Showing papers in "Annual Review of Genomics and Human Genetics in 2000"
TL;DR: Functional differences in the apoE isoforms that affect (or did affect) survival before the reproductive years probably account, at least in part, for the allele frequencies of the present day.
Abstract: First recognized as a major determinant in lipoprotein metabolism and cardiovascular disease, apolipoprotein (apo) E has emerged as an important molecule in several biological processes not directly related to its lipid transport function, including Alzheimer's disease and cognitive function, immunoregulation, and possibly even infectious diseases. ApoE is a polymorphic protein arising from three alleles at a single gene locus. The three major isoforms, apoE4, apoE3, and apoE2, differ from one another only by single amino acid substitutions, yet these changes have profound functional consequences at both the cellular and molecular levels. ApoE3 seems to be the normal isoform in all known functions, while apoE4 and apoE2 can each be dysfunctional. Isoform (allele)-specific effects include the association of apoE2 with the genetic disorder type III hyperlipoproteinemia and with both increased and decreased risk for atherosclerosis and the association of apoE4 with increased risk for both atherosclerosis and Alzheimer's disease, impaired cognitive function, and reduced neurite outgrowth; isoform-specific differences in cellular signaling events may also exist. Functional differences in the apoE isoforms that affect (or did affect) survival before the reproductive years probably account, at least in part, for the allele frequencies of the present day.
1,588 citations
TL;DR: The development of statistical tests of natural selection at the DNA level in population samples has been ongoing for the past 13 years and the current state of the field is reviewed, and the available tests of selection are described.
Abstract: ▪ Abstract The development of statistical tests of natural selection at the DNA level in population samples has been ongoing for the past 13 years. The current state of the field is reviewed, and the available tests of selection are described. All tests use predictions from the theory of neutrally evolving sites as a null hypothesis. Departures from equilibrium-neutral expectations can indicate the presence of natural selection acting either at one or more of the sites under investigation or at a sufficiently tightly linked site. Complications can arise in the interpretation of departures from neutrality if populations are not at equilibrium for mutation and genetic drift or if populations are subdivided, both of which are likely scenarios for humans. Attempts to understand the nonequilibrium configuration of silent polymorphism in human mitochondrial DNA illustrate the difficulty of distinguishing between selection and alternative demographic hypotheses. The range of plausible alternatives to selection w...
335 citations
TL;DR: The issue of whether or not a population size bottleneck occurred among the authors' ancestors is under debate among geneticists as well as among anthropologists, and the Garden of Eden model of the origin of modern humans is confirmed.
Abstract: ▪ Abstract This is a review of genetic evidence about the ancient demography of the ancestors of our species and about the genesis of worldwide human diversity. The issue of whether or not a population size bottleneck occurred among our ancestors is under debate among geneticists as well as among anthropologists. The bottleneck, if it occurred, would confirm the Garden of Eden (GOE) model of the origin of modern humans. The competing model, multiregional evolution (MRE), posits that the number of human ancestors has been large, occupying much of the temperate Old World for the last two million years. While several classes of genetic marker seem to contain a strong signal of demographic recovery from a small number of ancestors, other nuclear loci show no such signal. The pattern at these loci is compatible with the existence of widespread balancing selection in humans. The study of human diversity at (putatively) neutral genetic marker loci has been hampered since the beginning by ascertainment bias since...
332 citations
TL;DR: This review summarizes the current understanding of the molecular pathology of each of these diseases, starting with a clinical picture followed by a focused description of the disease genes, the proteins involved, and the studies that have lent insight into their pathophysiology.
Abstract: Within the closing decade of the twentieth century, 14 neurological disorders were shown to result from the expansion of unstable trinucleotide repeats, establishing this once unique mutational mechanism as the basis of an expanding class of diseases. Trinucleotide repeat diseases can be categorized into two subclasses based on the location of the trinucleotide repeats: diseases involving noncoding repeats (untranslated sequences) and diseases involving repeats within coding sequences (exonic). The large body of knowledge accumulating in this fast moving field has provided exciting clues and inspired many unresolved questions about the pathogenesis of diseases caused by expanded trinucleotide repeats. This review summarizes the current understanding of the molecular pathology of each of these diseases, starting with a clinical picture followed by a focused description of the disease genes, the proteins involved, and the studies that have lent insight into their pathophysiology.
323 citations
TL;DR: It became clear that only approximately 80 genes of the 250 in the original minimal gene set are represented by orthologs in all life forms, and some of the genes that were included in the first version, based on a limited genome comparison, could be dispensable.
Abstract: ▪ Abstract Several theoretical and experimental studies have endeavored to derive the minimal set of genes that are necessary and sufficient to sustain a functioning cell under ideal conditions, that is, in the presence of unlimited amounts of all essential nutrients and in the absence of any adverse factors, including competition. A comparison of the first two completed bacterial genomes, those of the parasites Haemophilus influenzae and Mycoplasma genitalium, produced a version of the minimal gene set consisting of ∼250 genes. Very similar estimates were obtained by analyzing viable gene knockouts in Bacillus subtilis, M. genitalium, and Mycoplasma pneumoniae. With the accumulation and comparison of multiple complete genome sequences, it became clear that only ∼80 genes of the 250 in the original minimal gene set are represented by orthologs in all life forms. For ∼15% of the genes from the minimal gene set, viable knockouts were obtained in M. genitalium; unexpectedly, these included even some of the u...
311 citations
TL;DR: Because XPB and XPD function in both nucleotide excision repair and transcription initiation, the cellular phenotypes associated with a deficiency of each one of them include failure to repair mutagenic DNA lesions and defects in the recovery of RNA transcription after UV irradiation.
Abstract: DNA helicases are a highly conserved group of enzymes that unwind DNA. They function in all processes in which access to single-stranded DNA is required, including DNA replication, DNA repair and recombination, and transcription of RNA. Defects in helicases functioning in one or more of these processes can result in characteristic human genetic disorders in which genomic instability and predisposition to cancer are common features. So far, different helicase genes have been found mutated in six such disorders. Mutations in XPB and XPD can result in xeroderma pigmentosum, Cockayne syndrome, or trichothiodystrophy. Mutations in the RecQ-like genes BLM, WRN, and RECQL4 can result in Bloom syndrome, Werner syndrome, and Rothmund-Thomson syndrome, respectively. Because XPB and XPD function in both nucleotide excision repair and transcription initiation, the cellular phenotypes associated with a deficiency of each one of them include failure to repair mutagenic DNA lesions and defects in the recovery of RNA tra...
239 citations
TL;DR: Three clinical conditions displaying phenotypic overlap have been linked to mutation or deletion of the elastin gene at 7q11.23, and the understanding of these disorders has progressed from phenotypesic description to identification of causative mutations and insight into pathogenetic mechanisms for some aspects of the phenotype.
Abstract: Three clinical conditions displaying phenotypic overlap have been linked to mutation or deletion of the elastin gene at 7q11.23. Supravalvar aortic stenosis, an autosomal dominant disorder characterized by elastin arteriopathy, is caused by mutation or intragenic deletions of ELN resulting in loss of function. Autosomal dominant cutis laxa, a primarily cutaneous condition, is the result of frameshift mutations at ELN that cause a dominant-negative effect on elastic fiber structure. Williams syndrome, a neurodevelopmental disorder is due to a 1.5 Mb deletion that includes ELN and at least 15 contiguous genes. The disorder is characterized by dysmorphic facies, mental retardation or learning difficulties, elastin arteriopathy, a unique cognitive profile of relative strength in auditory rote memory and language and extreme weakness in visuospatial constructive cognition, and a typical personality that includes overfriendliness, anxiety, and attention problems. The understanding of these disorders has progressed from phenotypic description to identification of causative mutations and insight into pathogenetic mechanisms for some aspects of the phenotype.
228 citations
TL;DR: It is shown how the phylogenetic approach makes possible novel kinds of comparative analysis, including detection of domain shuffling and lateral gene transfer, reconstruction of the evolutionary diversification of gene families, tracing of evolutionary change in protein function at the amino acid level, and prediction of structure-function relationships.
Abstract: ▪ Abstract With the advent of high-throughput DNA sequencing and whole-genome analysis, it has become clear that the coding portions of the genome are organized hierarchically in gene families and superfamilies. Because the hierarchy of genes, like that of living organisms, reflects an ancient and continuing process of gene duplication and divergence, many of the conceptual and analytical tools used in phylogenetic systematics can and should be used in comparative genomics. Phylogenetic principles and techniques for assessing homology, inferring relationships among genes, and reconstructing evolutionary events provide a powerful way to interpret the ever increasing body of sequence data. In this review, we outline the application of phylogenetic approaches to comparative genomics, beginning with the inference of phylogeny and the assessment of gene orthology and paralogy. We also show how the phylogenetic approach makes possible novel kinds of comparative analysis, including detection of domain shuffling ...
206 citations
TL;DR: How the DNA sequence has facilitated the understanding of the biology and genetics of the major histocompatibility complex and some ways in which the sequence may be exploited in the future to explore the relationship between the extraordinary polymorphism of the region and its association with both autoimmune and infectious diseases are discussed.
Abstract: The entire 3.6-MbpDNA sequence of a human major histocompatibility complex derived from a composite of DNA clones from different haplotypes, was completed in 1999, primarily through the work of four main groups. At that time, it was the longest contiguous human DNA sequence to have been determined. The sequence is of extremely high quality and accuracy. In this review, we discuss how the DNA sequence has facilitated our understanding of the biology and genetics of the major histocompatibility complex. We suggest some ways in which the sequence may be exploited in the future to explore the relationship between the extraordinary polymorphism of the region and its association with both autoimmune and infectious diseases.
187 citations
TL;DR: This review discusses inherited iron deficiency and iron overload disorders and recent insights into their pathophysiology.
Abstract: Iron is an essential cofactor in a variety of cellular processes. Except for a few unusual bacterial species, iron is indispensable for living organisms. However, free iron is toxic because of its propensity to induce the formation of dangerous free radicals. Consequently, iron balance is tightly regulated. Disorders of iron homeostasis are among the most common afflictions of humans. This review discusses inherited iron deficiency and iron overload disorders and recent insights into their pathophysiology.
180 citations
TL;DR: The view is taken that work done on Drosophila melanogaster can serve as a model for understanding complex traits in humans, and the literature on this model system, as well as on humans, is reviewed.
Abstract: This review discusses the prospects for understanding the genetic basis of complex traits in humans. We take the view that work done on Drosophila melanogaster can serve as a model for understanding complex traits in humans, and the literature on this model system, as well as on humans, is reviewed. The prospects for success in understanding the genetic basis of complex traits depend, in part, on the nature of the forces acting on genetic variation. We suggest that different experimental approaches should be undertaken for traits caused by common genetic variants versus those arising from rare genetic variants.
TL;DR: Myocardial structure and signal transduction are now merging into a common field of research that will lead to a more complete understanding of the molecular mechanisms that underly heart disease.
Abstract: The identification of genetic mutations underlying familial structural heart disease has provided exciting new insights into how alterations in structural components of the cardiomyocyte lead to different forms of cardiomyopathy. Specifically, mutations in components of the sarcomere are frequently associated with hypertrophic cardiomyopathy, whereas mutations in cytoskeletal proteins lead to dilated cardiomyopathy. In addition, extrinsic stresses such as hypertension and valvular disease can produce myocardial remodeling that is very similar to that observed in genetic cardiomyopathy. For myocardial remodeling to occur, changes in gene expression must occur; therefore, changes in contractile function or wall stress must be communicated to the nucleus via signal transduction pathways. The identity of these signaling pathways has become a key question in molecular biology. Numerous signaling molecules have been implicated in the development of hypertrophy and failure, including the β-adrenergic receptor, G...
TL;DR: This review surveys the current platform technologies: separation-based approaches, which include mass spectrometry; homogeneous assays; and solid-phase/array-based assays%; and emerging technologies for present and future needs are indicated.
Abstract: The large-scale typing of sequence variation in genes and genomic DNA presents new challenges for which it is not clear that current technologies are sufficiently sensitive, robust, or scalable. This review surveys the current platform technologies: separation-based approaches, which include mass spectrometry; homogeneous assays; and solid-phase/array-based assays. We assess techniques for discovering and typing variation on a large scale, especially that of single-nucleotide polymorphisms. The in-depth focus is the DNA chip/array platform, and some of the published large-scale studies are closely examined. The problem of large-scale amplification is addressed, and emerging technologies for present and future needs are indicated.
TL;DR: It is argued that the scientific community must increase its commitment to public discourse and the public response to genetics advances during the 1990s and beyond.
Abstract: Throughout the twentieth century and continuing into the present, the general public has been fascinated by advances in genetic knowledge. At times, individuals and groups have either inadvertently or deliberately misused genetic knowledge in the service of political goals. At other times, advances in genetics have challenged deeply held societal or religious beliefs. During the 1990s, there were many advances that focused an unprecedented level of public attention and concern on genetics. In particular, the public has expressed deep concern about gene mapping, cloning, and genetically modified foods. In each case, the origin of the concern and the nature of the public response have been different. I consider these topics and argue that the scientific community must increase its commitment to public discourse.
TL;DR: During the first half-century, human genetics was very primitive, but by the end of the century it was comparable to that of the best-studied species, and this trend will surely extend to the next century.
Abstract: In the first half-century of genetics, 1900 to 1953, the main techniques were breeding experiments and microscopy. Emphasis was on transmission genetics and cytogenetics, and during the half-century these became mature sciences. But the gene remained elusive. In 1953, thanks to Watson and Crick, the nature of the gene was no longer a mystery. In the second half of the century, the techniques became more chemical and computers played an indispensable role. The emphasis was then on gene action and, in the human, on increasingly accurate gene mapping and the soon-to-be-completed DNA sequence. During the first half-century, human genetics was very primitive, but by the end of the century it was comparable to that of the best-studied species. This trend will surely extend to the next century. The humanitarian possibilities of new techniques are enormous, but social judgments about their use and the problems of an increasingly crowded planet temper our optimism.