Current Genomics - Volume 5, Issue 4, 2004

Atherosclerosis is a chief cause of heart attack, stroke and death in Western society. It is a disease of the large arteries characterised by the presence of atherosclerotic lesions, often observable as fatty streaks within the first decade of life. A number of factors influence the development and progression of atherosclerosis; however, hemodynamic forces appear to play a critical role in the earliest stages of lesion formation. Significantly, lesions selectively develop in the areas of the vasculature associated with low shear stress, such as at the bends and bifurcations of the arterial tree. In contrast, areas subjected to uniform laminar flow, as found in the straight tubular portions of arteries are considered athero-resistant. Hemodynamic forces influence the transcription of genes within the endothelial cells that line the entire vascular system. Transcriptional changes include the modulation of genes encoding cytokines, adhesion molecules, transcription factors and growth factors. Shear stress-responsive gene expression may underpin the role that hemodynamic forces play in vascular homeostasis and pathophysiology; however, it is not clear exactly how hemodynamic forces influence the genesis and progression of atherosclerosis. DNA microarray technology has recently been employed to identify novel hemodynamic flow-responsive genes and gene families. In the current study we compile such gene expression data from large-scale transcriptomic profiling and examine it within the pathological context of atherosclerosis. By understanding the molecular mechanisms underlying the role that hemodynamic forces play in the pathogenesis of vascular disease it may be possible to identify central mediators of the disease and to design new therapeutic strategies.

New initiatives to sequence complete genomes of related organisms have introduced a new era of large-scale evolutionary genomics. The comparative analysis of these genomes allows us to obtain a comprehensive view of many aspects of eukaryotic genome evolution. Consequently, new computational methods and approaches are being developed in order to investigate chromosomal organisation, rearrangements and segmental homology. Here, we review the different techniques currently available to identify homologous chromosomal segments in closely and more distantly related species and highlight some of the difficulties inherent to the statistical validation of putative genomic homology. In addition, advantages of cross-species genome analysis are discussed as well as novel approaches to study large-scale gene duplications.

Nuclear genome instability is known to play an important role in the origin of some human cancers. However, eukaryotic cells also have cytoplasmic genomes that are compartimentalised in the mitochondria. Mitochondria (mt) are essential for the regulation of several aspects of cell biology such as energy production, maintenance of redox status, molecular metabolism, calcium signalling and apoptosis. Oxidative stress causes significant mtDNA damage, which is thought to increase the risk of a growing number of degenerative diseases. MtDNA is highly suscepectable to mutations and contains fewer repair mechanisms than nuclear DNA, thus it may contribute to aging and be associated with the initial stages of carcinogenesis. Mitochondrial dysfunction might explain the dose-limiting toxicity of various therapeutic agents such as the nucleoside analogues used to combat HIV and hepatitis B viruses. The mitochondrial genome may represent a potential target for the development of cancer therapy. The role of mt-genomes in human diseases and in particular, in malignancy is still not fully understood. In this review, we focus on mitochondrial genome aberrations such as point mutations, instability of mono- or dinucleotide repeat, long deletions and change of the mtDNA copy number. The potential role played by mitochondria and mtDNA aberrations in malignancy, and the potential clinical use of the mtDNA markers are discussed.

In the evolutionary context, alterations in the basic DNA structure and fidelity of repair endow the genome with dynamism not only to survive but also to flourish. The genomic variation tools presented by evolution such as small tandem repeats (STRs), variable number of tandem repeats (VNTRs) and trinucleotide repeats (TNRs) are the most interesting. Cloning of several disease genes have identified the basic DNA structure instability attributed to nucleotide repeats in the form of changes in the tract length, threshold value, secondary structure formation, interruptions, mismatch repairs, the gene and its sequence involved as the basis for manifestation of a pathological phenotype, particularly several neurological disorders. The neurodegenerative disorders (NDDs) are chronic and progressive, characterized by selective and symmetric loss of neurons in motor, sensory and cognitive systems. The genetic anomalies that are responsible for these diseases are varied and complex. The observations on the disease age - of - onset with the length of expansion provided a strong indication that a novel toxic property of the altered protein or lack of expression of protein(s) is associated with the pathology. The conditions that ultimately lead to neuronal death, probably by apoptosis, involving oxidative stress, perturbed calcium homeostasis, mitochondrial dysfunction and activation of cysteine proteases called caspases include Huntington's disease, Machado-Joseph disease and amylotropic lateral sclerosis among trinucleotide disorders and other NDDs like Alzheimer's disease (AD) and Parkinson's disease (PD) seems to be shared. Presently, there are very few means to impede the disease progression, as there is loss of specific neuronal cell population in different disorders. The investigations on each aspect of these disorders will bring tremendous clinical benefits, offering better classification of the diseases and thus facilitating early diagnosis and genetic counseling. This review briefly summarizes research work directed towards understanding the pathophysiology of neurological disorders at the molecular level and highlights the trends in the current and future therapeutic approaches. Although the goal of delaying the onset of brain disorders may be within the grasp of modern medicine, there are several critical barriers to progress. Traditionally, in drug discovery, testing, and development, a combination of models, including in vivo, in vitro, transgenic, animal and microbial models is used. Advances in computer technology, in the form of “in silico” modeling systems, is there to complement currently available models and enable investigators to simulate alternative strategies to modulate neural function in a dynamic interactive mode and are expected to accelerate the drug discovery process. Understanding the complexities of the cellular pathology of the multistep, multifactorial diverse group of NDDs and associated paraphernalia of structural and functional alterations leading to proteinopathies would provide an opportunity for designing rational approaches for therapeutic regimen towards effective treatment. Successful discovery and development of therapeutic regimen will improve and reduce hospitalization and long-term care costs and suffering.

Autism is a neurodevelopmental disorder characterized by clinical, etiologic and genetic heterogeneity. It is often associated with other conditions, such as disorders of the CNS (tuberous sclerosis), developmental delay, attention deficit, epilepsy, and anxiety and mood disorders. Our survey found cytogenetically visible chromosomal anomalies in ∼7.4% (129 / 1749) of autistic patients documented as well as several sub-microscopic variants. Almost every chromosome is affected by numeric or structural aberrations. Among the most consistent cytogenetics findings are fragile X and duplication of maternal 15q11-q13. Molecular cytogenetics, together with genome scans and linkage / association studies, point to ≥22 chromosome regions harbouring putative autism susceptibility genes, such as 2q32, 3q25-q27, 7q31-q35, 15q11-q13, 16p13, Xp22, and Xq13. We hypothesize that there might be at least three types of autism susceptibility genes / mutations that can be (i) specific to an individual patient or family, (ii) in a genetically isolated sub-population and (iii) a common factor shared amongst different populations. The genes / mutations could act alone or interact with other genetic and / or epigenetic or environmental factors, causing autism or related disorders. This review emphasizes the potential of analysing chromosomal rearrangements as a means to rapidly define candidate disease loci for further investigation. To facilitate ongoing research we have established a new database of autism-associated chromosomal anomalies (http: / / tcag.bioinfo. sickkids.on.ca / autism).

Pneumonia is responsible for unacceptably high mortality rates among specific populations of patients, despite the use of conventional antibiotics and improvements in critical care. New treatments for severe pulmonary infection are therefore required. Manipulation of host defence genes using targeted gene therapy seems a logical strategy for severe pulmonary infection, and several groups have recently demonstrated that therapeutic genes can protect the healthy lung against the subsequent development of experimental pneumonia. This article reviews the problems facing the development of gene therapy for human pneumonia, with particular reference to safety issues and to the physical and biological barriers limiting efficient delivery of therapeutic transgenes to cells in the lung. The strengths and weaknesses of vectors currently available for pulmonary gene therapy are also considered, with emphasis on recent developments relating to adenovirus, adeno-associated virus and non-viral vector systems. Thereafter the specific gene therapy strategies used either to enhance clearance of pneumonia in laboratory animals or to immunise rodents against subsequent pulmonary challenge with human pathogens are discussed and placed in the context of future potential applications to human pneumonia.

Extracellular signal-regulated kinases 1 and 2 (ERKs) are central regulators of many physiological and pathological processes. Their activity is regulated by phosphorylation on both tyrosine and threonine residues within their activation loops by MAPK / ERK kinases 1 and 2 (MEKs). Removal of phosphate from either the tyrosine, the threonine, or from both residues together can inactivate ERKs. Indeed members of the three groups of protein phosphatases, protein Ser / Thr phosphatase, protein Tyr phosphatase, and dual specificity phosphatases have been implicated in the inactivation of ERKs. In this review, we describe the various mechanisms involved in the inactivation of ERKs during different stages of mitogenic stimulation of quiescent cells.