From association to causality: the new frontier for complex traits

Technological and analytical advances have led to an unprecedented catalog of genomic regions associated with a broad range of clinically relevant phenotypes in humans. However, some examples notwithstanding, the causes of the overwhelming majority of genetic diseases remain obscure. More importantly, an emerging lesson from genome-wide association studies is that, in most instances, the resolution necessary for identifying actual genes that underlie the phenotype is limited, as is our ability to develop mechanistic, testable disease models from such studies. These new realities will probably necessitate a paradigm shift in our approach to complex traits, for which the combinatorial application of genomic and functional studies will be necessary to understand the mechanism and pathology of genetic disease. Here I will discuss these issues and highlight how additional sequencing and genotyping of ever-increasing cohort sizes without functional interpretation is unlikely to improve our ability to dissect the genetic basis of complex traits

Shoot Meristem Function and Leaf Polarity: The Role of Class III HD–ZIP Genes

The shoot apical meristem comprises an organized cluster of cells with a central region population of self-maintaining stem cells providing peripheral region cells that are recruited to form differentiated lateral organs. Leaves, the principal lateral organ of the shoot, develop as polar structures typically with distinct dorsoventrality. Interdependent interactions between the meristem and developing leaf provide essential cues that serve both to maintain the meristem and to pattern dorsoventrality in the initiating leaf. A key component of both processes are the class III HD–ZIP genes. Current findings are defining the developmental role of members of this family and are identifying multiple mechanisms controlling expression of these genes

Dietary Restriction in Drosophila: Delayed Aging or Experimental Artefact?

Lifespan can be extended by reduction of dietary intake. This practice is referred to as dietary restriction (DR), and extension of lifespan by DR is evolutionarily conserved in taxonomically diverse organisms including yeast, invertebrates, and mammals. Although these two often-stated facts carry the implication that the mechanisms of DR are also evolutionarily conserved, extension of lifespan could be a case of evolutionary convergence, with different underlying mechanisms in different taxa. Furthermore, extension of lifespan by different methods of DR in the same organism may operate through different mechanisms. These topics remain unresolved because of the very fact that the mechanisms of DR are unknown. Given these uncertainties, it is essential that work on the mechanisms of DR is not clouded by imprecise descriptions of methods or by technical problems. Here we review the recent literature on DR in Drosophila to point out some methodological issues that can obscure mechanistic interpretations. We also indicate some experiments that could be performed to determine if DR in Drosophila operates through similar mechanisms to the process in rodents

Genetic Determinants of Human Health Span and Life Span: Progress and New Opportunities

We review three approaches to the genetic analysis of the biology and pathobiology of human aging. The first and so far the best-developed is the search for the biochemical genetic basis of varying susceptibilities to major geriatric disorders. These include a range of progeroid syndromes. Collectively, they tell us much about the genetics of health span. Given that the major risk factor for virtually all geriatric disorders is biological aging, they may also serve as markers for the study of intrinsic biological aging. The second approach seeks to identify allelic contributions to exceptionally long life spans. While linkage to a locus on Chromosome 4 has not been confirmed, association studies have revealed a number of significant polymorphisms that impact upon late-life diseases and life span. The third approach remains theoretical. It would require longitudinal studies of large numbers of middle-aged sib-pairs who are extremely discordant or concordant for their rates of decline in various physiological functions. We can conclude that there are great opportunities for research on the genetics of human aging, particularly given the huge fund of information on human biology and pathobiology, and the rapidly developing knowledge of the human genome

Human guanylate kinase (GUK1): cDNA sequence, expression and chromosomal localisation

AbstractGuanylate kinase (GK) catalyses the conversion of GMP to GTP as part of the cGMP cycle. In mammalian phototransduction, this cycle is essential for the regeneration of cGMP following its hydrolysis by phosphodiesterase. Mutations in different parts of this signalling cascade lead to retinal degeneration in humans. Protein studies have localized a locus for GK to a region of human chromosome 1 that also contains an autosomal recessive form of retinitis pigmentosa (RP12) and Usher's type 11a (USH2A). We report the sequence of this human GK (GUK1) and a further refinement of its localization to 1q32-41, placing it in the same interval as USH2A

Identification of novel genes expressed during metanephric induction through single-cell library screening

Identification of novel genes expressed during metanephric induction through single-cell library screening.BackgroundDevelopment of the mature kidney is dependent on a series of inductive events between a portion of the epithelial bud at the distal end of the nephric duct and a neighboring domain of committed metanephric mesenchyme. Several genes have been identified to date that are critical in the inductive process. For example, the deletion of Bmp7 from the mouse genome results in dysgenesis or agenesis of the kidney. These findings suggest that Bmp7 controls the expression of genes important for nephrogenesis, but the identity of these genes has remained largely undetermined.MethodsSingle cells were isolated from mouse metanephric mesenchyme during the time of induction (between E11.0 and E11.5) and cDNA libraries constructed from induced and uninduced tissue. Subtractive hybridization was performed to isolate genes that were expressed during E11.5 but not E11.0.ResultsUsing this approach, we identified eight previously known genes, three of which were known to be involved in metanephric induction, thus validating our approach, and nine novel genes. Eight of these genes were completely novel, whereas one was similar to a member of the yeast Anaphase Promoting Complex.ConclusionsThrough subtractive hybridization of mouse E11.0 and E11.5 metanephric mesenchyme single-cell cDNA libraries, we have identified novel genes that are candidates for involvement in nephrogenesis through their up-regulation during the inductive process

Population Bottlenecks as a Potential Major Shaping Force of Human Genome Architecture

The modern synthetic view of human evolution proposes that the fixation of novel mutations is driven by the balance among selective advantage, selective disadvantage, and genetic drift. When considering the global architecture of the human genome, the same model can be applied to understanding the rapid acquisition and proliferation of exogenous DNA. To explore the evolutionary forces that might have morphed human genome architecture, we investigated the origin, composition, and functional potential of numts (nuclear mitochondrial pseudogenes), partial copies of the mitochondrial genome found abundantly in chromosomal DNA. Our data indicate that these elements are unlikely to be advantageous, since they possess no gross positional, transcriptional, or translational features that might indicate beneficial functionality subsequent to integration. Using sequence analysis and fossil dating, we also show a probable burst of integration of numts in the primate lineage that centers on the prosimian–anthropoid split, mimics closely the temporal distribution of Alu and processed pseudogene acquisition, and coincides with the major climatic change at the Paleocene–Eocene boundary. We therefore propose a model according to which the gross architecture and repeat distribution of the human genome can be largely accounted for by a population bottleneck early in the anthropoid lineage and subsequent effectively neutral fixation of repetitive DNA, rather than positive selection or unusual insertion pressures

Managing Incidental Genomic Findings in Clinical Trials: Fulfillment of the Principle of Justice

<p>Managing Incidental Genomic Findings in Clinical Trials: Fulfillment of the Principle of Justice</p

Mutations impairing GSK3-mediated MAF phosphorylation cause cataract, deafness, intellectual disability, seizures, and a down syndrome-like facies

Transcription factors operate in developmental processes to mediate inductive events and cell competence, and perturbation of their function or regulation can dramatically affect morphogenesis, organogenesis, and growth. We report that a narrow spectrum of amino-acid substitutions within the transactivation domain of the v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF), a leucine zipper-containing transcription factor of the AP1 superfamily, profoundly affect development. Seven different de novo missense mutations involving conserved residues of the four GSK3 phosphorylation motifs were identified in eight unrelated individuals. The distinctive clinical phenotype, for which we propose the eponym Aymé-Gripp syndrome, is not limited to lens and eye defects as previously reported for MAF/Maf loss of function but includes sensorineural deafness, intellectual disability, seizures, brachycephaly, distinctive flat facial appearance, skeletal anomalies, mammary gland hypoplasia, and reduced growth. Disease-causing mutations were demonstrated to impair proper MAF phosphorylation, ubiquitination and proteasomal degradation, perturbed gene expression in primary skin fibroblasts, and induced neurodevelopmental defects in an in vivo model. Our findings nosologically and clinically delineate a previously poorly understood recognizable multisystem disorder, provide evidence for MAF governing a wider range of developmental programs than previously appreciated, and describe a novel instance of protein dosage effect severely perturbing developmen