Showing papers in "Current Genomics in 2004"
TL;DR: It is hypothesized that there might be at least three types of autism susceptibility genes/mutations that can be specific to an individual patient or family, in a genetically isolated sub-population and a common factor shared amongst different populations.
Abstract: Autism is a neurodevelopmental disorder characterised 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 15q11-13. Molecular cytogenetics, together with genome scans and linkage/association studies, point to ≥22 chromosome regions harbouring putative autism susceptibility genes, such as 2q32, 3q25-27, 7q31-q35, 15q11-13, 16p13, Xp22, and Xq13. We hypothesise 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 emphasises 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).
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TL;DR: This review compiles the present knowledge on the organization of this complex and the putative role of a small subset of its subunits and describes the major progress that has been made in understanding the molecular bases of respiratory chain complex I deficiency in humans.
Abstract: : The mechanism of NADH oxidation varies between living organisms, and is by far the most complex oxidizingsystem found in mitochondria. In human mitochondria, a unique, but huge structure, with more than 45 subunits, knownas complex I, copes with NADH oxidation. This review compiles our present knowledge on the organization of thiscomplex and the putative role of a small subset of its subunits. This review also describes the major progress that has beenmade in understanding the molecular bases of respiratory chain complex I deficiency in humans, with mutations identifiedin both the mitochondrial and the nuclear genes encoding complex I subunits. Finally, the puzzling questions raised by thevarying clinical presentations of patients with complex I deficiency are discussed in light of our limited knowledge oncomplex I function in mammalian cells. Key Words: Mitochondria, Respiratory Chain, Complex I deficiency, NADH. MITOCHONDRIAL OXIDATION OF REDUCEDNICOTINAMIDE ADENINE DINUCLEOTIDES:FROM THE MANY DEHYDROGENASES OF PLANTSTO THE UNIQUE MAMMALIAN COMPLEX I
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TL;DR: Researchers have identified molecular and biochemical pathways, which may not have been observable using standard methods, that are disrupted by some toxin exposures and environmental stressors, which will allow them to potentially formulate specific predictions on how vertebrate organisms and populations may be affected by both man- made and natural changes in the environment.
Abstract: Genetic diversity is the raw material needed by a species allowing adaptation to changing environmental conditions and thus ensuring long-term sustainability. The development of technologies for environmental genomics provides us with the opportunity to link information, at the whole genome level, with the response of an organism to its natural environment. Over the past 15 years a small tropical fish native to the rivers of India and south Asia, the zebrafish (Danio rerio), has become one of the most popular vertebrate model systems. Zebrafish are abundant and many populations exist that are reproductively isolated. They evolved under distinct environments, and this have lead to genetic diversity and, as a consequence, has created genotypic and phenotypic differences between the populations. For this fish species, a large number of molecular and genomic tools have been developed. As a result, the zebrafish has emerged as a popular model for the study of embryonic development and genetics as well as the study human disease counterparts. The advantages that zebrafish possess, in addition to newly developed large scale screening assays, such as automated in situ hybridization and transgenics for example, has lead to researchers using zebrafish to study toxicogenomics and environmental genomics. Researchers have identified molecular and biochemical pathways, which may not have been observable using standard methods, that are disrupted by some toxin exposures and environmental stressors. These studies will allow us to potentially formulate specific predictions on how vertebrate organisms and populations may be affected by both man- made and natural changes in the environment.
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TL;DR: This work summarises the recent progress in the usage of genomic data to analyse the evolution of other DNA recombination factors and reports on a strong conservation of a reasonable number of intron positions between plants, animals and fungi.
Abstract: The growing number of completely deciphered genomic sequences provides an enormous reservoir of data, which can be used for addressing questions related to functional and evolutionary biology. The wealth of this approach is documented by the fast growing numbers of recent publications in the field of evolutionary biology based on comparative genomics. Many proteins of the recombination machinery are conserved between plants, fungi and animals but some of them also show remarkable differences regarding their presence, copy number or molecular structure. For example, the protein responsible for double strand break (DSB) induction during meiosis, SPO11, which is related to the subunit A of the archaebacterial topoisomerase VI, is coded by a single gene in animals and fungi. In contrast, plants harbour three distantly related homologues, which seem to have non-redundant functions either in meiosis or in somatic cells and are indispensable for viability. Moreover, plants possess a homologue of the subunit B of the archaebacterial topoisomerase VI, not present in other eukaryotes. We also summarise the recent progress in the usage of genomic data to analyse the evolution of other DNA recombination factors. Finally, several recent studies report on a strong conservation of a reasonable number of intron positions between plants, animals and fungi. This kind of study provides a basis for comparative genomic analyses across kingdoms and demonstrates the existence of ancient introns, a topic of intensive debate.
TL;DR: The foundations of the “paucimorphisms hypothesis”, relevant available technologies and possible future approaches to systematically explore this hypothesis are considered.
Abstract: Definitions of polymorphism in a gene include occurrence of a rarer allele of at least 1% frequency; or occurrence of the commonest allele at less than 95% frequency. Many alleles of single nucleotide polymorphisms (SNPs) in genes occur at much higher frequency (up to 50%). Many common diseases have a substantial genetic component. The prevailing hypothesis for the molecular basis of common diseases is that it involves the combinatoric action of common polymorphic alleles of minor effect (common disease / common variant, CD / CV hypothesis). The ready development of genome-wide databases of high frequency SNPs is enabling the testing of this hypothesis. A contrasting approach has been the study of very highly selected cases and families by linkage and mutation detection techniques to identify rare mutations of large effect on a gene, often private to a single family (rare disease / rare variant, RD / RV hypothesis. These approaches have formed the mainstay of disease gene discovery, the latter having been feasible for a decade, the former just now becoming feasible. However, an intermediate possibility exists. Sequence changes at an intermediate frequency (herewith, “paucimorphisms”, arbitrarily 0.0005
TL;DR: With the entering of the post-genomic era, hints given by observational studies, and thus founded on statistical evidence, can be exploited to cast light upon biological pathways crucial in aging and longevity.
Abstract: The amount of research on human aging and longevity has been growing rapidly in recent years. Multidisciplinary approaches, which integrate classic population genetics methods with the principles of epidemiological and demographic investigation, are emerging as powerful tools for disentangling the complex gene network which modulates human lifespan. We try to summarize the different approaches and discuss the various aspects concerning their applications in studies of human aging and longevity. We also discuss the significance of the newly emerging DNA chip technology and its implications by highlighting new research topics. In fact, with the entering of the post-genomic era, hints given by observational studies, and thus founded on statistical evidence, can be exploited to cast light upon biological pathways crucial in aging and longevity.
TL;DR: Three newly determined structures by the pilot structural genomics projects were shown to demonstrate how to decipher biological function from the 3-D structure of a novel protein and how to interpret the structure-function relationship and its application on drug design.
Abstract: As more and more genomes have been sequenced, the hotspot of biological science is moving from the study on nucleic acids to that on proteins. One of the most representative affairs in this era is the launching of projects focusing on the high throughput determination of the protein three dimensional structures in a genome scale, named structural genomics projects. The common objective of the pilot projects is construction of a platform to clone hundreds to thousands of targets, and purify, at the first stage, the highly expressed and soluble proteins, then solve dozens to hundred of structures by means of X-ray crystallography or NMR. The first bottleneck in this pipeline is obtaining manipulable quantity (milligram level according to the necessity of the current crystallographic or NMR technology) of soluble proteins, which are properly folded. For this purpose, a series of methodologies have been established. His-tag makes it possible to purify the desired protein from the crude extract of the host cells or the mix of in vitro expression system in a single step of affinity purification. Beyond His-tag and other short affinity tags, a series of fusion tags have been developed for the purpose of solubility enhancement. Many expression hosts based on bacterium Escherichia coli or yeast Pichia pastoris have been constructed to express heterologous proteins. The influences of temperature during induction and co-expression with chaperones are systematically investigated. The effects of the N-terminal tags, either small or big ones, are examined and compared with those carrying a tag at the C-terminus. Some techniques of in vitro evolution are transferred and applied to increase the expression level and solubility of the targets. These efforts are helpful, at least at one hand, for speeding up the production of folded and concentrated proteins, the sample feeding the crystallographers and NMR spectroscopists. Furthermore three newly determined structures by the pilot structural genomics projects were shown to demonstrate how to decipher biological function from the 3-D structure of a novel protein and how to interpret the structure-function relationship and its application on drug design. In present paper, we review the popular techniques applied in the current structural genomics projects, their effects and possible improvements in the future, especially those for protein preparation and function interpretation.
TL;DR: Methods for detectingSCR, recombination mechanisms that generate SCR, mammalian and yeast genes that participate in SCR; and genetic diseases characterized by SCR phenotypes are discussed.
Abstract: Sister chromatids are preferred substrates for the recombinational repair of DNA lesions. Sister chromatid recombination (SCR) results in the exchange of genetic information between newly replicated chromatids and ensures that DNA lesions are either tolerated or repaired. Faulty recombinational repair has been correlated to several genetic diseases, including Bloom's syndrome, inheritable breast cancer (BRCA1 and BRCA2), and Fanconi's Anemia. One approach to understand SCR mechanisms is to clarify the SCR phenotypes in mutants defective in well-conserve d radiation repair (RAD) genes. These RAD genes include those that participate directly in the recombinational repair of DSBs, known as the RAD51 subgroup, and those that participate in the processing of the DNA break, known as the RAD50 subgroup. A systematic analysis of SCR recombination phenotypes in rad mutants revealed multiple pathways for spontaneous and DNA damage-associated SCR in yeast. Studies focused on vertebrate RAD51 genes have suggested similar pathways. In this review, we shall discuss methods for detecting SCR, recombination mechanisms that generate SCR, mammalian and yeast genes that participate in SCR, and genetic diseases characterized by SCR phenotypes.