Annual Review of Genomics and Human Genetics - Volume 11, 2010

Transcriptional regulation of gene expression plays a significant role in establishing the diversity of human cell types and biological functions from a common set of genes. The components of regulatory control in the human genome include cis-acting elements that act across immense genomic distances to influence the spatial and temporal distribution of gene expression. Here we review the established categories of distant-acting regulatory elements, discussing the classical and contemporary evidence of their regulatory potential and clinical importance. Current efforts to identify regulatory sequences throughout the genome and elucidate their biological significance depend heavily on advances in sequence conservation–based analyses and on increasingly large-scale efforts applying transgenic technologies in model organisms. We discuss the advantages and limitations of sequence conservation as a predictor of regulatory function and present complementary emerging technologies now being applied to annotate regulatory elements in vertebrate genomes.

For nearly three decades, the sequence of the human mitochondrial genome (mtDNA) has provided a molecular framework for understanding maternally inherited diseases. However, the vast majority of human mitochondrial disorders are caused by nuclear genome defects, which is not surprising since the mtDNA encodes only 13 proteins. Advances in genomics, mass spectrometry, and computation have only recently made it possible to systematically identify the complement of over 1,000 proteins that comprise the mammalian mitochondrial proteome. Here, we review recent progress in characterizing the mitochondrial proteome and highlight insights into its complexity, tissue heterogeneity, evolutionary origins, and biochemical versatility. We then discuss how this proteome is being used to discover the genetic basis of respiratory chain disorders as well as to expand our definition of mitochondrial disease. Finally, we explore future prospects and challenges for using the mitochondrial proteome as a foundation for systems analysis of the organelle.

There has been considerable excitement over the ability to construct linkage maps based only on genome-wide genotype data for single nucleotide polymorphic sites (SNPs) in a population sample. These maps, which are derived from estimates of linkage disequilibrium (LD), rely on population genetics theory to relate the decay of LD to the local rate of recombination, but other population processes also come into play. Here we contrast these LD maps to the classically derived, pedigree-based human recombination maps. The LD maps have a level of resolution greatly exceeding that of the pedigree maps, and at this fine scale, sperm typing allows a means of validation. While at a gross level both the pedigree maps and the sperm typing methods generally agree with LD maps, there are significant local differences between them, and the fact that these maps measure different genetic features should be remembered when using them for other genetic inferences.

Admixture mapping is based on the hypothesis that differences in disease rates between populations are due in part to frequency differences in disease-causing genetic variants. In admixed populations, these genetic variants occur more often on chromosome segments inherited from the ancestral population with the higher disease variant frequency. A genome scan for disease association requires only enough markers to identify the ancestral chromosome segments; for recently admixed populations, such as African Americans, 1,500–2,500 ancestry-informative markers (AIMs) are sufficient. The method was proposed over 50 years ago, but the AIM panels and statistical methods required have only recently become available. Since the first admixture scan in 2005, the genetic bases for a range of diseases/traits have been identified by admixture mapping. Here, we provide a historical perspective, review AIM panels and software packages, and discuss recent successes and unexpected insights into human diseases that exhibit disparate rates across human populations.

Coronary artery disease and its clinical manifestations, including myocardial infarction, are heritable traits, consistent with a role for inherited DNA sequence variation in conferring risk for disease. Knowledge of the new sequence variations in the genome that confer risk has the potential to illuminate new causal biologic pathways in humans and to thereby further improve diagnosis and treatment. Here, we review recent progress in mapping genetic loci related to coronary disease and risk factor phenotypes, including plasma lipoprotein concentrations. Genome-wide linkage (in families) and association (in populations) studies have identified more than a dozen genetic loci related to coronary disease. A key challenge now is to move from mapping loci to pinpointing causal genes and variants, and to develop a molecular understanding of how these genes lead to coronary disease.

The mammalian hair follicle (HF) is a complex structure composed of several distinct cell layers. The HF is an ectodermal appendage that resides in the skin, and unlike other tissues and organs, it possesses the remarkable ability to self-renew and undergoes a hair cycle that persists in adult life. Stem cells in the bulge region of the HF, as well as dermal papilla cells, play key roles in the regulation of successive hair cycles. Recent advances in molecular genetics have enabled the identification of many genes and pathways that are involved in HF morphogenesis and cycling. Furthermore, mutations in some of these genes are associated with hereditary hair diseases in humans. Identification of causative genes for hair diseases has provided a better understanding of the crucial roles of these genes in HF morphogenesis, development, and hair growth in humans.

Cancer profiling studies have had a profound impact on our understanding of the biology of cancers in a number of ways, including providing insights into the biological heterogeneity of specific cancer types, identification of novel oncogenes and tumor suppressors, and defining pathways that interact to drive the growth of individual cancers. Several large-scale genomic studies are underway that aim to catalog all biologically significant mutational events in each cancer type, and these findings will allow researchers to understand how mutational networks function within individual tumors. The identification of molecular predictive and prognostic tools to facilitate treatment decisions is an important step for individualized patient therapy and, ultimately, in improving patient outcomes. Whereas there are still significant challenges to implementing genomic testing and targeted therapy into routine clinical practice, rapid technological advancements provide hope for overcoming these obstacles.

Intellectual disability (ID) is the leading socio-economic problem of health care, but compared to autism and schizophrenia, it has received very little public attention. Important risk factors for ID are malnutrition, cultural deprivation, poor health care, and parental consanguinity. In the Western world, fetal alcohol exposure is the most common preventable cause. Most severe forms of ID have genetic causes. Cytogenetically detectable and submicroscopic chromosomal rearrangements account for approximately 25% of all cases. X-linked gene defects are responsible in 10–12% of males with ID; to date, 91 of these defects have been identified. In contrast, autosomal gene defects have been largely disregarded, but due to coordinated efforts and the advent of next-generation DNA sequencing, this is about to change. As shown for Fra(X) syndrome, this renewed focus on autosomal gene defects will pave the way for molecular diagnosis and prevention, shed more light on the pathogenesis of ID, and reveal new opportunities for therapy.

Human skeletal dysplasias are disorders that result from errors in bone, cartilage, and joint development. A complex series of signaling pathways, including the FGF, TGFβ, BMP, WNT, Notch, and Hedgehog pathways, are essential for proper skeletogenesis, and human skeletal dysplasias are often a consequence of primary or secondary dysregulation of these pathways. Although these pathways interact to regulate bone, cartilage, and joint formation, human genetic phenotypes point to the predominant action of specific components of these pathways. Mutations in the genes with a role in metabolic processing within the cell, the extracellular matrix, and transcriptional regulation can lead to dysregulation of cell–cell and cell–matrix signaling that alters tissue patterning, cell differentiation, proliferation, and apoptosis. We propose a morphogen rheostat model to conceptualize how mutations in different metabolic processes can lead to the integration of differential signaling inputs within a temporal and spatial context to generate apparently divergent skeletal phenotypes.

Lactation, an important characteristic of mammalian reproduction, has evolved by exploiting a diversity of strategies across mammals. Comparative genomics and transcriptomics experiments have now allowed a more in-depth analysis of the molecular evolution of lactation. Milk cell and mammary gland genomic studies have started to reveal conserved milk proteins and other components of the lactation system of monotreme, marsupial, and eutherian lineages. These analyses confirm the ancient origin of the lactation system and provide useful insight into the function of specific milk proteins in the control of lactation. These studies also illuminate the role of milk in the regulation of growth and development of the young beyond simple nutritive aspects.

The genomes of birds and nonavian reptiles (Reptilia) are critical for understanding genome evolution in mammals and amniotes generally. Despite decades of study at the chromosomal and single-gene levels, and the evidence for great diversity in genome size, karyotype, and sex chromosome diversity, reptile genomes are virtually unknown in the comparative genomics era. The recent sequencing of the chicken and zebra finch genomes, in conjunction with genome scans and the online publication of the Anolis lizard genome, has begun to clarify the events leading from an ancestral amniote genome—predicted to be large and to possess a diverse repeat landscape on par with mammals and a birdlike sex chromosome system—to the small and highly streamlined genomes of birds. Reptilia exhibit a wide range of evolutionary rates of different subgenomes and, from isochores to mitochondrial DNA, provide a critical contrast to the genomic paradigms established in mammals.

The neutral theory of molecular evolution has been widely accepted and is the guiding principle for studying evolutionary genomics and the molecular basis of phenotypic evolution. Recent data on genomic evolution are generally consistent with the neutral theory. However, many recently published papers claim the detection of positive Darwinian selection via the use of new statistical methods. Examination of these methods has shown that their theoretical bases are not well established and often result in high rates of false-positive and false-negative results. When the deficiencies of these statistical methods are rectified, the results become largely consistent with the neutral theory. At present, genome-wide analyses of natural selection consist of collections of single-locus analyses. However, because phenotypic evolution is controlled by the interaction of many genes, the study of natural selection ought to take such interactions into account. Experimental studies of evolution will also be crucial.

Since Darwin first noted that the process of speciation was indeed the “mystery of mysteries,” scientists have tried to develop testable models for the development of reproductive incompatibilities—the first step in the formation of a new species. Early theorists proposed that chromosome rearrangements were implicated in the process of reproductive isolation; however, the chromosomal speciation model has recently been questioned. In addition, recent data from hybrid model systems indicates that simple epistatic interactions, the Dobzhansky–Muller incompatibilities, are more complex. In fact, incompatibilities are quite broad, including interactions among heterochromatin, small RNAs, and distinct, epigenetically defined genomic regions such as the centromere. In this review, we will examine both classical and current models of chromosomal speciation and describe the “evolving” theory of genetic conflict, epigenetics, and chromosomal speciation.

Creationism continues to present a challenge to the teaching of evolution in the United States. With attempts to ban evolution education and to “balance” the teaching of evolution with creationism unavailing, creationists are increasingly favoring the approach of misrepresenting evolution as scientifically controversial. To understand the ongoing challenges facing evolution education in the United States, it is necessary to appreciate creationist actions at the different levels of educational governance—state legislatures, state boards of education, local boards of education, and finally the individual classroom—that serve as the battlegrounds for the evolution education wars. Scientists are in a unique position to defend the teaching of evolution, both by resisting creationist incursions as they occur and by helping to improve the teaching of evolution at both the precollege and college levels.

The existing research base on public attitudes about genetics shows that people's attitudes vary according to the specific technologies and purposes to which genetic knowledge is applied. Genetic testing is viewed highly favorably, genetically modified food is viewed with ambivalence, and cloning is viewed negatively. Attitudes are favorable for uses that maintain a perceived natural order and unfavorable for uses that are perceived to change it. Public concerns about control of genetic information and eugenics are evident, but their strength and relevance to policy preference are unclear. The pattern of attitudes can be explained by theories of attitude formation, and the existing base of information can be deepened and given more explanatory and predictive power by integrating future research into the various traditions that theorize attitude formation.

There are several features of genetic and genomic research that challenge established norms of informed consent. In this paper, we discuss these challenges, explore specific elements of informed consent for genetic and genomic research conducted in the United States, and consider alternative consent models that have been proposed. All of these models attempt to balance the obligation to respect and protect research participants with the larger social interest in advancing beneficial research as quickly as possible.

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 postdiscovery 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.

In this report, we describe the evolution and types of genetic information provided directly to consumers, discuss potential advantages and disadvantages of these products, and review research evaluating consumer responses to direct-to-consumer (DTC) genetic testing. The available evidence to date has focused on predictive tests and does not suggest that individuals, health care providers, or health care systems have been harmed by a DTC provision of genetic information. An understanding of consumer responses to susceptibility tests has lagged behind. The Multiplex Initiative is presented as a case study of research to understand consumers' responses to DTC susceptibility tests. Three priority areas are recommended for accelerated research activities to inform public policy regarding DTC genetic information: (a) exploring consumer's long-term responses to DTC genetic testing on a comprehensive set of outcomes, (b) evaluating optimal services to support decision making about genetic testing, and (c) evaluating best practices in promoting genetic competencies among health providers.