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  • Defining the Clinical Value of a Genomic Diagnosis in the Era of Next-Generation Sequencing.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2016-07-01
    Natasha T Strande,Jonathan S Berg

    As with all fields of medicine, the first step toward medical management of genetic disorders is obtaining an accurate diagnosis, which often requires testing at the molecular level. Unfortunately, given the large number of genetic conditions without a specific intervention, only rarely does a genetic diagnosis alter patient management-which raises the question, what is the added value of obtaining a molecular diagnosis? Given the fast-paced advancement of genomic technologies, this is an important question to address in the context of genome-scale testing. Here, we address the value of establishing a diagnosis using genome-scale testing and highlight the benefits and drawbacks of such testing. We also review and compare recent major studies implementing genome-scale sequencing methods to identify a molecular diagnosis in cohorts manifesting a broad range of Mendelian monogenic disorders. Finally, we discuss potential future applications of genomic sequencing, such as screening for rare conditions.

  • Clinical utility of contemporary molecular cytogenetics.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2008-10-25
    Bassem A Bejjani,Lisa G Shaffer

    The 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.

  • ENU mutagenesis, a way forward to understand gene function.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2008-10-25
    Abraham Acevedo-Arozena,Sara Wells,Paul Potter,Michelle Kelly,Roger D Cox,Steve D M Brown

    Arguably, 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.

  • Disorders of cholesterol metabolism and their unanticipated convergent mechanisms of disease.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2014-09-04
    Frances M Platt,Christopher Wassif,Alexandria Colaco,Andrea Dardis,Emyr Lloyd-Evans,Bruno Bembi,Forbes D Porter

    Cholesterol plays a key role in many cellular processes, and is generated by cells through de novo biosynthesis or acquired from exogenous sources through the uptake of low-density lipoproteins. Cholesterol biosynthesis is a complex, multienzyme-catalyzed pathway involving a series of sequentially acting enzymes. Inherited defects in genes encoding cholesterol biosynthetic enzymes or other regulators of cholesterol homeostasis result in severe metabolic diseases, many of which are rare in the general population and currently without effective therapy. Historically, these diseases have been viewed as discrete disorders, each with its own genetic cause and distinct pathogenic cascades that lead to its specific clinical features. However, studies have recently shown that three of these diseases have an unanticipated mechanistic convergence. This surprising finding is not only shedding light on details of cellular cholesterol homeostasis but also suggesting novel approaches to therapy.

  • Personalized pharmacogenomics: predicting efficacy and adverse drug reactions.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2014-06-06
    Munir Pirmohamed

    Drug response varies between individuals owing to disease heterogeneity, environmental factors, and genetic factors. Genetic factors can affect both the pharmacokinetics and pharmacodynamics of a drug, leading to changes in local and systemic drug exposure and/or changes in the function of the drug target, altering drug response. Several pharmacogenetic biomarkers are already utilized in clinical practice and have been shown to improve clinical outcomes. However, a large number of other biomarkers have never made it beyond the discovery stage. Concerted effort is needed to improve the translation of pharmacogenetic biomarkers into clinical practice, and this will involve the use of standardized phenotyping and genotyping strategies, collaborative work, multidisciplinary approaches to identifying and replicating associations, and cooperation with industry to facilitate translation and commercialization. Acceptance of these approaches by clinicians, regulators, patients, and the public will be important in determining future success.

  • No gene in the genome makes sense except in the light of evolution.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2014-04-30
    Wilfried Haerty,Chris P Ponting

    Evolutionary conservation has been an accurate predictor of functional elements across the first decade of metazoan genomics. More recently, there has been a move to define functional elements instead from biochemical annotations. Evolutionary methods are, however, more comprehensive than biochemical approaches can be and can assess quantitatively, especially for subtle effects, how biologically important--how injurious after mutation--different types of elements are. Evolutionary methods are thus critical for understanding the large fraction (up to 10%) of the human genome that does not encode proteins and yet might convey function. These methods can also capture the ephemeral nature of much noncoding functional sequence, with large numbers of functional elements having been gained and lost rapidly along each mammalian lineage. Here, we review how different strengths of purifying selection have impacted on protein-coding and non-protein-coding loci and on transcription factor binding sites in mammalian and fruit fly genomes.

  • The role of the inherited disorders of hemoglobin, the first "molecular diseases," in the future of human genetics.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2013-07-10
    David J Weatherall

    Although 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.

  • The human microbiome: our second genome.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2012-06-19
    Elizabeth A Grice,Julia A Segre

    The human genome has been referred to as the blueprint of human biology. In this review we consider an essential but largely ignored overlay to that blueprint, the human microbiome, which is composed of those microbes that live in and on our bodies. The human microbiome is a source of genetic diversity, a modifier of disease, an essential component of immunity, and a functional entity that influences metabolism and modulates drug interactions. Characterization and analysis of the human microbiome have been greatly catalyzed by advances in genomic technologies. We discuss how these technologies have shaped this emerging field of study and advanced our understanding of the human microbiome. We also identify future challenges, many of which are common to human genetic studies, and predict that in the future, analyzing genetic variation and risk of human disease will sometimes necessitate the integration of human and microbial genomic data sets.

  • Rapid turnover of functional sequence in human and other genomes.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2011-07-05
    Chris P Ponting,Christoffer Nellåker,Stephen Meader

    The amount of a genome's sequence that is functional has been surprisingly difficult to estimate accurately. This has severely hindered analyses asking whether the amount of functional genomic sequence correlates with organismal complexity. Most studies estimate these amounts by considering nucleotide substitution rates within aligned sequences. These approaches show reduced power to identify sequence that is aligned, functional, and constrained only within narrowly defined phyla. The neutral indel model exploits insertions or deletions (indels) rather than substitutions in predicting functional sequence. Surprisingly, this method indicates that half of all functional sequence is specific to individual eutherian lineages. This review considers the rates at which coding or noncoding and functional or nonfunctional sequence changes among mammalian genomes. In contrast to the slow rate at which protein-coding sequence changes, functional noncoding sequence appears to change or be turned over at rapid rates in mammals.

  • Unraveling a multifactorial late-onset disease: from genetic susceptibility to disease mechanisms for age-related macular degeneration.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2009-05-02
    Anand Swaroop,Emily Y Chew,Catherine Bowes Rickman,Gonçalo R Abecasis

    Aging-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.

  • Disorders of lysosome-related organelle biogenesis: clinical and molecular genetics.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2008-06-12
    Marjan Huizing,Amanda Helip-Wooley,Wendy Westbroek,Meral Gunay-Aygun,William A Gahl

    Lysosome-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.

  • Recent Advances in Defining the Genetic Basis of Rheumatoid Arthritis.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2016-05-25
    Chikashi Terao,Soumya Raychaudhuri,Peter K Gregersen

    Rheumatoid arthritis (RA) is the most common inflammatory arthritis and exhibits genetic overlap with other autoimmune and inflammatory disorders. Although predominant associations with the HLA-DRB1 locus have been known for decades, recent data have revealed additional insight into the likely causative variants within HLA-DRB1 as well as within other HLA loci that contribute to disease risk. In addition, more than 100 common variants in non-HLA loci have been implicated in disease susceptibility. Genetic factors are involved not only in the development of RA, but also with various disease subphenotypes, including production and circulating levels of autoantibodies and joint destruction. The major current challenge is to integrate these new data into a precise understanding of disease pathogenesis, including the critical cell types and molecular networks involved as well as interactions with environmental factors. We predict that delineating the functional effects of genetic variants is likely to drive new diagnostic and therapeutic approaches to the disease.

  • DNA strand break repair and human genetic disease.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2007-09-25
    Peter J McKinnon,Keith W Caldecott

    Each day tens of thousands of DNA single-strand breaks (SSBs) arise in every cell from the attack of deoxyribose and DNA bases by reactive oxygen species and other electrophilic molecules. DNA double-strand breaks (DSBs) also arise, albeit at a much lower frequency, from similar attacks and from the encounter of unrepaired SSBs and possibly other DNA structures by DNA replication forks. DSBs are also created during normal development of the immune system. Defects in the cellular response to DNA strand breaks underpin many human diseases, including disorders associated with cancer predisposition, immune dysfunction, radiosensitivity, and neurodegeneration. Here we provide an overview of the genetic diseases associated with defects in the repair/response to DNA strand breaks.

  • The genetic lexicon of dyslexia.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2007-04-21
    Silvia Paracchini,Thomas Scerri,Anthony P Monaco

    Reading abilities are acquired only through specific teaching and training. A significant proportion of children fail to achieve these skills despite normal intellectual abilities and an appropriate opportunity to learn. Difficulty in learning to read is attributable to specific dysfunctions of the brain, which so far remain poorly understood. However, it is recognized that the neurological basis for dyslexia, or reading disability, is caused in large part by genetic factors. Linkage studies have successfully identified several regions of the human genome that are likely to harbor susceptibility genes for dyslexia. In the past few years there have been exciting advances with the identification of four candidate genes located within three of these linked chromosome regions: DYX1C1 on chromosome 15, ROBO1 on chromosome 3, and KIAA0319 and DCDC2 on chromosome 6. Functional studies of these genes are offering new insights about the biological mechanisms underlying the development of dyslexia and, in general, of cognition.

  • Old Dogs, New Tricks: Monogenic Autoinflammatory Disease Unleashed.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2016-07-01
    Monique Stoffels,Daniel L Kastner

    Autoinflammatory diseases are inborn disorders of the innate immune system characterized by episodes of systemic inflammation that are mediated largely by myeloid cells. The field of autoinflammatory diseases has been established since 1999, following the identification of the first genes underlying periodic fever syndromes. This review focuses on developments that have transformed the field in the last two years. We discuss three newly described monogenic autoinflammatory diseases [deficiency of adenosine deaminase 2 (DADA2), a subtype of macrophage activation syndrome (MAS), and stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy (SAVI)], discuss the possibilities of somatic mosaicism and digenic inheritance, and give an update on new concepts in pathways involved in familial Mediterranean fever (FMF). Finally, the new monogenic autoinflammatory disease haploinsufficiency of A20 (HA20) underscores the placement of monogenic diseases in the firmament of common autoinflammatory phenotypes. The advances in the last two years have shed light on the pathophysiology of several autoinflammatory diseases and have elucidated new pathways that play a role in innate immunity.

  • Sequencing primate genomes: what have we learned?
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2009-07-28
    Tomas Marques-Bonet,Oliver A Ryder,Evan E Eichler

    We 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.

  • Unraveling the Tangled Skein: The Evolution of Transcriptional Regulatory Networks in Development.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2015-06-17
    Mark Rebeiz,Nipam H Patel,Veronica F Hinman

    The molecular and genetic basis for the evolution of anatomical diversity is a major question that has inspired evolutionary and developmental biologists for decades. Because morphology takes form during development, a true comprehension of how anatomical structures evolve requires an understanding of the evolutionary events that alter developmental genetic programs. Vast gene regulatory networks (GRNs) that connect transcription factors to their target regulatory sequences control gene expression in time and space and therefore determine the tissue-specific genetic programs that shape morphological structures. In recent years, many new examples have greatly advanced our understanding of the genetic alterations that modify GRNs to generate newly evolved morphologies. Here, we review several aspects of GRN evolution, including their deep preservation, their mechanisms of alteration, and how they originate to generate novel developmental programs.

  • Ethical, legal, social, and policy implications of behavioral genetics.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2013-03-05
    Colleen M Berryessa,Mildred K Cho

    The field of behavioral genetics has engendered a host of moral and social concerns virtually since its inception. The policy implications of a genetic basis for behaviors are widespread and extend beyond the clinic to the socially important realms of education, criminal justice, childbearing, and child rearing. The development of new techniques and analytic approaches, including whole-genome sequencing, noninvasive prenatal genetic testing, and optogenetics, has clearly changed the study of behavioral genetics. However, the social context of biomedical research has also changed profoundly over the past few decades, and in ways that are especially relevant to behavioral genetics. The ever-widening scope of behavioral genetics raises ethical, legal, social, and policy issues in the potential new applications to criminal justice, education, the military, and reproduction. These issues are especially critical to address because of their potentially disproportionate effects on vulnerable populations such as children, the unborn, and the incarcerated.

  • Phenome-Wide Association Studies as a Tool to Advance Precision Medicine.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2016-05-06
    Joshua C Denny,Lisa Bastarache,Dan M Roden

    Beginning in the early 2000s, the accumulation of biospecimens linked to electronic health records (EHRs) made possible genome-phenome studies (i.e., comparative analyses of genetic variants and phenotypes) using only data collected as a by-product of typical health care. In addition to disease and trait genetics, EHRs proved a valuable resource for analyzing pharmacogenetic traits and developing reverse genetics approaches such as phenome-wide association studies (PheWASs). PheWASs are designed to survey which of many phenotypes may be associated with a given genetic variant. PheWAS methods have been validated through replication of hundreds of known genotype-phenotype associations, and their use has differentiated between true pleiotropy and clinical comorbidity, added context to genetic discoveries, and helped define disease subtypes, and may also help repurpose medications. PheWAS methods have also proven to be useful with research-collected data. Future efforts that integrate broad, robust collection of phenotype data (e.g., EHR data) with purpose-collected research data in combination with a greater understanding of EHR data will create a rich resource for increasingly more efficient and detailed genome-phenome analysis to usher in new discoveries in precision medicine.

  • The tension between data sharing and the protection of privacy in genomics research.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2012-03-13
    Jane Kaye

    Next-generation sequencing and global data sharing challenge many of the governance mechanisms currently in place to protect the privacy of research participants. These challenges will make it more difficult to guarantee anonymity for participants, provide information to satisfy the requirements of informed consent, and ensure complete withdrawal from research when requested. To move forward, we need to improve the current governance systems for research so that they are responsive to individual privacy concerns but can also be effective at a global level. We need to develop a system of e-governance that can complement existing governance systems but that places greater reliance on the use of technology to ensure compliance with ethical and legal requirements. These new governance structures must be able to address the concerns of research participants while at the same time ensuring effective data sharing that promotes public trust in genomics research.

  • Communicating genetic risk information for common disorders in the era of genomic medicine.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2013-09-06
    Denise M Lautenbach,Kurt D Christensen,Jeffrey A Sparks,Robert C Green

    Communicating genetic risk information in ways that maximize understanding and promote health is increasingly important given the rapidly expanding availability and capabilities of genomic technologies. A well-developed literature on risk communication in general provides guidance for best practices, including presentation of information in multiple formats, attention to framing effects, use of graphics, sensitivity to the way numbers are presented, parsimony of information, attentiveness to emotions, and interactivity as part of the communication process. Challenges to communicating genetic risk information include deciding how best to tailor it, streamlining the process, deciding what information to disclose, accepting that communications may have limited influence, and understanding the impact of context. Meeting these challenges has great potential for empowering individuals to adopt healthier lifestyles and improve public health, but will require multidisciplinary approaches and collaboration.

  • The repatterning of eukaryotic genomes by random genetic drift.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2011-07-16
    Michael Lynch,Louis-Marie Bobay,Francesco Catania,Jean-François Gout,Mina Rho

    Recent observations on rates of mutation, recombination, and random genetic drift highlight the dramatic ways in which fundamental evolutionary processes vary across the divide between unicellular microbes and multicellular eukaryotes. Moreover, population-genetic theory suggests that the range of variation in these parameters is sufficient to explain the evolutionary diversification of many aspects of genome size and gene structure found among phylogenetic lineages. Most notably, large eukaryotic organisms that experience elevated magnitudes of random genetic drift are susceptible to the passive accumulation of mutationally hazardous DNA that would otherwise be eliminated by efficient selection. Substantial evidence also suggests that variation in the population-genetic environment influences patterns of protein evolution, with the emergence of certain kinds of amino-acid substitutions and protein-protein complexes only being possible in populations with relatively small effective sizes. These observations imply that the ultimate origins of many of the major genomic and proteomic disparities between prokaryotes and eukaryotes and among eukaryotic lineages have been molded as much by intrinsic variation in the genetic and cellular features of species as by external ecological forces.

  • Patents in genomics and human genetics.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2010-07-02
    Robert Cook-Deegan,Christopher Heaney

    Genomics and human genetics are scientifically fundamental and commercially valuable. These fields grew to prominence in an era of growth in government and nonprofit research funding, and of even greater growth of privately funded research and development in biotechnology and pharmaceuticals. Patents on DNA technologies are a central feature of this story, illustrating how patent law adapts-and sometimes fails to adapt-to emerging genomic technologies. In instrumentation and for therapeutic proteins, patents have largely played their traditional role of inducing investment in engineering and product development, including expensive post-discovery clinical research to prove safety and efficacy. Patents on methods and DNA sequences relevant to clinical genetic testing show less evidence of benefits and more evidence of problems and impediments, largely attributable to university exclusive licensing practices. Whole-genome sequencing will confront uncertainty about infringing granted patents, but jurisprudence trends away from upholding the broadest and potentially most troublesome patent claims.

  • African genetic diversity: implications for human demographic history, modern human origins, and complex disease mapping.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2008-07-03
    Michael C Campbell,Sarah A Tishkoff

    Comparative studies of ethnically diverse human populations, particularly in Africa, are important for reconstructing human evolutionary history and for understanding the genetic basis of phenotypic adaptation and complex disease. African populations are characterized by greater levels of genetic diversity, extensive population substructure, and less linkage disequilibrium (LD) among loci compared to non-African populations. Africans also possess a number of genetic adaptations that have evolved in response to diverse climates and diets, as well as exposure to infectious disease. This review summarizes patterns and the evolutionary origins of genetic diversity present in African populations, as well as their implications for the mapping of complex traits, including disease susceptibility.

  • The genetics of narcolepsy.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2003-10-07
    Dorothee Chabas,Shahrad Taheri,Corinne Renier,Emmanuel Mignot

    Human narcolepsy is a genetically complex disorder. Family studies indicate a 20-40 times increased risk of narcolepsy in first-degree relatives and twin studies suggest that nongenetic factors also play a role. The tight association between narcolepsy-cataplexy and the HLA allele DQB1*0602 suggests that narcolepsy has an autoimmune etiology. In recent years, extensive genetic studies in animals, using positional cloning in dogs and gene knockouts in mice, have identified abnormalities in hypothalamic hypocretin (orexin) neurotransmission as key to narcolepsy pathophysiology. Though most patients with narcolepsy-cataplexy are hypocretin deficient, mutations or polymorphisms in hypocretin-related genes are extremely rare. It is anticipated that susceptibility genes that are independent of HLA and impinge on the hypocretin neurotransmitter system are isolated in human narcolepsy.

  • Nonsyndromic seizure disorders: epilepsy and the use of the internet to advance research.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2003-10-07
    Mark F Leppert,Nanda A Singh

    The progress in understanding the genetics of nonsyndromic epilepsy is the direct result of dramatic advances made by the Human Genome Project. The development of thousands of precisely mapped genetic markers and the nearly complete sequencing of the entire human genome in 2001 allowed genetic researchers in epilepsy to identify many loci and genes as causal in inherited idiopathic epilepsy. This substantial increase in information has required the development of accurate and online bioinformatic databases. Only the Internet can enable such large amounts of precise DNA sequence information to be transferred to researchers. Along with the construction of these databases has been the development of efficient search algorithms for specific DNA sequences and genetic information. This article summarizes the effect that this burst of new genomic information has had on research aimed at discovering the underlying genetic factors for nonsyndromic epilepsy. Many of the web sites important to epilepsy gene discovery are listed and discussed in this article, including sites with extensive information on genetic markers, genetic analysis, gene sequence, gene expression, gene mutations, and DNA sequence variation. Continued acquisition of information on naturally occurring DNA sequence variants will greatly help research directed towards understanding the genetic susceptibility of the common, nonsyndromic epilepsies and will lead to the promise of personalized medicine.

  • Enzyme therapy for lysosomal storage disease: principles, practice, and prospects.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2003-10-07
    Gregory A Grabowski,Robert J Hopkin

    Over the past three decades, enzyme therapy for lysosomal storage diseases has moved from an academic pursuit to direct delivery of effective clinical care for affected patients and families. This success is based on understanding the complexities of lysosomal biogenesis, lysosomal hydrolase sorting and hydrolytic requirements, and the target sites of pathology of these diseases. This article reviews these concepts and their application to the treatment of affected patients with Gaucher disease, Fabry disease, and mucopolysaccharidosis I. The principles, progress, and practice in these diseases provide prototypes for expansion of enzyme therapy to a growing set of these diseases.

  • Human nonsyndromic sensorineural deafness.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2003-10-07
    Thomas B Friedman,Andrew J Griffith

    Given the unique biological requirements of sound transduction and the selective advantage conferred upon a species capable of sensitive sound detection, it is not surprising that up to 1% of the approximately 30,000 or more human genes are necessary for hearing. There are hundreds of monogenic disorders for which hearing loss is one manifestation of a syndrome or the only disorder and therefore is nonsyndromic. Herein we review the supporting evidence for identifying over 30 genes for dominantly and recessively inherited, nonsyndromic, sensorineural deafness. The state of knowledge concerning their biological roles is discussed in the context of the controversies within an evolving understanding of the intricate molecular machinery of the inner ear.

  • Patterns of human genetic diversity: implications for human evolutionary history and disease.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2003-10-07
    Sarah A Tishkoff,Brian C Verrelli

    Since the completion of the human genome sequencing project, the discovery and characterization of human genetic variation is a principal focus for future research. Comparative studies across ethnically diverse human populations and across human and nonhuman primate species is important for reconstructing human evolutionary history and for understanding the genetic basis of human disease. In this review, we summarize data on patterns of human genetic diversity and the evolutionary forces (mutation, genetic drift, migration, and selection) that have shaped these patterns of variation across both human populations and the genome. African population samples typically have higher levels of genetic diversity, a complex population substructure, and low levels of linkage disequilibrium (LD) relative to non-African populations. We discuss these differences and their implications for mapping disease genes and for understanding how population and genomic diversity have been important in the evolution, differentiation, and adaptation of humans.

  • The inherited basis of diabetes mellitus: implications for the genetic analysis of complex traits.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2003-10-07
    Jose C Florez,Joel Hirschhorn,David Altshuler

    Diabetes encompasses a heterogeneous group of diseases, each with a substantial genetic component. We review the division of diabetes into different subtypes based on clinical phenotype, the fruitful pursuit of genes underlying monogenic forms of the disease, the successes and drawbacks of whole-genome linkage scans in type 1 and type 2 diabetes, and the recent identification of several diabetes genes by large association studies. We use the lessons learned from this extensive body of evidence to illustrate general implications for the genetic analysis of complex traits.

  • Molecular pathogenesis of pancreatic cancer.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2003-10-07
    Donna E Hansel,Scott E Kern,Ralph H Hruban

    Pancreatic cancer is an almost universally fatal disease, with a five-year survival rate of 5%. Research into both sporadic and inherited forms of pancreatic cancer has yielded tremendous advances in the understanding of this disease at the molecular level. Elucidating genetic alterations in pancreatic cancer has identified various abnormalities ranging from gross chromosomal abnormalities to point mutations, many of which influence the development and progression of pancreatic cancer. Identifying precursor lesions within pancreatic ducts has led to the formulation of a progression model of pancreatic cancer and subsequent identification of early- and late-stage changes leading to invasive cancer. Ultimately, understanding the genetic events underlying the development of pancreatic cancer may serve as a useful adjunct in the screening and treatment of patients suffering from, or at risk for, pancreatic cancer.

  • Sequence divergence, functional constraint, and selection in protein evolution.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2003-10-07
    Justin C Fay,Chung-I Wu

    The genome sequences of multiple species has enabled functional inferences from comparative genomics. A primary objective is to infer biological functions from the conservation of homologous DNA sequences between species. A second, more difficult, objective is to understand what functional DNA sequences have changed over time and are responsible for species' phenotypic differences. The neutral theory of molecular evolution provides a theoretical framework in which both objectives can be explicitly tested. Development of statistical tests within this framework has provided insight into the evolutionary forces that constrain and in some cases change DNA sequences and the resulting patterns that emerge. In this article, we review recent work on how functional constraint and changes in protein function are inferred from protein polymorphism and divergence data. We relate these studies to our understanding of the neutral theory and adaptive evolution.

  • Peroxisome biogenesis disorders.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2003-10-07
    Sabine Weller,Stephen J Gould,David Valle

    The peroxisome biogenesis disorders (PBDs) comprise 12 autosomal recessive complementation groups (CGs). The multisystem clinical phenotype varies widely in severity and results from disturbances in both development and metabolic homeostasis. Progress over the last several years has lead to identification of the genes responsible for all of these disorders and to a much improved understanding of the biogenesis and function of the peroxisome. Increasing availability of mouse models for these disorders offers hope for a better understanding of their pathophysiology and for development of therapies that might especially benefit patients at the milder end of the clinical phenotype.

  • Creationism and intelligent design.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2003-10-07
    Robert T Pennock

    Creationism, the rejection of evolution in favor of supernatural design, comes in many varieties besides the common young-earth Genesis version. Creationist attacks on science education have been evolving in the last few years through the alliance of different varieties. Instead of calls to teach "creation science," one now finds lobbying for "intelligent design" (ID). Guided by the Discovery Institute's "Wedge strategy," the ID movement aims to overturn evolution and what it sees as a pernicious materialist worldview and to renew a theistic foundation to Western culture, in which human beings are recognized as being created in the image of God. Common ID arguments involving scientific naturalism, "irreducible complexity," "complex specified information," and "icons of evolution," have been thoroughly examined and refuted. Nevertheless, from Kansas to Ohio to the U.S. Congress, ID continues lobbying to teach the controversy, and scientists need to be ready to defend good evolution education.

  • Forensics and mitochondrial DNA: applications, debates, and foundations.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2003-10-07
    Bruce Budowle,Marc W Allard,Mark R Wilson,Ranajit Chakraborty

    Debate on the validity and reliability of scientific methods often arises in the courtroom. When the government (i.e., the prosecution) is the proponent of evidence, the defense is obliged to challenge its admissibility. Regardless, those who seek to use DNA typing methodologies to analyze forensic biological evidence have a responsibility to understand the technology and its applications so a proper foundation(s) for its use can be laid. Mitochondrial DNA (mtDNA), an extranuclear genome, has certain features that make it desirable for forensics, namely, high copy number, lack of recombination, and matrilineal inheritance. mtDNA typing has become routine in forensic biology and is used to analyze old bones, teeth, hair shafts, and other biological samples where nuclear DNA content is low. To evaluate results obtained by sequencing the two hypervariable regions of the control region of the human mtDNA genome, one must consider the genetically related issues of nomenclature, reference population databases, heteroplasmy, paternal leakage, recombination, and, of course, interpretation of results. We describe the approaches, the impact some issues may have on interpretation of mtDNA analyses, and some issues raised in the courtroom.

  • The Drosophila melanogaster genome.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2003-10-07
    Susan E Celniker,Gerald M Rubin

    Drosophila's importance as a model organism made it an obvious choice to be among the first genomes sequenced, and the Release 1 sequence of the euchromatic portion of the genome was published in March 2000. This accomplishment demonstrated that a whole genome shotgun (WGS) strategy could produce a reliable metazoan genome sequence. Despite the attention to sequencing methods, the nucleotide sequence is just the starting point for genome-wide analyses; at a minimum, the genome sequence must be interpreted using expressed sequence tag (EST) and complementary DNA (cDNA) evidence and computational tools to identify genes and predict the structures of their RNA and protein products. The functions of these products and the manner in which their expression and activities are controlled must then be assessed-a much more challenging task with no clear endpoint that requires a wide variety of experimental and computational methods. We first review the current state of the Drosophila melanogaster genome sequence and its structural annotation and then briefly summarize some promising approaches that are being taken to achieve an initial functional annotation.

  • Gene annotation: prediction and testing.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2003-10-07
    Jennifer L Ashurst,John E Collins

    Fifty years after the publication of DNA structure, the whole human genome sequence will be officially finished. This achievement marks the beginning of the task to catalogue every human gene and identify each of their function expression patterns. Currently, researchers estimate that there are about 30,000 human genes and approximately 70% of these can be automatically predicted using a combination of ab initio and similarity-based programs. However, to experimentally investigate every gene's function, the research community requires a high-quality annotation of alternative splicing, pseudogenes, and promoter regions that can only be provided by manual intervention. Manual curation of the human genome will be a long-term project as experimental data are continually produced to confirm or refine the predictions, and new features such as noncoding RNAs and enhancers have not been fully identified. Such a highly curated human gene-set made publicly available will be a great asset for the experimental community and for future comparative genome projects.

  • Race, ancestry, and genes: implications for defining disease risk.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2003-10-07
    Rick A Kittles,Kenneth M Weiss

    Geneticists are interested in finding genes associated with disease. Because of widespread health disparities, race is a variable that is often said to be relevant in this context. The idea is that members of a preconceived "race" share common ancestry that may include genetic risk factors. Human variation has been shaped by the long-term processes of population history, and population samples that reflect that history carry statistical information about shared genetic variation or "ancestry." But race is an elusive concept and a term difficult even to define rigorously. Unfortunately, these problems are neither new nor related to recent genetic knowledge. Race is also one of the most politically charged subjects in American life because its associated sociocultural component has notoriously led to categorical treatment that has been misleading and politically misused. There are ways in which the concept of race (whether or not the term is used) can be a legitimate tool in the search for disease-associated genes. But in that context race reflects deeply confounded cultural as well as biological factors, and a careful distinction must be made between race as a statistical risk factor and causal genetic variables.

  • Genetics of human laterality disorders: insights from vertebrate model systems.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2003-05-06
    Brent W Bisgrove,Susan H Morelli,H Joseph Yost

    Many internal organs in the vertebrate body are asymmetrically oriented along the left-right (L-R) body axis. Organ asymmetry and some components of the molecular signaling pathways that direct L-R development are highly conserved among vertebrate species. Although individuals with full reversal of organ L-R asymmetry (situs inversus totalis) are healthy, significant morbidity and mortality is associated with perturbations in laterality that result in discordant orientation of organ systems and complex congenital heart defects. In humans and other vertebrates, genetic alterations of L-R signaling pathways can result in a wide spectrum of laterality defects. In this review we categorize laterality defects in humans, mice, and zebrafish into specific classes based on altered patterns of asymmetric gene expression, organ situs defects, and midline phenotypes. We suggest that this classification system provides a conceptual framework to help consolidate the disparate laterality phenotypes reported in humans and vertebrate model organisms, thereby refining our understanding of the genetics of L-R development. This approach helps suggest candidate genes and genetic pathways that might be perturbed in human laterality disorders and improves diagnostic criteria.

  • Databases and tools for browsing genomes.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2002-08-27
    Ewan Birney,Michele Clamp,Tim Hubbard

    To 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.

  • Structuring the universe of proteins.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2002-08-27
    Stephen K Burley,Jeffrey B Bonanno

    High-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.

  • Genetics of myeloid leukemias.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2002-08-27
    Louise M Kelly,D Gary Gilliland

    Human 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.

  • Molecular mechanisms for genomic disorders.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2002-07-27
    Ken Inoue,James R Lupski

    Genomic 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.

  • Patenting genes and genetic research: good or bad for innovation?
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2002-07-27
    Beth E Arnold,Eva Ogielska-Zei

    Our 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.

  • From Zebrafish to human: modular medical models.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2002-07-27
    Jordan T Shin,Mark C Fishman

    Genetic 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.

  • Developmental genomic approaches in model organisms.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2002-07-27
    Valerie Reinke,Kevin P White

    Functional 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.

  • Genetic "code": representations and dynamical models of genetic components and networks.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2002-07-27
    Alex Gilman,Adam P Arkin

    Dynamical 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 lambda, 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.

  • The application of tandem mass spectrometry to neonatal screening for inherited disorders of intermediary metabolism.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2002-07-27
    Donald H Chace,Theodore A Kalas,Edwin W Naylor

    This 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.

  • Human migrations and population structure: what we know and why it matters.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2002-07-27
    David B Goldstein,Lounès Chikhi

    The 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.

  • Balanced polymorphism selected by genetic versus infectious human disease.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2002-07-27
    Michael Dean,Mary Carrington,Stephen J O'Brien

    The 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.

  • Linkage analysis in psychiatric disorders: the emerging picture.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2002-07-27
    Pamela Sklar

    Gene 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.

  • Genetic and epigenetic alterations in colon cancer.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2002-07-27
    William M Grady,Sanford D Markowitz

    Colorectal 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.

  • Hedgehog signaling and human disease.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2002-07-27
    Allen E Bale

    Developmental 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.

  • Deciphering the genetic basis of Alzheimer's disease.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2002-07-27
    Dennis J Selkoe,Marcia B Podlisny

    A 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 beta-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 beta-protein levels as a way of treating or preventing all forms of the disease.

  • A personal history of the mouse genome.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2002-07-27
    Mary F Lyon

    The 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.

  • Linkage disequilibrium and association mapping.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2008-05-29
    B S Weir

    Linkage 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 rho 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 rho2 and the nonadditive variance components by rho4, suggesting that nonadditive components have less influence than additive components on association tests.

  • Positive selection in the human genome: from genome scans to biological significance.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2008-05-29
    Joanna L Kelley,Willie J Swanson

    Here 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.

  • A bird's-eye view of sex chromosome dosage compensation.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2008-05-21
    Arthur P Arnold,Yuichiro Itoh,Esther Melamed

    Intensive 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.

  • Human telomere structure and biology.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2008-05-10
    Harold Riethman

    Human 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.

  • The uneasy ethical and legal underpinnings of large-scale genomic biobanks.
    Annu. Rev. Genomics Hum. Genet. (IF 7.914) Pub Date : 2007-06-07
    Henry T Greely

    Abstract Large-scale genomic databases are becoming increasingly common. These databases, and the underlying biobanks, pose several substantial legal and ethical problems. Neither the usual methods for protecting subject confidentiality, nor even anonymity, are likely to protect subjects' identities in richly detailed databases. Indeed, in these settings, anonymity is itself ethically suspect. New methods of consent will need to be created to replace the blanket consent common to such endeavors, with a consent procedure that gives subjects some real control over what they might consider inappropriate use of their information and biological material. Through their use, these biobanks are also likely to yield information that will be of some clinical significance to the subjects, information that they should have access to. Failure to adjust to these new challenges is not only legally and ethically inappropriate, but puts at risk the political support on which biomedical research depends.

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