Annual Review of Genomics and Human Genetics - Volume 10, 2009
Volume 10, 2009
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Chromosomes in Leukemia and Beyond: From Irrelevant to Central Players
Vol. 10 (2009), pp. 1–18More LessAlthough it was definitely not obvious at first, consistent chromosomal translocations are major contributors to cellular transformation in some leukemias, lymphomas, sarcomas, prostate cancer, and other benign and malignant neoplasms. In the 50 years since the discovery of the Ph chromosome, the elucidation of recurring abnormalities has been an ongoing challenge that has evolved as new technologies allowed an ever more accurate definition of the precise changes in DNA resulting from these abnormalities. As we enter a new era of understanding enriched by gene expression studies, we still know little about the changes in the level of critical proteins, which may be the ultimate effectors of the genetic/epigenetic abnormalities in cancer.
Despite remarkable progress in identifying both obvious chromosome abnormalities and subtle changes in DNA such as mutations and small copy-number variations, the impact of this knowledge has been variable. The challenge for the future is to enhance our ability to translate these genetic changes into effective therapies for other malignant diseases.
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Unraveling a Multifactorial Late-Onset Disease: From Genetic Susceptibility to Disease Mechanisms for Age-Related Macular Degeneration
Vol. 10 (2009), pp. 19–43More LessAging-associated neurodegenerative diseases significantly influence the quality of life of affected individuals. Genetic approaches, combined with genomic technology, have provided powerful insights into common late-onset diseases, such as age-related macular degeneration (AMD). Here, we discuss current findings on the genetics of AMD to highlight areas of rapid progress and new challenges. We also attempt to integrate available genetic and biochemical data with cellular pathways involved in aging to formulate an integrated model of AMD pathogenesis.
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Syndromes of Telomere Shortening
Vol. 10 (2009), pp. 45–61More LessTelomeres and telomerase were initially discovered in pursuit of questions about how the ends of chromosomes are maintained. The implications of these discoveries to age-related disease have emerged in recent years with the recognition of a group of telomere-mediated syndromes. Telomere-mediated disease was initially identified in the context of dyskeratosis congenita, a rare syndrome of premature aging. More recently, mutations in telomerase components were identified in adults with idiopathic pulmonary fibrosis. These findings have revealed that the spectrum of telomere-mediated disease is broad and includes clinical presentations in both children and adults. We have previously proposed that these disorders be collectively considered as syndromes of telomere shortening. Here, the spectrum of these disorders and the unique telomere genetics that underlies them are reviewed. I also propose broader clinical criteria for defining telomere-mediated syndromes outside of dyskeratosis congenita, with the goal of facilitating their diagnosis and highlighting their pathophysiology.
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Chronic Pancreatitis: Genetics and Pathogenesis
Vol. 10 (2009), pp. 63–87More LessChronic pancreatitis (CP) is a persistent inflammation of the pancreas. Over the past 12 years, genetic studies of hereditary, familial, and idiopathic forms of CP have made great progress in defining the disease pathogenesis. Identification of gain-of-function missense and copy number mutations in the cationic trypsinogen gene (PRSS1) and loss-of-function variants in both the pancreatic secretory trypsin inhibitor (SPINK1) and chymotrypsinogen C (CTRC) genes has firmly established the pivotal role of prematurely activated trypsin within the pancreas in the etiology of CP. Loss-of-function variants in the cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-sensing receptor (CASR) genes also increase the risk of CP. Here, we review recent developments in this rapidly evolving field, highlight the importance of gene-gene and gene-environment interactions in causing the disease, and discuss the opportunities and challenges in identifying novel genetic factors that affect susceptibility/resistance to CP.
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The Genetics of Crohn's Disease
Vol. 10 (2009), pp. 89–116More LessFrom epidemiological data, based on concordance data in family studies, via linkage analysis to genome-wide association studies, we and others have accumulated robust evidence implicating more than 30 distinct genomic loci involved in the genetic susceptibility to Crohn's disease (CD). These loci encode genes involved in a number of homeostatic mechanisms: innate pattern recognition receptors (NOD2/CARD15, TLR4, CARD9), the differentiation of Th17-lymphocytes (IL-23R, JAK2, STAT3, CCR6, ICOSLG), autophagy (ATG16L1, IRGM, LRRK2), maintenance of epithelial barrier integrity (IBD5, DLG5, PTGER4, ITLN1, DMBT1, XBP1), and the orchestration of the secondary immune response (HLA-region, TNFSF15/TL1A, IRF5, PTPN2, PTPN22, NKX2-3, IL-12B, IL-18RAP, MST1). While many of these loci also predispose to pediatric CD, an additional number of childhood-onset loci have been identified recently (e.g., TNFRSF6B). Not only has the identification of these loci improved our understanding of the pathophysiology of CD, this knowledge also holds real promise for clinical practice.
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Genotyping Technologies for Genetic Research
Vol. 10 (2009), pp. 117–133More LessThe past few years have seen enormous advances in genotyping technology, including chips that accommodate in excess of 1 million SNP assays. In addition, the cost per genotype has been driven down to levels unimagined only a few years ago. These developments have resulted in an explosion of positive whole-genome association studies and the identification of many new genes for common diseases. Here I review high-throughput genotyping platforms as well as other approaches for lower numbers of assays but high sample throughput, which play an important role in genotype validation and study replication. Further, the utility of SNP arrays for detecting structural variation through the development of genotyping algorithms is reviewed and methods for long-range haplotyping are presented. It is anticipated that in the future, sample throughput and cost savings will be increased further through the combination of automation, microfluidics, and nanotechnologies.
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Applications of New Sequencing Technologies for Transcriptome Analysis
Vol. 10 (2009), pp. 135–151More LessTranscriptome analysis has been a key area of biological inquiry for decades. Over the years, research in the field has progressed from candidate gene-based detection of RNAs using Northern blotting to high-throughput expression profiling driven by the advent of microarrays. Next-generation sequencing technologies have revolutionized transcriptomics by providing opportunities for multidimensional examinations of cellular transcriptomes in which high-throughput expression data are obtained at a single-base resolution.
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The Posttranslational Processing of Prelamin A and Disease
Vol. 10 (2009), pp. 153–174More LessHuman geneticists have shown that some progeroid syndromes are caused by mutations that interfere with the conversion of farnesyl-prelamin A to mature lamin A. For example, Hutchinson-Gilford progeria syndrome is caused by LMNA mutations that lead to the accumulation of a farnesylated version of prelamin A. In this review, we discuss the posttranslational modifications of prelamin A and their relevance to the pathogenesis and treatment of progeroid syndromes.
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Genetic Testing in Israel: An Overview
Vol. 10 (2009), pp. 175–192More LessIn Israel, genetic screening and testing are widespread and are on the rise. The socialized medical system, the governmental National Program for the Detection and Prevention of Birth Defects, the central registry of genetic disorders, and the availability of medical genetic units influence the extensive utilization of genetic services. Israeli society is a complex one—ethnically, religiously, and culturally diverse, comprised of Jews of many ethnic backgrounds, as well as Christian and Moslem Arabs, Druze, and Bedouins. Multiple founder mutations have been documented in these various ethnic populations, often down to the level of specific villages or tribes. Although carrier screening and prenatal diagnostic testing are well established in the general population, the rejection of pregnancy termination by many religious communities often prevents participation in testing. Culturally appropriate genetic programs have been initiated in religious Jewish and non-Jewish communities in an attempt to overcome cultural barriers and reduce the frequency of severe genetic diseases nationwide.
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Stewardship of Human Biospecimens, DNA, Genotype, and Clinical Data in the GWAS Era*
Vol. 10 (2009), pp. 193–209More LessAn ethical quandary is emerging over custodianship of and access to DNA specimens and attached data, clinical and genetic, held in large disease cohort collections. The balance of patients’ rights and science/society's quest for broad open access must be resolved in order to realize the promise of gene association studies of complex human disease. A way forward may be to convene a colloquium of international medical and science organizations charged with developing global consensus guidance and ethical principles for access to and use of genomic biobanks.
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Schistosoma Genomics: New Perspectives on Schistosome Biology and Host-Parasite Interaction
Vol. 10 (2009), pp. 211–240More LessSchistosomiasis, caused mainly by Schistosoma japonicum, S. mansoni, and S. hematobium, remains one of the most prevalent and serious parasitic diseases worldwide. The blood flukes have a complex life cycle requiring adaptation for survival in fresh water as free-living forms and as parasites in snail intermediate and vertebrate definitive hosts. Functional genomics analyses, including transcriptomic and proteomic approaches, have been performed on schistosomes, in particular S. mansoni and S. japonicum, using powerful high-throughput methodologies. These investigations have not only chartered gene expression profiles across genders and developmental stages within mammalian and snail hosts, but have also characterized the features of the surface tegument, the eggshell and excretory–secretory proteomes of schistosomes. The integration of the genomic, transcriptomic, and proteomic information, together with genetic manipulation on individual genes, will provide a global insight into the molecular architecture of the biology, pathogenesis, and host-parasite interactions of the human blood flukes. Importantly, these functional genomics analyses lay a foundation on which to develop new antischistosome vaccines as well as drug targets and diagnostic markers for treatment and control of schistosomiasis.
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Evolution of Genomic Imprinting: Insights from Marsupials and Monotremes
Vol. 10 (2009), pp. 241–262More LessParent-of-origin gene expression (genomic imprinting) is widespread among eutherian mammals and also occurs in marsupials. Most imprinted genes are expressed in the placenta, but the brain is also a favored site. Although imprinting evolved in therian mammals before the marsupial-eutherian split, the mechanisms have continued to evolve in each lineage to produce differences between the two groups in terms of the number and regulation of imprinted genes. As yet there is no evidence for genomic imprinting in the egg-laying monotreme mammals, although these mammals also form a placenta (albeit short-lived) and transfer nutrients from mother to embryo. Therefore, imprinting was not essential for the evolution of the placenta and its importance in nutrient transfer but the elaboration of imprinted genes in marsupials and eutherians is associated with viviparity. Here we review the recent analyses of imprinted gene clusters in marsupials and monotremes, which have served to shed light on the origin and evolution of imprinting mechanisms in mammals.
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Methods for Genomic Partitioning
Vol. 10 (2009), pp. 263–284More LessThe emergence of massively parallel DNA sequencing platforms has made resequencing an affordable approach to study genetic variation. However, the cost of whole genome resequencing remains too high to apply to large numbers of human samples. Genomic partitioning methods allow enrichment for regions of interest at a scale that is matched to the throughput of the new sequencing platforms. We review general categories of methods for genomic partitioning including multiplex PCR, capture-by-circularization, and capture-by-hybridization. Parameters that are relevant to the performance of any given method include multiplexity, specificity, uniformity, input requirements, scalability, and cost. The successful development of genomic partitioning strategies will be key to taking full advantage of massively parallel sequencing, at least until resequencing of complete mammalian genomes becomes widely affordable.
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Biased Gene Conversion and the Evolution of Mammalian Genomic Landscapes
Vol. 10 (2009), pp. 285–311More LessRecombination is typically thought of as a symmetrical process resulting in large-scale reciprocal genetic exchanges between homologous chromosomes. Recombination events, however, are also accompanied by short-scale, unidirectional exchanges known as gene conversion in the neighborhood of the initiating double-strand break. A large body of evidence suggests that gene conversion is GC-biased in many eukaryotes, including mammals and human. AT/GC heterozygotes produce more GC- than AT-gametes, thus conferring a population advantage to GC-alleles in high-recombining regions. This apparently unimportant feature of our molecular machinery has major evolutionary consequences. Structurally, GC-biased gene conversion explains the spatial distribution of GC-content in mammalian genomes—the so-called isochore structure. Functionally, GC-biased gene conversion promotes the segregation and fixation of deleterious AT → GC mutations, thus increasing our genomic mutation load. Here we review the recent evidence for a GC-biased gene conversion process in mammals, and its consequences for genomic landscapes, molecular evolution, and human functional genomics.
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Inherited Variation in Gene Expression
Vol. 10 (2009), pp. 313–332More LessVariation in gene expression constitutes an important source of biological variability within and between populations that is likely to contribute significantly to phenotypic diversity. Recent conceptual, technical, and methodological advances have enabled the genome-scale dissection of transcriptional variation. Here, we outline common approaches for detecting gene expression quantitative trait loci, and summarize the insights gleaned from these studies regarding the genetic architecture of transcriptional variation and the nature of regulatory alleles. Particular emphasis is placed on human studies, and we discuss experimental designs that ensure that increasingly large and complex studies continue to advance our understanding of gene expression variation. We conclude by discussing the evolution of gene expression levels, and we explore prospects for leveraging new technological developments to investigate inherited variation in gene expression in even greater depth.
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Genomic Analyses of Sex Chromosome Evolution
Vol. 10 (2009), pp. 333–354More LessSex chromosomes have evolved multiple times in many taxa. The recent explosion in the availability of whole genome sequences from a variety of organisms makes it possible to investigate sex chromosome evolution within and across genomes. Comparative genomic studies have shown that quite distant species may share fundamental properties of sex chromosome evolution, while very similar species can evolve unique sex chromosome systems. Furthermore, within-species genomic analyses can illuminate chromosome-wide sequence and expression polymorphisms. Here, we explore recent advances in the study of vertebrate sex chromosomes achieved using genomic analyses.
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Sequencing Primate Genomes: What Have We Learned?
Vol. 10 (2009), pp. 355–386More LessWe summarize the progress in whole-genome sequencing and analyses of primate genomes. These emerging genome datasets have broadened our understanding of primate genome evolution revealing unexpected and complex patterns of evolutionary change. This includes the characterization of genome structural variation, episodic changes in the repeat landscape, differences in gene expression, new models regarding speciation, and the ephemeral nature of the recombination landscape. The functional characterization of genomic differences important in primate speciation and adaptation remains a significant challenge. Limited access to biological materials, the lack of detailed phenotypic data and the endangered status of many critical primate species have significantly attenuated research into the genetic basis of primate evolution. Next-generation sequencing technologies promise to greatly expand the number of available primate genome sequences; however, such draft genome sequences will likely miss critical genetic differences within complex genomic regions unless dedicated efforts are put forward to understand the full spectrum of genetic variation.
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Genotype Imputation
Vol. 10 (2009), pp. 387–406More LessGenotype imputation is now an essential tool in the analysis of genome-wide association scans. This technique allows geneticists to accurately evaluate the evidence for association at genetic markers that are not directly genotyped. Genotype imputation is particularly useful for combining results across studies that rely on different genotyping platforms but also increases the power of individual scans. Here, we review the history and theoretical underpinnings of the technique. To illustrate performance of the approach, we summarize results from several gene mapping studies. Finally, we preview the role of genotype imputation in an era when whole genome resequencing is becoming increasingly common.
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Genetics of Athletic Performance
Vol. 10 (2009), pp. 407–429More LessPerformance enhancing polymorphisms (PEPs) are examples of natural genetic variation that affect the outcome of athletic challenges. Elite athletes, and what separates them from the average competitor, have been the subjects of discussion and debate for decades. While training, diet, and mental fitness are all clearly important contributors to achieving athletic success, the fact that individuals reaching the pinnacle of their chosen sports often share both physical and physiological attributes suggests a role for genetics. That multiple members of a family often participate in highly competitive events, such as the Olympics, further supports this argument.
In this review, we discuss what is known regarding the genes and gene families, including the mitochondrial genome, that are believed to play a role in human athletic performance. Where possible, we describe the physiological impact of the critical gene variants and consider predictions about other potentially important genes. Finally, we discuss the implications of these findings on the future for competitive athletics.
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Genetic Screening for Low-Penetrance Variants in Protein-Coding Genes
Vol. 10 (2009), pp. 431–450More LessGenetic testing holds great promise as a screening tool to identify persons at risk for a disease at the presymptomatic stage. However, the complexities of gene-disease associations, even in single-gene diseases, pose important challenges. These challenges include defining the role of screening for mutations that have low penetrance, which cause disease in only a minority of patients with the genotype. On the basis of the high rate of false positives, medical expert panels to date have largely discouraged genetic testing for low-penetrance mutations for use in population-based screening, although official recommendations currently exist for only a few genes. We examine the relatively limited experience of population-based screening for low-penetrance mutations in clinical settings to date, including screening for glucose-6-phosphate dehydrogenase deficiency and a low-penetrance mutation for cystic fibrosis in newborns, type 1 Gaucher disease carrier screening, and screening for adults for hemochromatosis. The trend toward recommending restricting use of these tests by medical experts is contrasted with the growing availability of genetic tests, including those for low-penetrance mutations, through direct-to-consumer outlets.
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Previous Volumes
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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)