Current Genomics, Vol. 5, No. 5, 2004
Contents
Not Just a Fishing Trip – Environmental Genomics Using
Zebrafish Pp 395-407
Louise E. Coverdale, David Lean and C. Cristofre Martin
Multidisciplinary Approaches in Genetic Studies of Human
Aging and Longevity Pp 409-416
Q. Tan, A.I. Yashin, K. Christensen, B. Jeune, G. De
Benedictis, T.A. Kruse and J.W. Vaupel
Mechanisms of Epigenetic Variation: Polymorphic
Imprinting Pp 417-429
A. K. Naumova and S. Croteau
Paucimorphic Alleles versus Polymorphic Alleles and Rare
Mutations inDisease Causation: Theory, Observation and Detection Pp 431-438
Ian N.M. Day, Khalid K. Alharbi, Matt Smith, Mohammed A.
Aldahmesh, Xiao-He Chen, Andrew J. Lotery, Gabriella Pante-de-Sousa, Guangwei
Hou, Shu Ye, Diana Eccles, Nicholas C.P. Cross, Keith R. Fox, Santiago
Rodriguez
Interplay in the Computational Analysis of Genomic
Regulatory Sequences and Microarray Expression Data Pp 439-442
Chiara Sabatti
PGC-1a: A
Multifunctional Transcriptional Coactivator Involved in Human Metabolic
Disorders Pp 443-451
H. Oberkofler, F. Krempler and W. Patsch
STAT-1 and STAT-3: Closely Related Transcription Factors
with Antagonistic Effects on Cell Proliferation and Apoptosis Pp 453-457
D.S. Latchman and A. Stephanou
Abstracts
[Back to top]
Not Just a Fishing Trip – Environmental Genomics Using Zebrafish
Louise E. Coverdale, David Lean and C. Cristofre Martin
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 manmade and natural changes in the environment.
[Back to top]
Multidisciplinary Approaches in Genetic Studies of Human Aging and Longevity
Q. Tan, A.I. Yashin, K. Christensen, B. Jeune, G. De Benedictis, T.A. Kruse and J.W. Vaupel
[Back to top] Mechanisms
of Epigenetic Variation: Polymorphic Imprinting
A. K. Naumova and S. Croteau
Phenotypic variation among individuals often results from complex interactions between multiple factors: genetic, epigenetic, environmental and stochastic. Interaction between alleles of the same gene that is subject to allelic exclusion represents a particular case of regulatory variation. In mammals allelic exclusion is achieved through epigenetic silencing. DNA methylation, X-chromosome inactivation and genomic imprinting are the three epigenetic phenomena that are extensively studied in mammals.
Genomic imprinting is differential epigenetic DNA modification of the parental alleles. This implies that genes or chromosomal regions are marked differently when they go through female or male gametogenesis. The epigenetic marks (also termed imprints or gametic marks) persist throughout life and, hence, must be faithfully transmitted and maintained through multiple mitotic divisions.
However, emerging evidence suggests that genomic imprinting may vary among individuals (a phenomenon termed polymorphic imprinting), thereby providing an additional source of phenotypic variation in the population. An analysis of the reported instances of polymorphic imprinting provides clues for the understanding of mechanisms underlying interindividual imprinting variation in mammals.
[Back
to top] Paucimorphic Alleles versus
Polymorphic Alleles and Rare Mutations inDisease Causation: Theory, Observation
and Detection
Ian N.M. Day, Khalid K. Alharbi, Matt Smith, Mohammed A.
Aldahmesh, Xiao-He Chen, Andrew J. Lotery, Gabriella Pante-de-Sousa, Guangwei
Hou, Shu Ye, Diana Eccles, Nicholas C.P. Cross, Keith R. Fox, Santiago
Rodriguez
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<q<0.05) may exist and may have a moderate effect. A number of different loci may predispose to the same disease, although only one paucimorphic allele of one particular gene will be found in any one individual. Exploring the “paucimorphisms hypothesis” will require mutation detection applied both at the level of large numbers of relatively unselected cases and at the population level. In this review we consider the foundations of this hypothesis, relevant available technologies and possible future approaches to systematically explore this hypothesis.
[Back
to top] Interplay in the Computational Analysis of Genomic Regulatory
Sequences and Microarray Expression Data
Chiara Sabatti
Since the appearance of gene expression microarrays, the data produced has been used to guide the discovery of regulatory protein binding sites in the sequence upstream genes. In some instances, novel motifs have been discovered in the promoter region of genes with similar expression patterns. An other group of articles suggests the use of expression microarray data to sort through long lists of putative motifs. A common denominator of these studies is that expression, as measured through microarray, is used to better understand sequence information. Recently, a new trend seems to appear: using sequence information to better analyze the results of microarray experiments. What are the options currently available for the researcher?
[Back
to top] PGC-1a: A
Multifunctional Transcriptional Coactivator Involved in Human Metabolic
Disorders
H. Oberkofler, F. Krempler and W. Patsch
Nuclear hormone receptor function is controlled by a number of ancillary factors termed coregulators. Such coactivators and corepressors afford considerable flexibility in the coordinate expression of gene networks in numerous physiological, developmental and metabolic processes. PGC-1a, originally described as transcriptional coactivator of PPARg, has since been shown to act in a much broader context. PGC-1a coordinates the transcriptional programs of several key cellular pathways including mitochondrial biogenesis, thermogenesis, hepatic gluconeogenesis and b-oxidation of fatty acids via interactions with a growing number of transcription factors. A central issue to understand the diverse functions of PGC-1a is to gain insight into the mechanisms that confer specificity to its interactions with transfactors in response to intra- and extracellular signals. This review focuses on the different modes of regulation of PGC-1a function and the implications for tissue and context-specific transcriptional responses. Moreover, the role of sequence substitutions at the PGC-1a gene locus and their haplotype structure is discussed in relation to human disease phenotypes.
[Back
to top] STAT-1 and STAT-3: Closely Related Transcription Factors with
Antagonistic Effects on Cell Proliferation and Apoptosis
D.S. Latchman and A. Stephanou
The signal transducers and activators of transcription (STATs) are a family of transcription factors which were originally identified on the basis of their ability to transduce a signal from a cellular receptor into the nucleus and modulate the transcription of specific genes. Interestingly, recent studies have demonstrated that STAT-1 plays a key role in promoting apoptosis in a variety of cell types, whereas STAT-3 has an anti-apoptotic effect. Moreover, whilst STAT-3 promotes cellular proliferation and is activated in a variety of tumour cells, STAT-1 appears to have an anti-proliferative effect.
Although the initially characterised signal transduction events mediated by STAT-1 and STAT-3 involve the DNA binding and transcriptional activation domains of the factor, some of their other effects appear not to require DNA binding. For example, induction of apoptosis by STAT-1 can be produced by the C-terminal activation domain in the absence of the DNA binding domain. This therefore, appears to involve a co-activator effect in which STAT-1 is recruited to DNA via a DNA-bound transcription factor. In this regard, it is of interest that STAT-1 but not STAT-3 has been shown to interact with p53 and enhance its growth arrest and apoptosis- inducing properties .
Hence, STAT-1 and STAT-3 can mediate the regulation of gene transcription both by direct DNA binding and via a coactivator mechanism and despite their very similar structures, have antagonistic effects on cellular proliferation and apoptosis.