Trends in genetics

Evolution of complex structures: minicollagens shape the cnidarian nematocyst.

Publication Date: 2008 Aug 2 PMID: 18676050
Authors: David, C. N. - Ozbek, S. - Adamczyk, P. - Meier, S. - Pauly, B. - Chapman, J. - Hwang, J. S. - Gojobori, T. - Holstein, T. W.
Journal: Trends Genet

The generation of biological complexity by the acquisition of novel modular units is an emerging concept in evolutionary dynamics. Here, we review the coordinate evolution of cnidarian nematocysts, secretory organelles used for capture of prey, and of minicollagens, proteins constituting the nematocyst capsule. Within the Cnidaria there is an increase in nematocyst complexity from Anthozoa to Medusozoa and a parallel increase in the number and complexity of minicollagen proteins. This complexity is primarily manifest in a diversification of N- and C-terminal cysteine-rich domains (CRDs) involved in minicollagen polymerization. We hypothesize that novel CRD motifs alter minicollagen networks, leading to novel capsule structures and nematocyst types.

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Low duplicability and network fragility of cancer genes.

Publication Date: 2008 Jul 31 PMID: 18675489
Authors: Rambaldi, D. - Giorgi, F. M. - Capuani, F. - Ciliberto, A. - Ciccarelli, F. D.
Journal: Trends Genet

We identified genomic and network properties of approximately 600 genes mutated in different cancer types. These genes tend not to duplicate but, unlike most human singletons, they encode central hubs of highly interconnected modules within the protein-protein interaction network (PIN). We find that cancer genes are fragile components of the human gene repertoire, sensitive to dosage modification. Furthermore, other nodes of the human PIN with similar properties are rare and probably enriched in candidate cancer genes.

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Tools to study DNA repair: what's in the box?

Publication Date: 2008 Jul 31 PMID: 18675488
Authors: Feuerhahn, S. - Egly, J. M.
Journal: Trends Genet

Our understanding of the DNA repair mechanisms that preserve genome integrity has increased greatly in recent years. To follow the DNA repair process, researchers have developed sophisticated techniques including live cell imaging, local damage induction and refined biochemical assays. These techniques have helped to elucidate the 'orchestration' of DNA repair mechanisms (i.e. the order of factor assembly around the lesion, the identification of new functions of known factors and the discovery of novel key regulators involved in DNA repair). We will discuss the uses and the limitations of these methods and their applications in the study of DNA repair.

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Whole chromosome instability and cancer: a complex relationship.

Publication Date: 2008 Jul 31 PMID: 18675487
Authors: Ricke, R. M. - van Ree, J. H. - van Deursen, J. M.
Journal: Trends Genet

Although chromosome mis-segregation is a hallmark of cancer cells, its genetic basis and role in malignant transformation remain poorly understood. In recent years, several mouse models have been generated that harbor gene defects that perturb high-fidelity chromosome segregation. Analysis of these models has revealed that whole chromosome instability (W-CIN) can cause, inhibit or have no effect on tumorigenesis. Here we propose that the effect of W-CIN on tumor development depends on the particular W-CIN gene that is defective, including its other cellular functions, the extent or nature of the gene defect, the affected tissue or cell type and the context of other cancer gene mutations.

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Micromanagers of malignancy: role of microRNAs in regulating metastasis.

Publication Date: 2008 Jul 30 PMID: 18674843
Authors: Ma, L. - Weinberg, R. A.
Journal: Trends Genet

It has become evident that cancer pathogenesis involves, among other macromolecules, a class of small regulatory RNAs named microRNAs, and that microRNA expression profiles are associated with prognosis and therapeutic outcome in several human cancers. Although the oncogenic or tumor-suppressing functions of several microRNAs have been characterized, the mechanistic roles played by microRNAs specifically in mediating metastasis have been addressed only recently. In this review, we focus on our emerging understanding of the contributions of microRNAs to malignant progression, specifically their functions in mediating tumor invasion and metastasis. These findings illuminate the molecular basis of metastasis and begin to connect small-RNA discoveries to the development of novel clinical biomarkers and therapeutic targets in neoplastic diseases.

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Iron-sulfur cluster biogenesis and human disease.

Publication Date: 2008 Aug PMID: 18606475
Authors: Rouault, T. A. - Tong, W. H.
Journal: Trends Genet

Iron-sulfur (Fe-S) clusters are essential for numerous biological processes, including mitochondrial respiratory chain activity and various other enzymatic and regulatory functions. Human Fe-S cluster assembly proteins are frequently encoded by single genes, and inherited defects in some of these genes cause disease. Recently, the spectrum of diseases attributable to abnormal Fe-S cluster biogenesis has extended beyond Friedreich ataxia to include a sideroblastic anemia with deficiency of glutaredoxin 5 and a myopathy associated with a deficiency of a Fe-S cluster assembly scaffold protein, ISCU. Mutations within other mammalian Fe-S cluster assembly genes could be causative for human diseases that manifest distinctive combinations of tissue-specific impairments. Thus, defects in the iron-sulfur cluster biogenesis pathway could underlie many human diseases.

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The chromosome glue gets a little stickier.

Publication Date: 2008 Aug PMID: 18602182
Authors: McNairn, A. J. - Gerton, J. L.
Journal: Trends Genet

Since their discovery, the cohesin proteins have been intensely studied in multiple model systems to determine the mechanism of chromosome cohesion. Recent studies have demonstrated that cohesin is much more than a molecular glue that holds chromosomes together in mitosis. Indeed, cohesin performs critical roles in gene regulation, possibly through the formation of higher-order chromatin structure. Moreover, this newly appreciated role is necessary for proper development in metazoan species, with mutations in the cohesin pathway resulting in human developmental disorders.

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Origin of introns by 'intronization' of exonic sequences.

Publication Date: 2008 Aug PMID: 18597887
Authors: Irimia, M. - Rukov, J. L. - Penny, D. - Vinther, J. - Garcia-Fernandez, J. - Roy, S. W.
Journal: Trends Genet

The mechanisms of spliceosomal intron creation have proved elusive. Here we describe a new mechanism: the recruitment of internal exonic sequences ('intronization') in Caenorhabditis species. The numbers of intronization events and introns gained by other mechanisms are similar, suggesting that intronization significantly contributes to recent intron creation in nematodes. Intronization is more common than the reverse process, loss of splicing of retained introns. Finally, these findings link alternative splicing with modern intron creation.

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RNA-binding proteins in human genetic disease.

Publication Date: 2008 Aug PMID: 18597886
Authors: Lukong, K. E. - Chang, K. W. - Khandjian, E. W. - Richard, S.
Journal: Trends Genet

RNA-binding proteins (RBPs) are key components in RNA metabolism, regulating the temporal, spatial and functional dynamics of RNAs. Altering the expression of RBPs has profound implications for cellular physiology, affecting RNA processes from pre-mRNA splicing to protein translation. Recent genetic and proteomic data and evidence from animal models reveal that RBPs are involved in many human diseases ranging from neurologic disorders to cancer. Here we review the emerging evidence showing the involvement of RBPs in many disease networks and conclude that defects in RNA metabolism caused by aberrations in RBPs might underlie a broader spectrum of complex human disorders.

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Revealing the architecture of gene regulation: the promise of eQTL studies.

Publication Date: 2008 Aug PMID: 18597885
Authors: Gilad, Y. - Rifkin, S. A. - Pritchard, J. K.
Journal: Trends Genet

Expression quantitative trait loci (eQTL) mapping studies have become a widely used tool for identifying genetic variants that affect gene regulation. In these studies, expression levels are viewed as quantitative traits, and gene expression phenotypes are mapped to particular genomic loci by combining studies of variation in gene expression patterns with genome-wide genotyping. Results from recent eQTL mapping studies have revealed substantial heritable variation in gene expression within and between populations. In many cases, genetic factors that influence gene expression levels can be mapped to proximal (putatively cis) eQTLs and, less often, to distal (putatively trans) eQTLs. Beyond providing great insight into the biology of gene regulation, a combination of eQTL studies with results from traditional linkage or association studies of human disease may help predict a specific regulatory role for polymorphic sites previously associated with disease.

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Rapidly regulated genes are intron poor.

Publication Date: 2008 Aug PMID: 18586348
Authors: Jeffares, D. C. - Penkett, C. J. - Bahler, J.
Journal: Trends Genet

We show that genes with rapidly changing expression levels in response to stress contain significantly lower intron densities in yeasts, thale cress and mice. Therefore, we propose that introns can delay regulatory responses and are selected against in genes whose transcripts require rapid adjustment for survival of environmental challenges. These findings could provide an explanation for the apparent extensive intron loss during the evolution of some eukaryotic lineages.

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Cellular reactions to gene dosage imbalance: genomic, transcriptomic and proteomic effects.

Publication Date: 2008 Aug PMID: 18585818
Authors: Veitia, R. A. - Bottani, S. - Birchler, J. A.
Journal: Trends Genet

There is increasing evidence suggesting that stoichiometric imbalances in macromolecular complexes and in signaling/transcriptional networks are a source of dosage-dependent phenotypes. Such alterations can result from total or partial aneuploidy, gene copy number variants or regulatory alterations. Thus, some gene balance is required to ensure a normal function. This balance also dictates which genes are preferentially over- or underretained after single gene, segmental or whole genome duplications. Here, we review the mechanisms leading to dosage effects and compensation at the transcriptional and translational levels. Moreover, we propose that the involvement of a protein in a complex can affect its stability: formation of complexes might mask degradation signals in the monomers leading to their preferential degradation when in excess, alleviating dosage imbalances.

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Glossogeny and phylogeny: cultural evolution meets genetic evolution.

Publication Date: 2008 Aug PMID: 18585817
Authors: Fitch, W. T.
Journal: Trends Genet

Evolutionary theorists since Darwin have been interested in the parallels and interactions between biological and cultural evolution. Recent applications of empirical techniques originally developed to analyze molecular genetic data to linguistic data offer new insights into the historical evolution of language, revealing fascinating parallels between language change and biological evolution. This work offers considerable potential toward unified theories of genetic and cultural change.

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