Annual Review of Genomics and Human Genetics - Volume 2, 2001

It is well recognized that most medications exhibit wide interpatient variability in their efficacy and toxicity. For many medications, these interindividual differences are due in part to polymorphisms in genes encoding drug metabolizing enzymes, drug transporters, and/or drug targets (e.g., receptors, enzymes). Pharmacogenomics is a burgeoning field aimed at elucidating the genetic basis for differences in drug efficacy and toxicity, and it uses genome-wide approaches to identify the network of genes that govern an individual's response to drug therapy. For some genetic polymorphisms (e.g., thiopurine S-methyltransferase), monogenic traits have a marked effect on pharmacokinetics (e.g., drug metabolism), such that individuals who inherit an enzyme deficiency must be treated with markedly different doses of the affected medications (e.g., 5%–10% of the standard thiopurine dose). Likewise, polymorphisms in drug targets (e.g., beta adrenergic receptor) can alter the sensitivity of patients to treatment (e.g., beta-agonists), changing the pharmacodynamics of drug response. Recognizing that most drug effects are determined by the interplay of several gene products that govern the pharmacokinetics and pharmacodynamics of medications, pharmacogenomics research aims to elucidate these polygenic determinants of drug effects. The ultimate goal is to provide new strategies for optimizing drug therapy based on each patient's genetic determinants of drug efficacy and toxicity. This chapter provides an overview of the current pharmacogenomics literature and offers insights for the potential impact of this field on the safe and effective use of medications.

Inherited defects in DNA repair or the processing of DNA damage can lead to disease. Both autosomal recessive and autosomal dominant modes of inheritance are represented. The diseases as a group are characterized by genomic instability, with eventual appearance of cancer. The inherited defects frequently have a specific DNA damage sensitivity, with cells from affected individuals showing normal resistance to other genotoxic agents. The known defects are subtle alterations in transcription, replication, or recombination, with alternate pathways of processing permitting cellular viability. Distinct diseases may arise from different mutations in one gene; thus, clinical phenotypes may reflect the loss of different partial functions of a gene. The findings indicate that partial defects in transcription or recombination lead to genomic instability, cancer, and characteristic disease phenotypes.

The population of Quebec, Canada (7.3 million) contains ∼6 million French Canadians; they are the descendants of ∼8500 permanent French settlers who colonized Nouvelle France between 1608 and 1759. Their well-documented settlements, internal migrations, and natural increase over four centuries in relative isolation (geographic, linguistic, etc.) contain important evidence of social transmission of demographic behavior that contributed to effective family size and population structure. This history is reflected in at least 22 Mendelian diseases, occurring at unusually high prevalence in its subpopulations. Immigration of non-French persons during the past 250 years has given the Quebec population further inhomogeneity, which is apparent in allelic diversity at various loci. The histories of Quebec's subpopulations are, to a great extent, the histories of their alleles. Rare pathogenic alleles with high penetrance and associated haplotypes at 10 loci (CFTR, FAH, HBB, HEXA, LDLR, LPL, PAH, PABP2, PDDR, and SACS) are expressed in probands with cystic fibrosis, tyrosinemia, β-thalassemia, Tay-Sachs, familial hypercholesterolemia, hyperchylomicronemia, PKU, oculopharyngeal muscular dystrophy, pseudo vitamin D deficiency rickets, and spastic ataxia of Charlevoix-Saguenay, respectively) reveal the interpopulation and intrapopulation genetic diversity of Quebec. Inbreeding does not explain the clustering and prevalence of these genetic diseases; genealogical reconstructions buttressed by molecular evidence point to founder effects and genetic drift in multiple instances. Genealogical estimates of historical meioses and analysis of linkage disequilibrium show that sectors of this young population are suitable for linkage disequilibrium mapping of rare alleles. How the population benefits from what is being learned about its structure and how its uniqueness could facilitate construction of a genomic map of linkage disequilibrium are discussed.

A population of about 5 million at the northern corner of Europe is unlikely to arouse the attention of the human genetics community, unless it offers something useful for others to learn. A combination of coincidences has finally made this population one that, out of proportion for its size, has by example shaped research in human disease genetics. This chapter summarizes advances made in medical genetics that are based on research facilitated by Finland's population structure. The annotation of the human genome for its polymorphism and involvement in disease is not over; it is, therefore, of interest to assess whether genetic studies in populations such as the Finnish might help in the remaining tasks.

Congenital disorders of glycosylation (CDG) are a rapidly growing group of genetic diseases that are due to defects in the synthesis of glycans and in the attachment of glycans to other compounds. Most CDG are multisystem diseases that include severe brain involvement. The CDG causing sialic acid deficiency of N-glycans can be diagnosed by isoelectrofocusing of serum sialotransferrins. An efficient treatment, namely oral D-mannose, is available for only one CDG (CDG-Ib). In many patients with CDG, the basic defect is unknown (CDG-x). Glycan structural analysis, yeast genetics, and knockout animal models are essential tools in the elucidation of novel CDG. Eleven primary genetic glycosylation diseases have been discovered and their basic defects identified: six in the N-glycan assembly, three in the N-glycan processing, and two in the O-glycan (glycosaminoglycan) assembly. This review summarizes their clinical, biochemical, and genetic characteristics and speculates on further developments in this field.

The chromosomal region, 15q11-q13, involved in Prader-Willi and Angelman syndromes (PWS and AS) represents a paradigm for understanding the relationships between genome structure, epigenetics, evolution, and function. The PWS/AS region is conserved in organization and function with the homologous mouse chromosome 7C region. However, the primate 4 Mb PWS/AS region is bounded by duplicons derived from an ancestral HERC2 gene and other sequences that may predispose to chromosome rearrangements. Within a 2 Mb imprinted domain, gene function depends on parental origin. Genetic evidence suggests that PWS arises from functional loss of several paternally expressed genes, including those that function as RNAs, and that AS results from loss of maternal UBE3A brain-specific expression. Imprinted expression is coordinately controlled in cis by an imprinting center (IC), a genetic element functional in germline and/or early postzygotic development that regulates the establishment of parental specific allelic differences in replication timing, DNA methylation, and chromatin structure.

Gene therapy can be broadly defined as the transfer of genetic material to cure a disease or at least to improve the clinical status of a patient. One of the basic concepts of gene therapy is to transform viruses into genetic shuttles, which will deliver the gene of interest into the target cells. Based on the nature of the viral genome, these gene therapy vectors can be divided into RNA and DNA viral vectors. The majority of RNA virus-based vectors have been derived from simple retroviruses like murine leukemia virus. A major shortcoming of these vectors is that they are not able to transduce nondividing cells. This problem may be overcome by the use of novel retroviral vectors derived from lentiviruses, such as human immunodeficiency virus (HIV). The most commonly used DNA virus vectors are based on adenoviruses and adeno-associated viruses. Although the available vector systems are able to deliver genes in vivo into cells, the ideal delivery vehicle has not been found. Thus, the present viral vectors should be used only with great caution in human beings and further progress in vector development is necessary.

Use of the World Wide Web (“the web”) and our knowledge of human genetics are both currently expanding rapidly. By allowing swift, universal, and free access to data, the web has already played an important role in human genetics research. It has also begun to change the way that information is shared in clinical genetics and, to a lesser degree, affect how education in human genetics occurs. There are scores of web sites helpful to those interested in either research or clinical aspects of human genetics. The web and related communication technologies should continue to play increasingly important roles in human genetics.

One of the fruits of the Human Genome Project is the discovery of millions of DNA sequence variants in the human genome. The majority of these variants are single nucleotide polymorphisms (SNPs). A dense set of SNP markers opens up the possibility of studying the genetic basis of complex diseases by population approaches. In all study designs, a large number of individuals must be genotyped with a large number of markers. In this review, the current status of SNP genotyping is discussed in terms of the mechanisms of allelic discrimination, the reaction formats, and the detection modalities. A number of genotyping methods currently in use are described to illustrate the approaches being taken. Although no single genotyping method is ideally suited for all applications, a number of good genotyping methods are available to meet the needs of many study designs. The challenges for SNP genotyping in the near future include increasing the speed of assay development, reducing the cost of the assays, and performing multiple assays in parallel. Judging from the accelerated pace of new method development, it is hopeful that an ideal SNP genotyping method will be developed soon.

There is an urgent need to develop novel classes of antibiotics to counter the threat of the spread of multiply resistant bacterial pathogens. The availability of the complete genome sequence of many pathogenic microbes provides information on every potential drug target and is an invaluable resource in the search for novel compounds. Here, we review the approaches being taken to exploit the genome databases through a combination of bioinformatics, transcriptional analysis, and a further understanding of the molecular basis of the disease process. The emphasis is changing from compound screening to target hunting, as the latter offers flexible ways to design and optimize the next generation of broad-spectrum antibiotics.

Usher syndrome (USH) is defined by the association of sensorineural deafness and visual impairment due to retinitis pigmentosa. The syndrome has three distinct clinical subtypes, referred to as USH1, USH2, and USH3. Each subtype is genetically heterogeneous, and 12 loci have been detected so far. Four genes have been identified, namely, USH1B, USH1C, USH1D, and USH2A. USH1B, USH1C, and USH1D encode an unconventional myosin (myosin VIIA), a PDZ domain–containing protein (harmonin), and a cadherin-like protein (cadherin-23), respectively. Mutations of these genes cause primary defects of the sensory cells in the inner ear, and probably also in the retina. In the inner ear, the USH1 genes, I propose, are involved in the same signaling pathway, which may control development and/or maintenance of the hair bundles of sensory cells via an adhesion force (a) at the junctions between these cells and supporting cells and (b) at the level of the lateral links that interconnect the stereocilia. In contrast, the molecular pathogenesis of USH2A, which is owing to a defect of a novel extracellular matrix protein, is likely to be different from that of USH1.

The known disorders of cholesterol biosynthesis have expanded rapidly since the discovery that Smith-Lemli-Opitz syndrome is caused by a deficiency of 7-dehydrocholesterol. Each of the six now recognized sterol disorders—mevalonic aciduria, Smith-Lemli-Opitz syndrome, desmosterolosis, Conradi-Hünermann syndrome, CHILD syndrome, and Greenberg dysplasia—has added to our knowledge of the relationship between cholesterol metabolism and embryogenesis. One of the most important lessons learned from the study of these disorders is that abnormal cholesterol metabolism impairs the function of the hedgehog class of embryonic signaling proteins, which help execute the vertebrate body plan during the earliest weeks of gestation. The study of the enzymes and genes in these several syndromes has also expanded and better delineated an important class of enzymes and proteins with diverse structural functions and metabolic actions that include sterol biosynthesis, nuclear transcriptional signaling, regulation of meiosis, and even behavioral modulation.

Systems biology studies biological systems by systematically perturbing them (biologically, genetically, or chemically); monitoring the gene, protein, and informational pathway responses; integrating these data; and ultimately, formulating mathematical models that describe the structure of the system and its response to individual perturbations. The emergence of systems biology is described, as are several examples of specific systems approaches.

A genetic basis for interindividual variation in susceptibility to human infectious diseases has been indicated by twin, adoptee, pedigree, and candidate gene studies. This has led to the identification of a small number of strong genetic associations with common variants for malaria, HIV infection, and infectious prion diseases. Numerous other genes have shown less strong associations with these and some other infectious diseases, such as tuberculosis, leprosy, and persistent hepatitis viral infections. Many immunogenetic loci influence susceptibility to several infectious pathogens. Recent genetic linkage analyses of measures of infection as well as of infectious disease, including some genome-wide scans, have found convincing evidence of genetic linkage to chromosomal regions wherein susceptibility genes have yet to be identified. These studies indicate a highly polygenic basis for susceptibility to many common infectious diseases, with some emerging examples of interaction between variants of specific polymorphic host and pathogen genes.

This review covers the ethical, legal, and policy issues associated with the generation and dissemination of genetic information. First, conceptual issues, such as the definition of terms and the description of two modes of analysis, are addressed. Research findings on public attitudes toward privacy and genetics and other factors relevant to policy making are also reviewed. Second, the example of genetic research is used to highlight the importance of attention to the intrinsic harms associated with violations of genetic privacy. Subtopics include national databases and biobanks, gene brokers, and pharmacogenomics. Third, the example of insurer access to genetic information is used to highlight the importance of attention to discrimination and other instrumental harms associated with failures of regulation. Fourth, a summary of the preceding sections leads into an outline of a program for realizing the benefits of the new science in a manner that affirms rather than erodes privacy and other important values.

The genetic analysis of life span has only begun in mammals, invertebrates, such as Caenorhabditis elegans and Drosophila, and yeast. Even at this primitive stage of the genetic analysis of aging, the physiological observations that rate of metabolism is intimately tied to life span is supported. In many examples from mice to worms to flies to yeast, genetic variants that affect life span also modify metabolism. Insulin signaling regulates life span coordinately with reproduction, metabolism, and free radical protective gene regulation in C. elegans. This may be related to the findings that caloric restriction also regulates mammalian aging, perhaps via the modulation of insulin-like signaling pathways. The nervous system has been implicated as a key tissue where insulin-like signaling and free radical protective pathways regulate life span in C. elegans and Drosophila. Genes that determine the life span could act in neuroendocrine cells in diverse animals. The involvement of insulin-like hormones suggests that the plasticity in life spans evident in animal phylogeny may be due to variation in the timing of release of hormones that control vitality and mortality as well as variation in the response to those hormones. Pedigree analysis of human aging may reveal variations in the orthologs of the insulin pathway genes and coupled pathways that regulate invertebrate aging. Thus, genetic approaches may identify a set of circuits that was established in ancestral metazoans to regulate their longevity.

With the completion of the human genome, sequence analysis of gene function will move into the center of future genome research. One of the key strategies for studying gene function involves the genetic dissection of biological processes in animal models. Mouse mutants are of particular importance for the analysis of disease pathogenesis and transgenic techniques, and gene targeting have become routine tools. Recently, phenotype-driven strategies using chemical mutagenesis have been the target of increasing interest. In this review, the current state of ENU mutagenesis and its application as a systematic tool of genome analysis are examined.

The nose of Homo sapiens is a sophisticated chemical sensor. It is able to smell almost any type of volatile molecule, often at extraordinarly low concentrations, and can make fine perceptual discriminations between structurally related molecules. The diversity of odor recognition is mediated by odorant receptor (OR) genes, discovered in 1991 by Buck & Axel. OR genes form the largest gene families in mammalian genomes. A decade after their discovery, advances in the sequencing of the human genome have provided a first draft of the human OR repertoire: It consists of ∼1000 sequences, residing in multiple clusters spread throughout the genome, with more than half being pseudogenes. Allelic variants are beginning to be recognized and may provide an opportunity for genotype-phenotype correlations. Here, I review the current knowledge of the human OR repertoire and summarize the limited information available regarding putative pheromone and taste receptors in humans.