Mapping Insertions, Deletions and SNPs on Venter's Chromosomes

Costantini, Maria; Bernardi, Giorgio

doi:10.1371/journal.pone.0005972

Cited by 16 publications

(14 citation statements)

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“…Furthermore, we confirm the negative association between SINE counts and deletion rates observed previously [8,21]. The positive association of GC content and density of coding exons with insertion rates, and their negative association with deletion rates, point to genomic regions that tolerate more insertions than deletions; such regions were indeed found to be present in GC-rich, gene-rich isochores in Venter's genome by a recent study [43]. The negative association of the density of conserved elements with deletion rates reiterates a previous observation about conserved and functional regions being depleted of small deletions [8].…”

Section: Discussionsupporting

confidence: 91%

A genome-wide view of mutation rate co-variation using multivariate analyses

2011

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BackgroundWhile the abundance of available sequenced genomes has led to many studies of regional heterogeneity in mutation rates, the co-variation among rates of different mutation types remains largely unexplored, hindering a deeper understanding of mutagenesis and genome dynamics. Here, utilizing primate and rodent genomic alignments, we apply two multivariate analysis techniques (principal components and canonical correlations) to investigate the structure of rate co-variation for four mutation types and simultaneously explore the associations with multiple genomic features at different genomic scales and phylogenetic distances.ResultsWe observe a consistent, largely linear co-variation among rates of nucleotide substitutions, small insertions and small deletions, with some non-linear associations detected among these rates on chromosome X and near autosomal telomeres. This co-variation appears to be shaped by a common set of genomic features, some previously investigated and some novel to this study (nuclear lamina binding sites, methylated non-CpG sites and nucleosome-free regions). Strong non-linear relationships are also detected among genomic features near the centromeres of large chromosomes. Microsatellite mutability co-varies with other mutation rates at finer scales, but not at 1 Mb, and shows varying degrees of association with genomic features at different scales.ConclusionsOur results allow us to speculate about the role of different molecular mechanisms, such as replication, recombination, repair and local chromatin environment, in mutagenesis. The software tools developed for our analyses are available through Galaxy, an open-source genomics portal, to facilitate the use of multivariate techniques in future large-scale genomics studies.

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Section: Discussionsupporting

confidence: 91%

A genome-wide view of mutation rate co-variation using multivariate analyses

2011

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“…Along the same line, we also knew that the density of DNase hypersensitive sites (and thus open chromatin) increases with the increasing GC of isochores (Di Filippo and Bernardi 2008, 2009) and that the latter are preferential regions for insertions and deletions in the human genome (Costantini and Bernardi 2009). …”

Section: Discussionmentioning

confidence: 84%

Isochores and the Regulation of Gene Expression in the Human Genome

Arhondakis

Auletta

Bernardi

2011

Genome Biology and Evolution

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It is well established that changes in the phenotype depend much more on changes in gene expression than on changes in protein-coding genes, and that cis-regulatory sequences and chromatin structure are two major factors influencing gene expression. Here, we investigated these factors at the genome-wide level by focusing on the trinucleotide patterns in the 0.1- to 25-kb regions flanking the human genes that are present in the GC-poorest L1 and GC-richest H3 isochore families, the other families exhibiting intermediate patterns. We could show 1) that the trinucleotide patterns of the 25-kb gene-flanking regions are representative of the very different patterns already reported for the whole isochores from the L1 and H3 families and, expectedly, identical in upstream and downstream locations; 2) that the patterns of the 0.1- to 0.5-kb regions in the L1 and H3 isochores are remarkably more divergent and more specific when compared with those of the 25-kb regions, as well as different in the upstream and downstream locations; and 3) that these patterns fade into the 25-kb patterns around 5kb in both upstream and downstream locations. The 25-kb findings indicate differences in nucleosome positioning and density in different isochore families, those of the 0.1- to 0.5-kb sequences indicate differences in the transcription factors that bind upstream and downstream of genes. These results indicate differences in the regulation of genes located in different isochore families, a point of functional and evolutionary relevance.

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“…This indicates that sites of increased SNP density do not necessarily harbor excess of structural variations. This also suggests that the rate of singlenucleotide substitution may depend on a number of factors (25) and that the presence of structural alteration in the vicinity is only one of these factors. Taken together, these findings suggest that at the time scales of population divergence, the presence of structural alteration is likely to cause an increase in the local singlenucleotide substitution rate in the vicinity.…”

Section: Resultsmentioning

confidence: 99%

A time-invariant principle of genome evolution

Babu

2010

Proc. Natl. Acad. Sci. U.S.A.

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Uncovering general principles of genome evolution that are timeinvariant and that operate in germ and somatic cells has implications for genome-wide association studies (GWAS), gene therapy, and disease genomics. Here we investigate the relationship between structural alterations (e.g., insertions and deletions) and singlenucleotide substitutions by comparing the following genomes that diverged at different times across germ-and somatic-cell lineages: (i) the reference human and chimpanzee genome (in million years), (ii) the reference human and personal genomes (in tens of thousands of years), and (iii) structurally altered regions in cancer and genetically engineered cells (in days). At the species level, genes with structural alteration in nearby regions show increased singlenucleotide changes and tend to evolve faster. In personal genomes, the single-nucleotide substitution rate is higher near sites of structural alteration and decreases with increasing distance. In human cancer cell populations and in cells genetically engineered using zinc-finger nucleases, single-nucleotide changes occur frequently near sites of structural alterations. We present evidence that structural alteration induces single-nucleotide changes in nearby regions and discuss possible molecular mechanisms that contribute to this phenomenon. We propose that the low fidelity of nonreplicative error-prone repair polymerases, which are used during insertion or deletion, result in break-repair-induced single-nucleotide mutations in the vicinity of structural alteration. Thus, in the mutational landscape, structural alterations are linked to single-nucleotide changes across different time scales in both somatic-and germ-cell lineages. We discuss implications for genome evolution, GWAS, disease genomics, and gene therapy and emphasize the need to investigate both types of mutations within a single framework.single-nucleotide substitution | structural alteration | mutation | DNA repair U nderstanding how mutations contribute to genetic variation in a population and drive the evolution of new species is a fundamental problem in the postgenomic era. In recent years, intermediate-scale mutations (e.g., insertion, deletion, translocation, and inversion) that result in structural variation have gained considerable attention (1). Although the genome-wide impact of mutations of different sizes (e.g., single-nucleotide changes and structural alterations such as insertion or deletion of genetic material) has been investigated separately, it has long been speculated (2, 3), and increasing evidence suggests, that mutations of different sizes are correlated in prokaryotes and eukaryotes (4-13). Although these studies have provided evidence for such a relationship, how this phenomenon affects functional elements in the genome has not been systematically investigated in humans. Specifically, the implications for sequence (protein and nucleic acid) evolution and the nature of such dependence in genomes that "diverged" at different time scales, i.e., at the tim...

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Mapping Insertions, Deletions and SNPs on Venter's Chromosomes

Cited by 16 publications

References 50 publications

A genome-wide view of mutation rate co-variation using multivariate analyses

A genome-wide view of mutation rate co-variation using multivariate analyses

Isochores and the Regulation of Gene Expression in the Human Genome

A time-invariant principle of genome evolution

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