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Mutational Mechanisms (mutational + mechanism)

Distribution by Scientific Domains

Life Sciences	100%

Selected Abstracts

UMD-predictor, a new prediction tool for nucleotide substitution pathogenicity,application to four genes: FBN1, FBN2, TGFBR1, and TGFBR2,

HUMAN MUTATION, Issue 6 2009
Mélissa Yana Frédéric
Abstract Approximately half of gene lesions responsible for human inherited diseases are due to an amino acid substitution, showing that this mutational mechanism plays a large role in diseases. Distinguishing neutral sequence variations from those responsible for the phenotype is of major interest in human genetics. Because in vitro validation of mutations is not always possible in diagnostic settings, indirect arguments must be accumulated to define whether a missense variation is causative. To further differentiate neutral variants from pathogenic nucleotide substitutions, we developed a new tool, UMD-Predictor®. This tool provides a combinatorial approach that associates the following data: localization within the protein, conservation, biochemical properties of the mutant and wild-type residues, and the potential impact of the variation on mRNA. To evaluate this new tool, we compared it to the SIFT, PolyPhen, and SNAP software, the BLOSUM62 and Yu's Biochemical Matrices. All tools were evaluated using variations from well-validated datasets extracted from four UMD,LSDB databases (UMD,FBN1, UMD,FBN2, UMD,TGFBR1, and UMD,TGFBR2) that contain all published mutations of the corresponding genes, that is, 1,945 mutations, among which 796 different substitutions corresponding to missense mutations. Our results show that the UMD-Predictor® algorithm is the most efficient tool to predict pathogenic mutations in this context with a positive predictive value of 99.4%, a sensitivity of 95.4%, and a specificity of 92.2%. It can thus enhance the interpretation of variations in these genes, and could easily be applied to any other disease gene through the freely available UMD® generic software (http://www.umd.be). Hum Mutat 30:1,8, 2009. © 2009 Wiley-Liss, Inc. [source]

THE EVOLUTION OF THE VERTEBRATE ,-GLOBIN GENE PROMOTER

EVOLUTION, Issue 2 2002
Nadia A. Chuzhanova
Abstract Complexity analysis is capable of highlighting those gross evolutionary changes in gene promoter regions (loosely termed "promoter shuffling") that are undetectable by conventional DNA sequence alignment. Complexity analysis was therefore used here to identify the modular components (blocks) of the orthologous ,-globin gene promoter sequences of 22 vertebrate species, from zebrafish to humans. Considerable variation between the ,-globin gene promoters was apparent in terms of block presence/absence, copy number, and relative location. Some sequence blocks appear to be ubiquitous, whereas others are restricted to a specific taxon. Block similarities were also evident between the promoters of the paralogous human ,-like globin genes. It may be inferred that a wide variety of different mutational mechanisms have operated upon the ,-globin gene promoter over evolutionary time. Because these include gross changes such as deletion, duplication, amplification, elongation, contraction, and fusion, as well as the steady accumulation of single base-pair substitutions, it is clear that some redefinition of the term "promoter shuffling" is required. This notwithstanding, and as previously described for the vertebrate growth hormone gene promoter, the modular structure of the ,-globin promoter region and those of its paralogous counterparts have continually been rearranged into new combinations through the alteration, or shuffling, of preexisting blocks. Some of these changes may have had no influence on promoter function, but others could have altered either the level of gene expression or the responsiveness of the promoter to external stimuli. The comparative study of vertebrate ,-globin gene promoter regions described here confirms the generality of the phenomenon of sequence block shuffling and thus supports the view that it could have played an important role in the evolution of differential gene expression. [source]

Microsatellites: genomic distribution, putative functions and mutational mechanisms: a review

MOLECULAR ECOLOGY, Issue 12 2002
You-Chun Li
Abstract Microsatellites, or tandem simple sequence repeats (SSR), are abundant across genomes and show high levels of polymorphism. SSR genetic and evolutionary mechanisms remain controversial. Here we attempt to summarize the available data related to SSR distribution in coding and noncoding regions of genomes and SSR functional importance. Numerous lines of evidence demonstrate that SSR genomic distribution is nonrandom. Random expansions or contractions appear to be selected against for at least part of SSR loci, presumably because of their effect on chromatin organization, regulation of gene activity, recombination, DNA replication, cell cycle, mismatch repair system, etc. This review also discusses the role of two putative mutational mechanisms, replication slippage and recombination, and their interaction in SSR variation. [source]

Mapping of IS6110 flanking regions in clinical isolates of Mycobacterium tuberculosis demonstrates genome plasticity

MOLECULAR MICROBIOLOGY, Issue 6 2000
R. M. Warren
Southern hybridization was used in combination with IS6110 insertion-locus-specific probes in a comparative study to determine the structure of chromosomal domains flanking IS6110 elements in clinical isolates of Mycobacterium tuberculosis. The resulting restriction fragment length polymorphism (RFLP) data demonstrated three mutational mechanisms responsible for the polymorphisms observed: IS6110 insertion, chromosomal mutation and deletion. The frequency of IS6110 insertion within many of the chromosomal regions demonstrates that preferential integration regions are common in M. tuberculosis. Mapping the IS6110 insertion positions and chromosomal deletions in relation to the M. tuberculosis H37Rv and M. bovis BCG genome sequences reveals numerous disruptions of predicted open reading frames (ORFs). A phylogenetic tree, based on the mutational data, showed a number of independently evolving lineages of M. tuberculosis, while analysis of the mutational events occurring at each branch point suggests both divergent and convergent evolution. A significant positive correlation was demonstrated between the mutation rate and the frequency of occurrence of different isolates in families of strains, suggesting that evolution may impact on strain ,fitness' or that strain proliferation may increase the chance of mutation. We conclude that the genome of clinical isolates of M. tuberculosis continues to evolve. [source]

Mobile DNA elements in primate and human evolution

AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY, Issue S45 2007
Jinchuan Xing
Abstract Roughly 50% of the primate genome consists of mobile, repetitive DNA sequences such as Alu and LINE1 elements. The causes and evolutionary consequences of mobile element insertion, which have received considerable attention during the past decade, are reviewed in this article. Because of their unique mutational mechanisms, these elements are highly useful for answering phylogenetic questions. We demonstrate how they have been used to help resolve a number of questions in primate phylogeny, including the human,chimpanzee,gorilla trichotomy and New World primate phylogeny. Alu and LINE1 element insertion polymorphisms have also been analyzed in human populations to test hypotheses about human evolution and population affinities and to address forensic issues. Finally, these elements have had impacts on the genome itself. We review how they have influenced fundamental ongoing processes like nonhomologous recombination, genomic deletion, and X chromosome inactivation. Yrbk Phys Anthropol 50:2,19, 2007. © 2007 Wiley-Liss, Inc. [source]