Annual Review of Genomics and Human Genetics - Volume 5, 2004

Rapid advances in genetic research are leading to an expanding array of genetic tests. Primary care providers will increasingly be challenged to identify patients whose symptoms, physical findings, or family history indicate the need for genetic testing, and to determine how to use genetic information most effectively to improve disease prevention. In addressing these challenges, practitioners will need to consider the range of different uses of genetic testing, including diagnosis in symptomatic and asymptomatic people, risk assessment, reproductive decision-making, and population screening. They will need a set of core skills and knowledge to evaluate family history and to recognize clinical findings that indicate genetic risk. At the same time, the primary care perspective will contribute to the evaluation of appropriate uses of genetic testing. A partnership between medical genetics and primary care will help to ensure the development of effective policies, educational tools, and practice guidelines for the coming era of genomic health care.

The genomes from three mammals (human, mouse, and rat), two worms, and several yeasts have been sequenced, and more genomes will be completed in the near future for comparison with those of the major model organisms. Scientists have used various methods to align and compare the sequenced genomes to address critical issues in genome function and evolution. This review covers some of the major new insights about gene content, gene regulation, and the fraction of mammalian genomes that are under purifying selection and presumed functional. We review the evolutionary processes that shape genomes, with particular attention to variation in rates within genomes and along different lineages. Internet resources for accessing and analyzing the treasure trove of sequence alignments and annotations are reviewed, and we discuss critical problems to address in new bioinformatic developments in comparative genomics.

Genetic screening utilizes analytical approaches adapted for high throughput to identify carrier and affected individuals in a targeted population. Currently, genetic screening focuses on carrier screening, prenatal screening, and newborn screening. Newborn screening should serve as a model for all genetic screening, with more than forty years of experience and numerous lessons learned. As with all genetic screening, there are policy concerns in newborn screening regarding which disorders and technologies should be selected, and how centralized or decentralized the process to set policy should be. The need to share experiences and develop databases transcends all other policy considerations in genetic screening. The future will see population-based screening for adult-onset disorders. However, there needs to be extensive research to define predictive risk for various ethnocultural groups and to determine effective interventions. Ethical concerns regarding the timing of population screening, as well as the scope of use of information, will need to be resolved if genomic medicine will achieve its promise of a predictive, preventive, and personalized medicine.

Nutritional genomics has tremendous potential to change the future of dietary guidelines and personal recommendations. Nutrigenetics will provide the basis for personalized dietary recommendations based on the individual's genetic make up. This approach has been used for decades for certain monogenic diseases; however, the challenge is to implement a similar concept for common multifactorial disorders and to develop tools to detect genetic predisposition and to prevent common disorders decades before their manifestation. The preliminary results involving gene-diet interactions for cardiovascular diseases and cancer are promising, but mostly inconclusive. Success in this area will require the integration of different disciplines and investigators working on large population studies designed to adequately investigate gene-environment interactions. Despite the current difficulties, preliminary evidence strongly suggests that the concept should work and that we will be able to harness the information contained in our genomes to achieve successful aging using behavioral changes; nutrition will be the cornerstone of this endeavor.

Besides its obvious intrinsic value, knowledge of population history, and of the demographic and evolutionary changes that accompany it, has proven fundamental to address applied research in human genetics. In this review we place current European genetic diversity in the context of the global human genome diversity and review the evidence supporting a recent African origin of the Europeans. We then discuss the results and the interpretation of genetic studies attempting to quantify the relative importance of various gene flow processes, both within Europe and from Asia into Europe, focusing especially on the initial, Paleolithic colonization of the continent, and on later, Paleolithic postglacial and Neolithic dispersals. Finally, we discuss how knowledge of the patterns of genetic diversity in Europe, and of their inferred generating processes, can be extremely useful in planning health care and in biomedical research.

Prostate cancer is a heterogeneous disease with multiple loci contributing to susceptibility. Traditionally, genome-wide scans using high-risk families have utilized stratification by number of affected individuals, family history of other cancers, or family age at diagnosis to improve genetic homogeneity. In addition to locus heterogeneity, for later onset diseases such as prostate cancer, a major limitation to mapping efforts is that key parental DNA samples are rarely available. The lack of available samples from upper generations reduces inheritance information, and as a result, the standard 10-cM genome scan does not provide full power to detect linkage. To increase the ability to find disease-associated loci, much denser genome-wide scans must be undertaken in multiple ethnic groups. In addition, new ways of defining homogenous subsets of families need to be developed.

Model organisms, especially the budding yeast, are leading systems in the transformation of biology into an information science. With the availability of genome sequences and genome-scale data generation technologies, the extraction of biological insight from complex integrated molecular networks has become a major area of research. Here I examine key concepts and review research developments. I propose specific areas of research effort to drive network analysis in directions that will promote modeling with increasing predictive power.

Atherosclerosis, the primary cause of coronary artery disease (CAD) and stroke, is a disorder with multiple genetic and environmental contributions. Genetic-epidemiologic studies have identified a surprisingly long list of genetic and nongenetic risk factors for CAD. However, such studies indicate that family history is the most significant independent risk factor (15, 52, 77). Many Mendelian disorders associated with atherosclerosis, such as familial hypercholesterolemia (FH), have been characterized, but they explain only a small percentage of disease susceptibility (although a substantial fraction of early CAD). Most cases of myocardial infarction (MI) and stroke result from the interactions of multiple genetic and environmental factors, none of which can cause disease by itself. Successful discovery of these genetic factors will require using complementary approaches with animal models, large-scale human genetic studies, and functional experiments. This review emphasizes the common, complex forms of CAD.

Since Watson & Crick's 1953 description of the structure of DNA, significant progress has been achieved in the control of congenital disorders, most of which has benefited industrialized countries. Little advantage accrued to developing nations, most of which in the same time frame achieved a significant epidemiological transition, resulting in congenital disorders attaining public health significance. The burden of congenital disorders in these lower-resource countries is high and they need to develop medical genetic services. We present a new pragmatic approach for the care and prevention of congenital disorders in these countries, pioneered initially by the World Health Organization.

The genome sequences of important model systems are available and the focus is now shifting to large-scale experiments enabled by this data. Following in the footsteps of genomics, we have functional genomics, proteomics, and even metabolomics, roughly paralleling the biological hierarchy of the transcription, translation, and production of small molecules. Proteomics is initially concerned with determining the structure, expression, localization, biochemical activity, interactions, and cellular roles of as many proteins as possible. There has been great progress owing to novel instrumentation, experimental strategies, and bioinformatics methods. The area of protein-protein interactions has been especially fruitful. First pass interaction maps of some model organisms exist, and the proteins in many important organelles are about to be determined. Researchers are also beginning to integrate large-scale data sets from various “omics” disciplines in targeted investigations of specific biomedical areas and in pursuit of a general framework for systems biology.

Over the past two decades, detailed studies of mitochondrial DNA and the Y chromosome have increased our understanding of the history and population genetics of Native American populations. Variation in autosomal DNA has also been investigated, but to a more limited extent. A low level of genetic diversity in Native American populations is a robust finding from all lines of evidence. In contrast to the previous multiple migration scenarios for the Pleistocene peopling of the Americas, it now seems that a single migration satisfactorily explains the genetic data. Native Americans show greater genetic similarity to populations in east central Asia than they do to the current easternmost Siberian populations. Recent studies on the Y chromosome indicate a date of entry (about 17,000 years ago) into the Americas roughly consistent with the archaeological record. Native Americans experienced two episodes of reduced population size: one with the peopling of the Americas and the other with European contact. The former is the more important determinant for the number of gene lineages and founding haplotypes seen in populations. It may also be an important determinant of the genetic variation underlying common complex diseases, and especially diabetes. The tribal structure of contemporary Native American populations is relevant to the distribution of rare Mendelian disorders because most tribes constitute relatively small, semi-independent gene pools. This leads us to expect that the allelic spectrum for Mendelian diseases will be simple within individual tribes but complex for Native Americans as a whole.

As recently as 20 years ago, there was relatively little information about the number and distribution of recombinational events in human meiosis, and we knew virtually nothing about factors affecting patterns of recombination. However, the generation of a variety of linkage-based genetic mapping tools and, more recently, cytological approaches that enable us to directly visualize the recombinational process in meiocytes, have led to an increased understanding of human meiosis. In this review, we discuss the different approaches used to study meiotic recombination in humans, our understanding of factors that affect the number and location of recombinational events, and clinical consequences of variation in the recombinational process.

With the completion of the human genome sequence and the advent of technologies to study functional aspects of genomes, molecular comparisons between humans and other primates have gained momentum. The comparison of the human genome to the genomes of species closely related to humans allows the identification of genomic features that set primates apart from other mammals and of features that set certain primates—notably humans—apart from other primates. In this article, we review recent progress in these areas with an emphasis on how comparative approaches may be used to identify functionally relevant features unique to the human genome.

Autism is one of the most heritable complex disorders, with compelling evidence for genetic factors and little or no support for environmental influence. The estimated prevalence of autism has increased since molecular genetic studies began, owing to loosening of diagnostic criteria and, more importantly, to more complete ascertainment strategies. This has led to a reduction in the sibling relative risk, but strong heritability estimates remain. It is essential to recognize that genetics is the only current approach to understanding the pathophysiology of autism in which there is not the usual concern about whether one is studying a consequence rather than a cause. There are hundreds, if not thousands, of patients with autism spectrum disorder with documented single-gene mutations or chromosomal abnormalities. Autism may be one of the most complex, yet strongly genetic, disorders in which chromosomal disorders, relatively rare highly penetrant mutations, and multiplicative effects of common variants all have support in different cases and families. The field of complex genetics is replete with many researchers and reviewers who want to promote their overly focused interest in one method at the exclusion of others. However, it is essential that the restricted interests of patients with autism not be reflected in overly restrictive genetic approaches if we are to better understand the genetics of autism in the most expeditious and thorough manner.

During the past decade, the molecular mechanisms underlying the mammalian circadian clock have been defined. A core set of circadian clock genes common to most cells throughout the body code for proteins that feed back to regulate not only their own expression, but also that of clock output genes and pathways throughout the genome. The circadian system represents a complex multioscillatory temporal network in which an ensemble of coupled neurons comprising the principal circadian pacemaker in the suprachiasmatic nucleus of the hypothalamus is entrained to the daily light/dark cycle and subsequently transmits synchronizing signals to local circadian oscillators in peripheral tissues. Only recently has the importance of this system to the regulation of such fundamental biological processes as the cell cycle and metabolism become apparent. A convergence of data from microarray studies, quantitative trait locus analysis, and mutagenesis screens demonstrates the pervasiveness of circadian regulation in biological systems. The importance of maintaining the internal temporal homeostasis conferred by the circadian system is revealed by animal models in which mutations in genes coding for core components of the clock result in disease, including cancer and disturbances to the sleep/wake cycle.

Completing the primary genomic sequence of Arabidopsis thaliana was a major milestone, being the first plant genome and only the third high-quality finished eukaryotic genome sequence. Understanding how the genome sequence comprehensively encodes developmental programs and environmental responses is the next major challenge for all plant genome projects. This requires fully characterizing the genes, the regulatory sequences, and their functions. We discuss several functional genomics approaches to decode the linear sequence of the reference plant Arabidopsis thaliana, including full-length cDNA collections, microarrays, natural variation, knockout collections, and comparative sequence analysis. Genomics provides the essential tools to speed the work of the traditional molecular geneticist and is now a scientific discipline in its own right.

Epigenetics is comprised of the stable and heritable (or potentially heritable) changes in gene expression that do not entail a change in DNA sequence. The role of epigenetics in the etiology of human disease is increasingly recognized with the most obvious evidence found for genes subject to genomic imprinting. Mutations and epimutations in imprinted genes can give rise to genetic and epigenetic phenotypes, respectively; uniparental disomy and imprinting defects represent epigenetic disease phenotypes. There are also genetic disorders that affect chromatin structure and remodeling. These disorders can affect chromatin in trans or in cis, as well as expression of both imprinted and nonimprinted genes. Data from Angelman and Beckwith-Wiedemann syndromes and other disorders indicate that a monogenic or oligogenic phenotype can be caused by a mixed epigenetic and genetic and mixed de novo and inherited (MEGDI) model. The MEGDI model may apply to some complex disease traits and could explain negative results in genome-wide genetic scans.