodegeneration, raising many questions about the role of these enzymes (and protein synthesis in general) in neuronal function. In this review, we summarize the current knowledge of genetic diseases that are associated with mutations in ARS-encoding genes, discuss the potential pathogenic mechanisms underlying these disorders, and point to likely areas of future research that will advance our understanding about the role of ARSs in genetic diseases.
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A Bird's-Eye View of Sex Chromosome Dosage Compensation
Vol. 9 (2008), pp. 109–127More LessIntensive study of a few genetically tractable species with XX/XY sex chromosomes has produced generalizations about the process of sex chromosome dosage compensation that do not fare well when applied to ZZ/ZW sex chromosome systems, such as those in birds. The inherent sexual imbalance in dose of sex chromosome genes has led to the evolution of sex-chromosome-wide mechanisms for balancing gene dosage between the sexes and relative to autosomal genes. Recent advances in our knowledge of avian genomes have led to a reexamination of sex-specific dosage compensation (SSDC) in birds, which is less effective than in known XX/XY systems. Insights about the mechanisms of SSDC in birds also suggest similarities to and differences from those in XX/XY species. Birds are thus offering new opportunities for studying dosage compensation in a ZZ/ZW system, which should shed light on the evolution of SSDC more broadly.
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Linkage Disequilibrium and Association Mapping
Vol. 9 (2008), pp. 129–142More LessLinkage disequilibrium refers to the association between alleles at different loci. The standard definition applies to two alleles in the same gamete, and it can be regarded as the covariance of indicator variables for the states of those two alleles. The corresponding correlation coefficient ρ is the parameter that arises naturally in discussions of tests of association between markers and genetic diseases. A general treatment of association tests makes use of the additive and nonadditive components of variance for the disease gene. In almost all expressions that describe the behavior of association tests, additive variance components are modified by the squared correlation coefficient ρ 2 and the nonadditive variance components by ρ4, suggesting that nonadditive components have less influence than additive components on association tests.
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Positive Selection in the Human Genome: From Genome Scans to Biological Significance
Vol. 9 (2008), pp. 143–160More LessHere we review the evidence for positive selection in the human genome and its role in human evolution and population differentiation. In recent years, there has been a dramatic increase in the use of genome-wide scans to identify adaptively evolving loci in the human genome. Attention is now turning to understanding the biological relevance and adaptive significance of the regions identified as being subject to recent positive selection. Examples of adaptively evolving loci are discussed, specifically LCT and FOXP2. Comprehensive studies of these loci also provide information about the functional relevance of the selected alleles. We discuss current studies examining the role of positive selection in shaping copy number variation and noncoding genomic regions and highlight challenges presented by the study of positive selection in the human genome.
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The Current Landscape for Direct-to-Consumer Genetic Testing: Legal, Ethical, and Policy Issues
Vol. 9 (2008), pp. 161–182More LessThis review surveys the developing market for direct-to-consumer (DTC) genetic tests and examines the range of companies and tests available, the regulatory landscape, the concerns raised about DTC testing, and the calls for enhanced oversight. We provide a comparative overview of the situation, particularly in the United States and Europe, by exploring the regulatory frameworks for medical devices and clinical laboratories. We also discuss a variety of other mechanisms such as general controls on advertising and consumer law mechanisms.
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Transcriptional Control of Skeletogenesis
Vol. 9 (2008), pp. 183–196More LessThe skeleton contains three specific cell types: chondrocytes in cartilage and osteoblasts and osteoclasts in bone. Our understanding of the transcriptional mechanisms that lead to cell differentiation along these three lineages has increased considerably in the past ten years. In the case of chondrocytes and osteoblasts advances have been made possible largely through the molecular elucidation of human skeletal dysplasias. This review discusses the key transcription factors that regulate skeletogenesis and highlights their function, mode of action, and regulation by other factors, with a special emphasis on how human genetics has contributed to this knowledge.
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A Mechanistic View of Genomic Imprinting
Vol. 9 (2008), pp. 197–216More LessGenomic imprinting results in the expression of genes in a parent-of-origin-dependent manner. The mechanism and developmental consequences of genomic imprinting are most well characterized in mammals, plants, and certain insect species (e.g., sciarid flies and coccid insects). However, researchers have observed imprinting phenomena in species in which imprinting of endogenous genes is not known to exist or to be developmentally essential. In this review, I survey the known mechanisms of imprinting, focusing primarily on examples from mammals, where imprinting is relatively well characterized. Where appropriate, I draw attention to imprinting mechanisms in other organisms to compare and contrast how diverse organisms employ different strategies to perform the same process. I discuss how the various mechanisms come into play in the context of the imprint life cycle. Finally, I speculate why imprinting may be more widely prevalent than previously thought.
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Phylogenetic Inference Using Whole Genomes
Bruce Rannala, and Ziheng YangVol. 9 (2008), pp. 217–231More LessThe availability of genome-wide data provides unprecedented opportunities for resolving difficult phylogenetic relationships and for studying population genetic processes of mutation, selection, and recombination on a genomic scale. The use of appropriate statistical models becomes increasingly important when we are faced with very large datasets, which can lead to improved precision but not necessarily improved accuracy if the analytical methods have systematic biases. This review provides a critical examination of methods for analyzing genomic datasets from multiple loci, including concatenation, separate gene-by-gene analyses, and statistical models that accommodate heterogeneity in different aspects of the evolutionary process among data partitions. We discuss factors that may cause the gene tree to differ from the species tree, as well as strategies for estimating species phylogenies in the presence of gene tree conflicts. Genomic datasets provide computational and statistical challenges that are likely to be a focus of research for years to come.
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Transgenerational Epigenetic Effects
Vol. 9 (2008), pp. 233–257More LessTransgenerational epigenetic effects include all processes that have evolved to achieve the nongenetic determination of phenotype. There has been a long-standing interest in this area from evolutionary biologists, who refer to it as non-Mendelian inheritance. Transgenerational epigenetic effects include both the physiological and behavioral (intellectual) transfer of information across generations. Although in most cases the underlying molecular mechanisms are not understood, modifications of the chromosomes that pass to the next generation through gametes are sometimes involved, which is called transgenerational epigenetic inheritance. There is a trend for those outside the field of molecular biology to assume that most cases of transgenerational epigenetic effects are the result of transgenerational epigenetic inheritance, in part because of a misunderstanding of the terms. Unfortunately, this is likely to be far from the truth.
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Evolution of Dim-Light and Color Vision Pigments
Vol. 9 (2008), pp. 259–282More LessA striking level of diversity of visual systems in different species reflects their adaptive responses to various light environments. To study the adaptive evolution of visual systems, we need to understand how visual pigments, the light-sensitive molecules, have tuned their wavelengths of light absorption. The molecular basis of spectral tuning in visual pigments, a central unsolved problem in phototransduction, can be understood only by studying how different species have adapted to various light environments. Certain amino acid replacements at 30 residues explain some dim-light and color vision in vertebrates. To better understand the molecular and functional adaptations of visual pigments, we must identify all critical amino acid replacements that are involved in the spectral tuning and elucidate the effects of their interactions on the spectral shifts.
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Genetic Basis of Thoracic Aortic Aneurysms and Dissections: Focus on Smooth Muscle Cell Contractile Dysfunction
Vol. 9 (2008), pp. 283–302More LessThoracic aortic aneurysms leading to type A dissections (TAAD) can be inherited in isolation or in association with genetic syndromes, such as Marfan syndrome and Loeys-Dietz syndrome. When TAAD occurs in the absence of syndromic features, it is inherited in an autosomal dominant manner with decreased penetrance and variable expression, the disease is referred to as familial TAAD. Familial TAAD exhibits significant clinical and genetic heterogeneity. The first genes identified to cause TAAD were FBN1, TGFBR2, and TGFBR1. The identification and characterization of these genes suggested that increased TGF-β signaling plays a role in pathogenesis. The recent discovery that mutations in the vascular smooth muscle cell (SMC)-specific β-myosin (MYH11) and α-actin (ACTA2) can also cause this disorder has focused attention on the importance of the maintenance of SMC contractile function in preserving aortic structure and preventing TAAD.
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Cohesin and Human Disease
Jinglan Liu, and Ian D. KrantzVol. 9 (2008), pp. 303–320More LessCornelia de Lange syndrome (CdLS) is a dominant multisystem disorder caused by a disruption of cohesin function. The cohesin ring complex is composed of four protein subunits and more than 25 additional proteins involved in its regulation. The discovery that this complex also has a fundamental role in long-range regulation of transcription in Drosophila has shed light on the mechanism likely responsible for its role in development. In addition to the three cohesin proteins involved in CdLS, a second multisystem, recessively inherited, developmental disorder, Roberts-SC phocomelia, is caused by mutations in another regulator of the cohesin complex, ESCO2. Here we review the phenotypes of these disorders, collectively termed cohesinopathies, as well as the mechanism by which cohesin disruption likely causes these diseases.
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Genetic Predisposition to Breast Cancer: Past, Present, and Future
Vol. 9 (2008), pp. 321–345More LessIn recent years, our understanding of genetic predisposition to breast cancer has advanced significantly. Three classes of predisposition factors, categorized by their associated risks of breast cancer, are currently known. BRCA1 and BRCA2 are high-penetrance breast cancer predisposition genes identified by genome-wide linkage analysis and positional cloning. Mutational screening of genes functionally related to BRCA1 and/or BRCA2 has revealed four genes, CHEK2, ATM, BRIP1, and PALB2; mutations in these genes are rare and confer an intermediate risk of breast cancer. Association studies have further identified eight common variants associated with low-penetrance breast cancer predisposition. Despite these discoveries, most of the familial risk of breast cancer remains unexplained. In this review, we describe the known genetic predisposition factors, expound on the methods by which they were identified, and consider how further technological and intellectual advances may assist in identifying the remaining genetic factors underlying breast cancer susceptibility.
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From Linkage Maps to Quantitative Trait Loci: The History and Science of the Utah Genetic Reference Project
Vol. 9 (2008), pp. 347–358More LessOne of the early decisions in what became the Human Genome Project was to recruit families that would serve as a reference set, thereby focusing efforts to create human genetic maps on the same sets of DNA samples. The families recruited from Utah provided the most widely used samples in the Centre d′Etudes du Polymorphisme Humain (CEPH) set, were instrumental in generating human linkage maps, and often serve as the benchmark for establishing allele frequency when a new variant is identified. In addition, the immortalized cell lines created from the peripheral blood cells of these subjects are a broadly used resource and have yielded insights in many areas, from the genetics of gene expression to the regulation of telomeres. More recently, these families were recontacted and underwent extensive, protocol-based evaluation to create a phenotypic database, which will aid in the study of the genetic basis of quantitative traits. As with the earlier efforts, this project involved collaborations among many investigators and has yielded insights into multiple traits.
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Disorders of Lysosome-Related Organelle Biogenesis: Clinical and Molecular Genetics*
Vol. 9 (2008), pp. 359–386More LessLysosome-related organelles (LROs) are a heterogeneous group of vesicles that share various features with lysosomes, but are distinct in function, morphology, and composition. The biogenesis of LROs employs a common machinery, and genetic defects in this machinery can affect all LROs or only an individual LRO, resulting in a variety of clinical features. In this review, we discuss the main components of LRO biogenesis. We also summarize the function, composition, and resident cell types of the major LROs. Finally, we describe the clinical characteristics of the major human LRO disorders.
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Next-Generation DNA Sequencing Methods
Vol. 9 (2008), pp. 387–402More LessRecent scientific discoveries that resulted from the application of next-generation DNA sequencing technologies highlight the striking impact of these massively parallel platforms on genetics. These new methods have expanded previously focused readouts from a variety of DNA preparation protocols to a genome-wide scale and have fine-tuned their resolution to single base precision. The sequencing of RNA also has transitioned and now includes full-length cDNA analyses, serial analysis of gene expression (SAGE)-based methods, and noncoding RNA discovery. Next-generation sequencing has also enabled novel applications such as the sequencing of ancient DNA samples, and has substantially widened the scope of metagenomic analysis of environmentally derived samples. Taken together, an astounding potential exists for these technologies to bring enormous change in genetic and biological research and to enhance our fundamental biological knowledge.
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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)