Annual Review of Genomics and Human Genetics - Volume 3, 2002
Volume 3, 2002
- Review Articles
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A Personal History of the Mouse Genome
Vol. 3 (2002), pp. 1–16More LessThe chapter describes some personal reminiscences of various stages in the growth of knowledge of the mouse genome in the past 50 years. Initially mapping was done by crossing new mutants with linkage testing stocks, a slow and laborious method. In the 1950s major mutagenesis experiments led to spin-offs in terms of new mutants, new knowledge of phenomena including sex determination and X-chromosome inactivation, and further understanding of the t-complex. The 1970s saw the development of recombinant inbred (RI) strains and the use of biochemical variants for mapping. In addition the linkage groups were assigned to chromosomes. Techniques of embryo surgery were developed, leading to work with embryonic stem (ES) cells and hence to the identification of gene functioning by knockouts and transgenesis. Another major advance in the 1970s and 1980s was the beginning of comparative mapping, which is now so important. With the advent of DNA technology, progress in mapping increased considerably. Progress became even faster with the use of interspecific backcrosses and with the development of microsatellite markers. The completion of the mouse DNA sequence is now imminent, opening fascinating prospects for the analysis of gene function.
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The Application of Tandem Mass Spectrometry to Neonatal Screening for Inherited Disorders of Intermediary Metabolism
Vol. 3 (2002), pp. 17–45More LessThis review is intended to serve as a practical guide for geneticists to current applications of tandem mass spectrometry to newborn screening. By making dried-blood spot analysis more sensitive, specific, reliable, and inclusive, tandem mass spectrometry has improved the newborn detection of inborn errors of metabolism. Its innate ability to detect and quantify multiple analytes from one prepared blood specimen in a single analysis permits broad recognition of amino acid, fatty acid, and organic acid disorders. An increasing number of newborn screening programs are either utilizing or conducting pilot studies with tandem mass spectrometry. It is therefore imperative that the genetics community be familiar with tandem mass spectrometric newborn screening.
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Hedgehog Signaling and Human Disease
Vol. 3 (2002), pp. 47–65More LessDevelopmental pathways first elucidated by genetic studies in the fruit fly Drosophila melanogaster are conserved in vertebrates. The hedgehog pathway, first discovered because of its involvement in early Drosophila development, plays a key role in human embryogenesis. Dissruption of this pathway has been associated with congenital anomalies of the central nervous system, axial skeleton, limbs, and occasionally other organs. Many developmental genes continue to play an important role in regulation of cell growth and differentiation after embryogenesis, and mutations that lead to activation of the hedgehog pathway result in skin cancer and other malignancies in children and adults.
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Deciphering the Genetic Basis of Alzheimer's Disease
Vol. 3 (2002), pp. 67–99More LessA remarkable rise in life expectancy during the past century has made Alzheimer's disease (AD) the most common form of progressive cognitive failure in humans. Compositional analyses of the classical brain lesions, the senile (amyloid) plaques and neurofibrillary tangles, preceded and has guided the search for genetic alterations. Four genes have been unequivocally implicated in inherited forms of AD, and mutations or polymorphisms in these genes cause excessive cerebral accumulation of the amyloid ß-protein and subsequent neuronal and glial pathology in brain regions important for memory and cognition. This understanding of the genotype-to-phenotype conversions of familial AD has led to the development of pharmacological strategies to lower amyloid ß-protein levels as a way of treating or preventing all forms of the disease.
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GENETIC AND EPIGENETIC ALTERATIONS IN COLON CANCER
Vol. 3 (2002), pp. 101–128More LessColorectal cancer affected approximately 135,000 people in the United States in 2001, resulting in 57,000 deaths. Colorectal cancer develops as the result of the progressive accumulation of genetic and epigenetic alterations that lead to the transformation of normal colonic epithelium to colon adenocarcinoma. The loss of genomic stability is a key molecular and pathophysiologic step in this process and serves to create a permissive environment for the occurrence of alterations in tumor suppressor genes and oncogenes. Alterations in these genes, which include APC, CTNNB1, K-RAS, MADH4/SMAD4, and TGFBR2, appear to promote colon tumorigenesis by perturbing the function of signaling pathways, such as the TGF-ß signaling pathway, or by affecting genes that regulate genomic stability, such as the mutation mismatch repair genes.
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HUMAN MIGRATIONS AND POPULATION STRUCTURE: What We Know and Why it Matters
Vol. 3 (2002), pp. 129–152More Less▪ AbstractThe increasingly obvious medical relevance of human genetic variation is fueling the development of a rich interface between medical genetics and the study of human genetic history. A key feature of this interface is a step increase in the size and diversity of genetic data sets, permitting a range of new questions to be addressed concerning our evolutionary history. Similarly, methodologies first developed to study genetic history are being tailored to address medical challenges, including mapping genes that influence diseases and variable drug reactions. In this paper we do not attempt a comprehensive review of human genetic history. Rather we briefly outline some of the complications and challenges in the study of human genetic history, drawing particular attention to new opportunities created by the explosive growth in genetic information and technologies. First we discuss the complexity of human migration and demographic history, taking both a genetic and archaeological perspective. Then we show how these apparently academic issues are becoming increasingly important in medical genetics, focusing on association studies, the common disease/common variant hypothesis, the evaluation of variable drug response, and inferences about gene function from patterns of genetic variation. Finally we describe some of the inferential approaches available for interpreting human genetic variation, focusing both on current limitations and future developments.
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DEVELOPMENTAL GENOMIC APPROACHES IN MODEL ORGANISMS
Vol. 3 (2002), pp. 153–178More Less▪ AbstractFunctional genomics technologies can help decipher how information encoded in the genome is translated into morphology, physiology, and behavior during the development of complex organisms. A number of researchers have begun to apply DNA microarrays and other functional genomics approaches to study development. Here we review recent studies that take the first steps toward relating genome-wide information to developmental events, we discuss recent genomics approaches taken in animal model systems used to study human disease, and we outline methods that may be useful for constructing genome-wide maps of developmental processes.
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GENETICS OF MYELOID LEUKEMIAS
Vol. 3 (2002), pp. 179–198More Less▪ AbstractHuman leukemias are typified by acquired recurring chromosomal translocations. Cloning of these translocation breakpoints has provided important insights into pathogenesis of disease as well as novel therapeutic approaches. Chronic myelogenous leukemias (CML) are caused by constitutively activated tyrosine kinases, such as BCR/ABL, that confer a proliferative and survival advantage to hematopoietic progenitors but do not affect differentiation. These activated kinases are validated targets for therapy with selective tyrosine kinase inhibitors, a paradigm that may have broad applications in treatment of hematologic malignancies as well as solid tumors. Chromosomal translocations in acute myeloid leukemias (AML) most often result in loss-of-function mutations in transcription factors that are required for normal hematopoietic development. These latter mutations, however, are not sufficient to cause AML. The available evidence indicates that activating mutations in the hematopoietic tyrosine kinases FLT3 and c-KIT, and in N-RAS and K-RAS, confer proliferative advantage to hematopoietic progenitors and cooperate with loss-of-function mutations in hematopoietic transcription factors to cause an acute leukemia phenotype characterized by proliferation and impaired differentiation. The data supporting this hypothesis and the clinical and therapeutic implications of these observations are reviewed.
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MOLECULAR MECHANISMS FOR GENOMIC DISORDERS
Ken Inoue, and James R. LupskiVol. 3 (2002), pp. 199–242More Less▪ AbstractGenomic rearrangements play a major role in the pathogenesis of human genetic diseases. Nonallelic homologous recombination (NAHR) between low-copy repeats (LCRs) that flank unique genomic segments results in changes of genome organization and can cause a loss or gain of genomic segments. These LCRs appear to have arisen recently during primate speciation via paralogous segmental duplication, thus making the human species particularly susceptible to genomic rearrangements. Genomic disorders are defined as a group of diseases that result from genomic rearrangements, mostly mediated by NAHR. Molecular investigations of genomic disorders have revealed genome architectural features associated with susceptibility to rearrangements and the recombination mechanisms responsible for such rearrangements. The human genome sequence project reveals that LCRs may account for 5% of the genome, suggesting that many novel genomic disorders might still remain to be recognized.
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STRUCTURING THE UNIVERSE OF PROTEINS
Vol. 3 (2002), pp. 243–262More Less▪ AbstractHigh-throughput sequencing of human genomes and those of important model organisms (mouse, Drosophila melanogaster, Caenorhabditis elegans, fungi, archaea) and bacterial pathogens has laid the foundation for another “big science” initiative in biology. Together, X-ray crystallographers, nuclear magnetic resonance (NMR) spectroscopists, and computational biologists are pursuing high-throughput structural studies aimed at developing a comprehensive three-dimensional view of the protein structure universe. The new science of structural genomics promises more than 10,000 experimental protein structures and millions of calculated homology models of related proteins. The evolutionary underpinnings and technological challenges of automating target selection, protein expression and purification, sample preparation, NMR and X-ray data measurement/analysis, homology modeling, and structure/function annotation are discussed in detail. An informative case study from one of the structural genomics centers funded by the National Institutes of Health and the National Institute of General Medical Sciences (NIH/NIGMS) demonstrates how this experimental/computational pipeline will reveal important links between form and function in biology and provide new insights into evolution and human health and disease.
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BALANCED POLYMORPHISM SELECTED BY GENETIC VERSUS INFECTIOUS HUMAN DISEASE*
Vol. 3 (2002), pp. 263–292More Less▪ AbstractThe polymorphisms within the human genome include several functional variants that cause debilitating inherited diseases. An elevated frequency of some of these deleterious mutations can be explained by a beneficial effect that confers a selective advantage owing to disease resistance in carriers of such mutations during an infectious disease outbreak. We here review plausible examples of balanced functional polymorphisms and their roles in the defense against pathogens. The genome organization of the chemokine receptor and HLA gene clusters and their influence on the HIV/AIDS epidemic provides compelling evidence for the interaction of infectious and genetic diseases in recent human history.
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DATABASES AND TOOLS FOR BROWSING GENOMES
Vol. 3 (2002), pp. 293–310More Less▪ AbstractTo maximize the value of genome sequences they need to be integrated with other types of biological data and with each other. The entire collection of data then needs to be made available in a way that is easy to view and mine for complex relationships. The recently determined vertebrate genome sequences of human and mouse are so large that building the infrastructure to manage these datasets is a major challenge. This article reviews the database systems and tools for analysis that have so far been developed to address this.
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FROM ZEBRAFISH TO HUMAN: Modular Medical Models
Vol. 3 (2002), pp. 311–340More Less▪ AbstractGenetic screens in Drosophila melanogaster, Caenorhabditis elegans, and Danio rerio clarified the logic of metazoan development by revealing critical unitary steps and pathways to embryogenesis. Can genetic screens similarly organize medicine? We here examine human diseases that resemble mutations in Danio rerio, the zebrafish, the one vertebrate species for which large-scale genetic screens have been performed and extensively analyzed. Zebrafish mutations faithfully phenocopy many human disorders. Each mutation, once cloned, provides candidate genes and pathways for evaluation in the human. The collection of mutations in their entirety potentially provides a medical taxonomy, one based in developmental biology and genetics.
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GENETIC “CODE”: Representations and Dynamical Models of Genetic Components and Networks
Alex Gilman, and Adam P. ArkinVol. 3 (2002), pp. 341–369More Less▪ AbstractDynamical modeling of biological systems is becoming increasingly widespread as people attempt to grasp biological phenomena in their full complexity and make sense of an accelerating stream of experimental data. We review a number of recent modeling studies that focus on systems specifically involving gene expression and regulation. These systems include bacterial metabolic operons and phase-variable piliation, bacteriophages T7 and λ, and interacting networks of eukaryotic developmental genes. A wide range of conceptual and mathematical representations of genetic components and phenomena appears in these works. We discuss these representations in depth and give an overview of the tools currently available for creating and exploring dynamical models. We argue that for modeling to realize its full potential as a mainstream biological research technique the tools must become more general and flexible, and formal, standardized representations of biological knowledge and data must be developed.
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LINKAGE ANALYSIS IN PSYCHIATRIC DISORDERS: The Emerging Picture
Vol. 3 (2002), pp. 371–413More Less▪ AbstractGene finding in genetically complex diseases has been difficult as a result of many factors that have diagnostic and methodologic considerations. For bipolar disorder and schizophrenia, numerous family, twin, and adoption studies have identified a strong genetic component to these behavioral psychiatric disorders. Despite difficulties that include diagnostic differences between sample populations and the lack of statistical significance in many individual studies, several promising patterns have emerged, suggesting that true susceptibility loci for schizophrenia and bipolar disorder may have been identified. In this review, the genetic epidemiology of these disorders is covered as well as linkage findings on chromosomes 4, 12, 13, 18, 21, and 22 in bipolar disorder and on chromosomes 1, 6, 8, 10, 13, 15, and 22 in schizophrenia. The sequencing of the human genome and identification of numerous single nucleotide polymorphisms (SNP) should substantially enhance the ability of investigators to identify disease-causing genes in these areas of the genome.
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PATENTING GENES AND GENETIC RESEARCH TOOLS: Good or Bad for Innovation?
Vol. 3 (2002), pp. 415–432More Less▪ AbstractOur goal with this article is to inform the debate over gene patenting, by providing an understanding of (a) the scope of patent claims that are actually being issued on genetic inventions in the United States, (b) the issues that impact their enforcement, and (c) the role that patents and patent licensing play in the commercialization of genetic technologies and products. We conclude by discussing whether the current legal regime effectively balances the beneficial role of patents in the development of new genetic technologies and products against negative impacts on genetic research or clinical genetic testing, or whether the current laws should be amended.
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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)