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Annual Review of Genomics and Human Genetics

Amanda Krause, Heather Seymour, Michèle Ramsay
This review highlights molecular genetic studies of monogenic traits where common pathogenic mutations occur in black families from sub-Saharan Africa. Examples of founder mutations have been identified for oculocutaneous albinism, cystic fibrosis, Fanconi anemia, and Gaucher disease. Although there are few studies from Africa, some of the mutations traverse populations across the continent, and they are almost all different from the common mutations observed in non-African populations. Myotonic dystrophy is curiously absent among Africans, and nonsyndromic deafness does not arise from mutations in GJB2 and GJB7...
August 31, 2018: Annual Review of Genomics and Human Genetics
Saffron A G Willis-Owen, William O C Cookson, Miriam F Moffatt
Asthma is a common, clinically heterogeneous disease with strong evidence of heritability. Progress in defining the genetic underpinnings of asthma, however, has been slow and hampered by issues of inconsistency. Recent advances in the tools available for analysis-assaying transcription, sequence variation, and epigenetic marks on a genome-wide scale-have substantially altered this landscape. Applications of such approaches are consistent with heterogeneity at the level of causation and specify patterns of commonality with a wide range of alternative disease traits...
August 31, 2018: Annual Review of Genomics and Human Genetics
Priya Duggal, William A Petri
Malnutrition is a complex disorder, defined by an imbalance, excess, or deficiency of nutrient intake. The visible signs of malnutrition are stunted growth and wasting, but malnourished children are also more likely to have delays in neurocognitive development, vaccine failure, and susceptibility to infection. Despite malnutrition being a major global health problem, we do not yet understand the pathogenesis of this complex disorder. Although lack of food is a major contributor to childhood malnutrition, it is not the sole cause...
August 31, 2018: Annual Review of Genomics and Human Genetics
Liad Holtzman, Charles A Gersbach
The eukaryotic epigenome has an instrumental role in determining and maintaining cell identity and function. Epigenetic components such as DNA methylation, histone tail modifications, chromatin accessibility, and DNA architecture are tightly correlated with central cellular processes, while their dysregulation manifests in aberrant gene expression and disease. The ability to specifically edit the epigenome holds the promise of enhancing understanding of how epigenetic modifications function and enabling manipulation of cell phenotype for research or therapeutic purposes...
August 31, 2018: Annual Review of Genomics and Human Genetics
A Sazonovs, J C Barrett
Genome-wide association studies (GWASs) have revolutionized human disease genetics by discovering tens of thousands of associations between common variants and complex diseases. In parallel, huge technological advances in DNA sequencing have made it possible to measure and analyze rare variation in populations. This review considers these two stories and how they have come together. We first review the history of GWASs and sequencing. We then consider how to understand the biological mechanisms that drive signals of strong association in the absence of rare-variant studies...
August 31, 2018: Annual Review of Genomics and Human Genetics
Sayantan Das, Gonçalo R Abecasis, Brian L Browning
Genotype imputation has become a standard tool in genome-wide association studies because it enables researchers to inexpensively approximate whole-genome sequence data from genome-wide single-nucleotide polymorphism array data. Genotype imputation increases statistical power, facilitates fine mapping of causal variants, and plays a key role in meta-analyses of genome-wide association studies. Only variants that were previously observed in a reference panel of sequenced individuals can be imputed. However, the rapid increase in the number of deeply sequenced individuals will soon make it possible to assemble enormous reference panels that greatly increase the number of imputable variants...
August 31, 2018: Annual Review of Genomics and Human Genetics
Divya Jayaraman, Byoung-Il Bae, Christopher A Walsh
Primary microcephaly (MCPH, for "microcephaly primary hereditary") is a disorder of brain development that results in a head circumference more than 3 standard deviations below the mean for age and gender. It has a wide variety of causes, including toxic exposures, in utero infections, and metabolic conditions. While the genetic microcephaly syndromes are relatively rare, studying these syndromes can reveal molecular mechanisms that are critical in the regulation of neural progenitor cells, brain size, and human brain evolution...
August 31, 2018: Annual Review of Genomics and Human Genetics
Sarine Markossian, Kenny K Ang, Christopher G Wilson, Michelle R Arkin
The genetic determinants of many diseases, including monogenic diseases and cancers, have been identified; nevertheless, targeted therapy remains elusive for most. High-throughput screening (HTS) of small molecules, including high-content analysis (HCA), has been an important technology for the discovery of molecular tools and new therapeutics. HTS can be based on modulation of a known disease target (called reverse chemical genetics) or modulation of a disease-associated mechanism or phenotype (forward chemical genetics)...
August 31, 2018: Annual Review of Genomics and Human Genetics
H W Goonasekera, C S Paththinige, V H W Dissanayake
Hemoglobinopathies are the most common single-gene disorders in the world. Their prevalence is predicted to increase in the future, and low-income hemoglobinopathy-endemic regions need to manage most of the world's affected persons. International organizations, governments, and other stakeholders have initiated national or regional prevention programs in both endemic and nonendemic countries by performing population screening for α- and β-thalassemia, HbE disease, and sickle cell disease in neonates, adolescents, reproductive-age adults (preconceptionally or in the early antenatal period), and family members of diagnosed cases...
August 31, 2018: Annual Review of Genomics and Human Genetics
Carina M Schlebusch, Mattias Jakobsson
In the last three decades, genetic studies have played an increasingly important role in exploring human history. They have helped to conclusively establish that anatomically modern humans first appeared in Africa roughly 250,000-350,000 years before present and subsequently migrated to other parts of the world. The history of humans in Africa is complex and includes demographic events that influenced patterns of genetic variation across the continent. Through genetic studies, it has become evident that deep African population history is captured by relationships among African hunter-gatherers, as the world's deepest population divergences occur among these groups, and that the deepest population divergence dates to 300,000 years before present...
August 31, 2018: Annual Review of Genomics and Human Genetics
Lia Chappell, Andrew J C Russell, Thierry Voet
Single-cell multiomics technologies typically measure multiple types of molecule from the same individual cell, enabling more profound biological insight than can be inferred by analyzing each molecular layer from separate cells. These single-cell multiomics technologies can reveal cellular heterogeneity at multiple molecular layers within a population of cells and reveal how this variation is coupled or uncoupled between the captured omic layers. The data sets generated by these techniques have the potential to enable a deeper understanding of the key biological processes and mechanisms driving cellular heterogeneity and how they are linked with normal development and aging as well as disease etiology...
August 31, 2018: Annual Review of Genomics and Human Genetics
Pontus Skoglund, Iain Mathieson
The first decade of ancient genomics has revolutionized the study of human prehistory and evolution. We review new insights based on prehistoric modern human genomes, including greatly increased resolution of the timing and structure of the out-of-Africa expansion, the diversification of present-day non-African populations, and the earliest expansions of those populations into Eurasia and America. Prehistoric genomes now document population transformations on every inhabited continent-in particular the effect of agricultural expansions in Africa, Europe, and Oceania-and record a history of natural selection that shapes present-day phenotypic diversity...
August 31, 2018: Annual Review of Genomics and Human Genetics
Wanda K O'Neal, Michael R Knowles
In many respects, genetic studies in cystic fibrosis (CF) serve as a paradigm for a human Mendelian genetic success story. From recognition of the condition as a heritable pathological entity to implementation of personalized treatments based on genetic findings, this multistep pathway of progress has focused on the genetic underpinnings of CF clinical disease. Along this path was the recognition that not all CFTR gene mutations produce the same disease and the recognition of the complex, multifactorial nature of CF genotype-phenotype relationships...
August 31, 2018: Annual Review of Genomics and Human Genetics
Stephen Burgess, Christopher N Foley, Verena Zuber
An observational correlation between a suspected risk factor and an outcome does not necessarily imply that interventions on levels of the risk factor will have a causal impact on the outcome (correlation is not causation). If genetic variants associated with the risk factor are also associated with the outcome, then this increases the plausibility that the risk factor is a causal determinant of the outcome. However, if the genetic variants in the analysis do not have a specific biological link to the risk factor, then causal claims can be spurious...
August 31, 2018: Annual Review of Genomics and Human Genetics
Chonlaphat Sukasem, Theodora Katsila, Therdpong Tempark, George P Patrinos, Wasun Chantratita
The Global Genomic Medicine Collaborative, a multinational coalition of genomic and policy experts working to implement genomics in clinical care, considers pharmacogenomics to be among the first areas in genomic medicine that can provide guidance in routine clinical practice, by linking genetic variation and drug response. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe life-threatening reactions to medications with a high incidence worldwide. Genomic screening prior to drug administration is a key opportunity and potential paradigm for using genomic medicine to reduce morbidity and mortality and ultimately eliminate one of the most devastating adverse drug reactions...
August 31, 2018: Annual Review of Genomics and Human Genetics
Daniel M Jordan, Ron Do
While sequence-based genetic tests have long been available for specific loci, especially for Mendelian disease, the rapidly falling costs of genome-wide genotyping arrays, whole-exome sequencing, and whole-genome sequencing are moving us toward a future where full genomic information might inform the prognosis and treatment of a variety of diseases, including complex disease. Similarly, the availability of large populations with full genomic information has enabled new insights about the etiology and genetic architecture of complex disease...
August 31, 2018: Annual Review of Genomics and Human Genetics
Thomas N Williams, Swee Lay Thein
In the 100 years since sickle cell anemia (SCA) was first described in the medical literature, studies of its molecular and pathophysiological basis have been at the vanguard of scientific discovery. By contrast, the translation of such knowledge into treatments that improve the lives of those affected has been much too slow. Recent years, however, have seen major advances on several fronts. A more detailed understanding of the switch from fetal to adult hemoglobin and the identification of regulators such as BCL11A provide hope that these findings will be translated into genomic-based approaches to the therapeutic reactivation of hemoglobin F production in patients with SCA...
August 31, 2018: Annual Review of Genomics and Human Genetics
R Rodney Howell
Mike, a memorable young patient with untreated phenylketonuria, as well as others affected by genetic disorders that could be treated if diagnosed in infancy, launched my six-decade career. This autobiographical article reflects on my childhood, early research, and professional experiences in pediatric genetics. My laboratory research focused on inborn errors of metabolism, including the glycogen storage diseases. My effort to organize newborn screening through the recommended uniform screening panel shaped and standardized newborn screening nationwide...
August 31, 2018: Annual Review of Genomics and Human Genetics
Jorge L Contreras, Bartha M Knoppers
Over its 30 or so years of existence, the genomic commons-the worldwide collection of publicly accessible repositories of human and nonhuman genomic data-has enjoyed remarkable, perhaps unprecedented, success. Thanks to the rapid public data release policies initiated by the Human Genome Project, free access to a vast array of scientific data is now the norm, not only in genomics, but in scientific disciplines of all descriptions. And far from being a monolithic creation of bureaucratic fiat, the genomic commons is an exemplar of polycentric, multistakeholder governance...
August 31, 2018: Annual Review of Genomics and Human Genetics
Sarah C Borrie, Hilde Brems, Eric Legius, Claudia Bagni
The Ras-MAPK and PI3K-AKT-mTOR signaling cascades were originally identified as cancer regulatory pathways but have now been demonstrated to be critical for synaptic plasticity and behavior. Neurodevelopmental disorders arising from mutations in these pathways exhibit related neurological phenotypes, including cognitive dysfunction, autism, and intellectual disability. The downstream targets of these pathways include regulation of transcription and protein synthesis. Other disorders that affect protein translation include fragile X syndrome (an important cause of syndromal autism), and other translational regulators are now also linked to autism...
August 31, 2017: Annual Review of Genomics and Human Genetics
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