Annual Review of Genomics and Human Genetics - Volume 12, 2011

This article describes a fragment of history on the growing impact of genetics on the practice of medicine over 50 years, as experienced by a medical geneticist who helped to provide services to patients at risk of genetic disorders. It is a personal account influenced by a fascination with chromosomes that has drawn him into many studies, including sex determination, gene discovery, fetal diagnosis, phylogenomics, and karyotype evolution.

The ability of chromosome microarray analysis (CMA) to detect submicroscopic genetic abnormalities has revolutionized the clinical diagnostic approach to individuals with intellectual disability, neurobehavioral phenotypes, and congenital malformations. The recognition of the underlying copy number variant (CNV) in respective individuals may allow not only for better counseling and anticipatory guidance but also for more specific therapeutic interventions in some cases. The use of CMA technology in prenatal diagnosis is emerging and promises higher sensitivity for several highly penetrant, clinically severe microdeletion and microduplication syndromes. Genetic counseling complements the diagnostic testing with CMA, given the presence of CNVs of uncertain clinical significance, incomplete penetrance, and variable expressivity in some cases. While oligonucleotide arrays with high-density exonic coverage remain the gold standard for the detection of CNVs, single-nucleotide polymorphism (SNP) arrays allow for detection of consanguinity and most cases of uniparental disomy and provide a higher sensitivity to detect low-level mosaic aneuploidies.

Whereas single-nucleotide polymorphisms and their role in predisposition to disease have been studied extensively, the analysis of structural variants—genomic changes such as insertions, deletions, inversions, duplications, and translocations—is still in its infancy. Changes in copy number, also known as copy-number variations (CNVs), constitute one such group of these structural variants. CNVs are structural genomic variants that arise from deletions (loss) or duplications (gain), and as a consequence result in a copy-number change of the respective genomic region. CNVs may include entire genes or regions of transcribed sequence, or, indeed, comprise only nontranscribed sequences. Whereas the duplication or deletion of a gene can be expected to have an effect on gene dosage, the consequences of CNVs in nontranscribed sequences are less obvious. Here we review CNVs that involve regulatory nontranscribed regions of the genome, describe the associated human phenotypes, and discuss possible disease mechanisms.

Atrial fibrillation (AF) has become a growing global epidemic and a financial burden for society. The past 10 years have seen significant advances in our understanding of the genetic aspects of AF: At least 2 chromosomal loci and 17 causal genes have been identified in familial AF, and an additional 7 common variants and single-nucleotide polymorphisms in 11 different genes have been indicated in nonfamilial AF. However, the current management strategies for AF are suboptimal. The integration of genetic information into clinical practice may aid the early identification of AF patients who are at risk as well as the characterization of molecular pathways that culminate in AF, with the eventual result of better treatment. Never before has such an opportunity arisen to advance our understanding of the biology of AF through the translation of genetics findings from the bench to the bedside.

This new analysis of 194 DNA exonerations, representing 171 criminal events, examines the types of evidence and DNA testing that have been used to free the victims of wrongful conviction. The types of DNA testing used to free the innocent parallels the growth of these techniques in forensic science. Short tandem repeat (STR) analysis now prevails (70%), though Y-STR analysis (16%) and mitochondrial testing (10%) are still used when STR analysis is not feasible, and the recently developed mini-STRs have been used for exonerations since 2008 (2.6%). The types of exculpatory evidence included intimate swabs (65%), clothing (53%), hair (13%), fingernail evidence (5%), cigarettes (3%), and other evidence. The most common factor associated with wrongful convictions was misidentification (75%), including misidentification by the victim (65%). False confessions (including admissions and pleas) were obtained in 30% of the cases, and informant testimony (including jailhouse and government informants) was used in 22% of the false convictions. Several types of invalid forensic science testimony were used to wrongfully convict in the 146 trials where transcripts or reliable forensic science data were available for analysis. Invalid testimony included serology (38%), hair comparison (22%), fingerprint comparison (2%), and bite mark comparison (3%). In 43% of the exonerations, the true perpetrator of the crime was identified through postconviction testing.

The work conducted using genome-wide approaches during the past several years has invigorated the field, and represents the dawn of molecular genetics of schizophrenia. The aggregate data increasingly support a combination of rare and common genetic variation in schizophrenia, a major role for polygenic inheritance, and a genetic overlap of schizophrenia and other psychiatric disorders, such as bipolar disorder and autism. The current and upcoming resequencing programs (full exomes to full genomes), in combination with the use of more informative genotyping arrays, will allow a more thorough dissection of the molecular genetics of the disorder. A main challenge for the field is the translation of established genetic associations into a better pathophysiological understanding of schizophrenia.

Vocal communication mediated by speech and language is a uniquely human trait, and has served an important evolutionary role in the development of our species. Deficits in speech and language functions can be of numerous types, including aphasia, stuttering, articulation disorders, verbal dyspraxia, and specific language impairment; language deficits are also related to dyslexia. Most communication disorders are prominent in children, where they are common. A number of these disorders have been shown to cluster in families, suggesting that genetic factors are involved, but their etiology at the molecular level is not well understood. In the past decade, genetic methods have proven to be powerful for understanding these etiologies. Linkage studies and molecular genetic analyses in a large family containing multiple individuals affected with verbal dyspraxia led to the discovery of mutations in the FOXP2 gene. This gene encodes a forkhead domain transcription factor, a finding that has led researchers to a new avenue of investigation into the substrates and mechanisms that underlie human speech development. In studies of stuttering, linkage and candidate gene approaches in consanguineous families identified mutations in the lysosomal enzyme-targeting pathway genes GNPTAB, GNPTG, and NAGPA, revealing a role for inherited defects in cell metabolism in this disorder. In specific language impairment, linkage studies have identified several loci, and candidate gene association studies are making progress in identifying causal variants at these loci. Although only a small fraction of all cases of speech and language disorders can be explained by genetic findings to date, the significant progress made thus far suggests that genetic approaches will continue to provide important avenues for research on this group of disorders.

Embryonic stem cells (ESCs) first derived from the inner cell mass of blastocyst-stage embryos have the unique capacity of indefinite self-renewal and potential to differentiate into all somatic cell types. Similar developmental potency can be achieved by reprogramming differentiated somatic cells into induced pluripotent stem cells (iPSCs). Both types of pluripotent stem cells provide great potential for fundamental studies of tissue differentiation, and hold promise for disease modeling, drug development, and regenerative medicine. Although much has been learned about the molecular mechanisms that underlie pluripotency in such cells, our understanding remains incomplete. A comprehensive understanding of ESCs and iPSCs requires the deconstruction of complex transcription regulatory networks, epigenetic mechanisms, and biochemical interactions critical for the maintenance of self-renewal and pluripotency. In this review, we will discuss recent advances gleaned from application of global “omics” techniques to dissect the molecular mechanisms that define the pluripotent state.

The completion of the human genome reference sequence ushered in a new era for the study and discovery of human transposable elements. It now is undeniable that transposable elements, historically dismissed as junk DNA, have had an instrumental role in sculpting the structure and function of our genomes. In particular, long interspersed element-1 (LINE-1 or L1) and short interspersed elements (SINEs) continue to affect our genome, and their movement can lead to sporadic cases of disease. Here, we briefly review the types of transposable elements present in the human genome and their mechanisms of mobility. We next highlight how advances in DNA sequencing and genomic technologies have enabled the discovery of novel retrotransposons in individual genomes. Finally, we discuss how L1-mediated retrotransposition events impact human genomes.

Personalized medicine is a broad and rapidly advancing field of health care that is informed by each person's unique clinical, genetic, genomic, and environmental information. Personalized medicine depends on multidisciplinary health care teams and integrated technologies (e.g., clinical decision support) to utilize our molecular understanding of disease in order to optimize preventive health care strategies. Human genome information now allows providers to create optimized care plans at every stage of a disease, shifting the focus from reactive to preventive health care. The further integration of personalized medicine into the clinical workflow requires overcoming several barriers in education, accessibility, regulation, and reimbursement. This review focuses on providing a comprehensive understanding of personalized medicine, from scientific discovery at the laboratory bench to integration of these novel ways of understanding human biology at the bedside.

Human groups show structured levels of genetic similarity as a consequence of factors such as geographical subdivision and genetic drift. Surveying this structure gives us a scientific perspective on human origins, sheds light on evolutionary processes that shape both human adaptation and disease, and is integral to effectively carrying out the mission of global medical genetics and personalized medicine. Surveys of population structure have been ongoing for decades, but in the past three years, single-nucleotide-polymorphism (SNP) array technology has provided unprecedented detail on human population structure at global and regional scales. These studies have confirmed well-known relationships between distantly related populations and uncovered previously unresolvable relationships among closely related human groups. SNPs represent the first dense genome-wide markers, and as such, their analysis has raised many challenges and insights relevant to the study of population genetics with whole-genome sequences. Here we draw on the lessons from these studies to anticipate the directions that will be most fruitful to pursue during the emerging whole-genome sequencing era.

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.

Genetic studies have provided valuable insight into the pathological mechanisms underlying Parkinson's disease (PD). The elucidation of genetic components to what was once largely considered a nongenetic disease has given rise to a multitude of cell and animal models enabling the dissection of molecular pathways involved in disease etiology. Here, we review advances obtained from models of dominant mutations in α-synuclein and LRRK2 as well as recessive PINK1, parkin and DJ-1 mutations. Recent genome-wide association studies have implicated genetic variability at two of these loci, α-synuclein and LRRK2, as significant risk factors for developing sporadic PD. This, coupled with the established role of mitochondrial impairment in both familial and sporadic PD, highlights the likelihood of common mechanisms fundamental to the etiology of both.

Understanding how individuals differ from one another and from closely related species is a fundamental problem in biology. Recent evidence suggests that much of the variation both within and between species is due to differential gene regulation. Here we review differential gene regulation focusing on evolutionary-developmental (evo-devo) biology, global comparison of genomic sequences, whole-genome gene expression, and transcription factor (TF) binding profiles. We also explore the relationship between divergence rate of regulatory sequences, coding sequences, and TF binding events using several different measures and discuss their implications in the context of evolution of regulatory networks. Finally, we discuss the current status and future challenges in relating regulatory variation to the divergence across and within species.

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.

RNA, normally thought of as a conduit in gene expression, has a novel mode of action in ciliated protozoa. Maternal RNA templates provide both an organizing guide for DNA rearrangements and a template that can transport somatic mutations to the next generation. This opportunity for RNA-mediated genome rearrangement and DNA repair is profound in the ciliate Oxytricha, which deletes 95% of its germline genome during development in a process that severely fragments its chromosomes and then sorts and reorders the hundreds of thousands of pieces remaining. Oxytricha's somatic nuclear genome is therefore an epigenome formed through RNA templates and signals arising from the previous generation. Furthermore, this mechanism of RNA-mediated epigenetic inheritance can function across multiple generations, and the discovery of maternal template RNA molecules has revealed new biological roles for RNA and has hinted at the power of RNA molecules to sculpt genomic information in cells.

Important technological advances in genomics are driving a new understanding of the evolution of sex determination in vertebrates. In particular, comparative chromosome mapping in reptiles has shown an intriguing distribution of homology in sex chromosomes across reptile groups. When this new understanding is combined with the widespread distribution of genetic and temperature-dependent sex-determination mechanisms among reptiles, it is apparent that transitions between modes have occurred many times, as they have for amphibians (particularly between male and female heterogamety). It is also likely that thermosensitivity in sex determination is a key factor in those transitions in reptiles, and possibly in amphibians too. New models of sex determination involving temperature thresholds are providing the framework for the investigation of transitions and making possible key predictions about the homologies and sex-determination patterns expected among taxa in these groups. Molecular cytogenetics and other genomic approaches are essential to providing the fundamental material necessary to make advances in this field.

Advances in next-generation sequencing technology are enabling the systematic analyses of whole cancer genomes, providing insights into the landscape of somatic mutations and the great genetic heterogeneity that defines the unique signature of an individual tumor. Moreover, integrated studies of the genome, epigenome, and transcriptome reveal mechanisms of tumorigenesis at multiple levels. Progress in sequencing technologies and bioinformatics will improve the costs, sensitivity, and accuracy of detecting somatic mutations, while large-scale projects are underway to coordinate cancer genome sequencing at the global level to facilitate the generation and dissemination of high-quality uniform genetic data. These developments will create opportunities for deeper studies of cancer genetics and the clinical application of genome sequencing, and will motivate further research in cancer pathogenesis.