The rise and fall of breakpoint reuse depending on genome resolution

<p>Abstract</p> <p>Background</p> <p>During evolution, large-scale genome rearrangements of chromosomes shuffle the order of homologous genome sequences ("synteny blocks") across species. Some years ago, a controversy erupted in genome rearrangement studies over whether rearrangements recur, causing breakpoints to be reused.</p> <p>Methods</p> <p>We investigate this controversial issue using the synteny block's for human-mouse-rat reported by Bourque <it>et al</it>. and a series of synteny blocks we generated using Mauve at resolutions ranging from coarse to very fine-scale. We conducted analyses to test how resolution affects the traditional measure of the breakpoint reuse rate<it>.</it></p> <p>Results</p> <p>We found that the inversion-based breakpoint reuse rate is low at fine-scale synteny block resolution and that it rises and eventually falls as synteny block resolution decreases. By analyzing the cycle structure of the breakpoint graph of human-mouse-rat synteny blocks for human-mouse and comparing with theoretically derived distributions for random genome rearrangements, we showed that the implied genome rearrangements at each level of resolution become more “random” as synteny block resolution diminishes. At highest synteny block resolutions the Hannenhalli-Pevzner inversion distance deviates from the Double Cut and Join distance, possibly due to small-scale transpositions or simply due to inclusion of erroneous synteny blocks. At synteny block resolutions as coarse as the Bourque <it>et al</it>. blocks, we show the breakpoint graph cycle structure has already converged to the pattern expected for a random distribution of synteny blocks.</p> <p>Conclusions</p> <p>The inferred breakpoint reuse rate depends on synteny block resolution in human-mouse genome comparisons. At fine-scale resolution, the cycle structure for the transformation appears less random compared to that for coarse resolution. Small synteny blocks may contain critical information for accurate reconstruction of genome rearrangement history and parameters.</p

Assessing the Role of Tandem Repeats in Shaping the Genomic Architecture of Great Apes

Background: Ancestral reconstructions of mammalian genomes have revealed that evolutionary breakpoint regions are clustered in regions that are more prone to break and reorganize. What is still unclear to evolutionary biologists is whether these regions are physically unstable due solely to sequence composition and/or genome organization, or do they represent genomic areas where the selection against breakpoints is minimal. Methodology and Principal Findings: Here we present a comprehensive study of the distribution of tandem repeats in great apes. We analyzed the distribution of tandem repeats in relation to the localization of evolutionary breakpoint regions in the human, chimpanzee, orangutan and macaque genomes. We observed an accumulation of tandem repeats in the genomic regions implicated in chromosomal reorganizations. In the case of the human genome our analyses revealed that evolutionary breakpoint regions contained more base pairs implicated in tandem repeats compared to synteny blocks, being the AAAT motif the most frequently involved in evolutionary regions. We found that those AAAT repeats located in evolutionary regions were preferentially associated with Alu elements. Significance: Our observations provide evidence for the role of tandem repeats in shaping mammalian genome architecture. We hypothesize that an accumulation of specific tandem repeats in evolutionary regions can promote genome instability by altering the state of the chromatin conformation or by promoting the insertion of transposable elements

Breaking Good: Accounting For Fragility Of Genomic Regions In Rearrangement Distance Estimation

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Models of evolution by genome rearrangements are prone to two types of flaws: One is to ignore the diversity of susceptibility to breakage across genomic regions, and the other is to suppose that susceptibility values are given. Without necessarily supposing their precise localization, we call "solid" the regions that are improbably broken by rearrangements and "fragile" the regions outside solid ones. We propose a model of evolution by inversions where breakage probabilities vary across fragile regions and over time. It contains as a particular case the uniform breakage model on the nucleotidic sequence, where breakage probabilities are proportional to fragile region lengths. This is very different from the frequently used pseudouniform model where all fragile regions have the same probability to break. Estimations of rearrangement distances based on the pseudouniform model completely fail on simulations with the truly uniform model. On pairs of amniote genomes, we show that identifying coding genes with solid regions yields incoherent distance estimations, especially with the pseudouniform model, and to a lesser extent with the truly uniform model. This incoherence is solved when we coestimate the number of fragile regions with the rearrangement distance. The estimated number of fragile regions is surprisingly Small, suggesting that a minority of regions are recurrently used by rearrangements. Estimations for several pairs of genomes at different divergence times are in agreement with a slowly evolvable colocalization of active genomic regions in the cell.8514271439FAPESP [2013/25084-2]French Agence Nationale de la Recherche (ANR) [ANR-10-BINF-01-01]ICT FP7 european programme EVOEVOFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Evolution and lineage dynamics of a transmissible cancer in Tasmanian devils.

Devil facial tumour 1 (DFT1) is a transmissible cancer clone endangering the Tasmanian devil. The expansion of DFT1 across Tasmania has been documented, but little is known of its evolutionary history. We analysed genomes of 648 DFT1 tumours collected throughout the disease range between 2003 and 2018. DFT1 diverged early into five clades, three spreading widely and two failing to persist. One clade has replaced others at several sites, and rates of DFT1 co-infection are high. DFT1 gradually accumulates copy number variants (CNVs) and its telomere lengths are short but constant. Recurrent CNVs reveal genes under positive selection, sites of genome instability and repeated loss of a small derived chromosome. Cultured DFT1 cell lines have increased CNV frequency and undergo highly reproducible convergent evolution. Overall, DFT1 is a remarkably stable lineage whose genome illustrates how cancer cells adapt to diverse environments and persist in a parasitic niche.This work was supported by grants from Wellcome (102942/Z/13/A), the National Science Foundation (DEB-1316549), the University of Tasmania Foundation (Eric Guiler Tasmanian Devil Research Grants), the Australian Research Council (DE 170101116) and a Philip Leverhulme Prize from the Leverhulme Trust. YMK was supported by a Herchel Smith Postgraduate Fellowship

The complexity of genome rearrangement combinatorics under the infinite sites model

Rearrangements are discrete processes whereby discrete segments of DNA are deleted, replicated and inserted into novel positions. A sequence of such configurations, termed a rearrangement evolution, results in jumbled DNA arrangements, frequently observed in cancer genomes. We introduce a method that allows us to precisely count these different evolutions for a range of processes including breakage-fusion-bridge-cycles, tandem-duplications, inverted-duplications, reversals, transpositions and deletions, showing that the space of rearrangement evolution is superexponential in size. These counts assume the infinite sites model of unique breakpoint usage

Breaking Good: Accounting for Fragility of Genomic Regions in Rearrangement Distance Estimation

International audienceModels of evolution by genome rearrangements are prone to two types of flaws: One is to ignore the diversity of susceptibility tobreakage across genomic regions, and the other is to suppose that susceptibility values are given. Without necessarily supposing theirprecise localization,we call “solid” the regions that are improbably broken by rearrangements and “fragile” the regions outside solidones.We propose a model of evolution by inversions where breakage probabilities vary across fragile regions and over time. It containsas a particular case the uniform breakage model on the nucleotidic sequence,where breakage probabilities are proportional to fragileregion lengths. This is very different from the frequently used pseudo uniform model where all fragile regions have the same probabilityto break. Estimations of rearrangement distances based on the pseudo uniform model completely fail on simulations with thetruly uniform model. On pairs of amniote genomes, we show that identifying coding genes with solid regions yields incoherentdistance estimations, especially with the pseudo uniform model, and to a lesser extent with the truly uniform model. This incoherenceis solved when we coestimate the number of fragile regions with the rearrangement distance. The estimated number of fragileregions is surprisingly small, suggesting that a minority of regions are recurrently used by rearrangements. Estimations for several pairsof genomes at different divergence times are in agreement with a slowly evolvable colocalization of active genomic regions in the cell

Evaluation of the Role of Functional Constraints on the Integrity of an Ultraconserved Region in the Genus Drosophila

Why gene order is conserved over long evolutionary timespans remains elusive. A common interpretation is that gene order conservation might reflect the existence of functional constraints that are important for organismal performance. Alteration of the integrity of genomic regions, and therefore of those constraints, would result in detrimental effects. This notion seems especially plausible in those genomes that can easily accommodate gene reshuffling via chromosomal inversions since genomic regions free of constraints are likely to have been disrupted in one or more lineages. Nevertheless, no empirical test has been performed to this notion. Here, we disrupt one of the largest conserved genomic regions of the Drosophila genome by chromosome engineering and examine the phenotypic consequences derived from such disruption. The targeted region exhibits multiple patterns of functional enrichment suggestive of the presence of constraints. The carriers of the disrupted collinear block show no defects in their viability, fertility, and parameters of general homeostasis, although their odorant perception is altered. This change in odorant perception does not correlate with modifications of the level of expression and sex bias of the genes within the genomic region disrupted. Our results indicate that even in highly rearranged genomes, like those of Diptera, unusually high levels of gene order conservation cannot be systematically attributed to functional constraints, which raises the possibility that other mechanisms can be in place and therefore the underpinnings of the maintenance of gene organization might be more diverse than previously thought

Whole-genome sequence analysis for pathogen detection and diagnostics

This dissertation focuses on computational methods for improving the accuracy of commonly used nucleic acid tests for pathogen detection and diagnostics. Three specific biomolecular techniques are addressed: polymerase chain reaction, microarray comparative genomic hybridization, and whole-genome sequencing. These methods are potentially the future of diagnostics, but each requires sophisticated computational design or analysis to operate effectively. This dissertation presents novel computational methods that unlock the potential of these diagnostics by efficiently analyzing whole-genome DNA sequences. Improvements in the accuracy and resolution of each of these diagnostic tests promises more effective diagnosis of illness and rapid detection of pathogens in the environment. For designing real-time detection assays, an efficient data structure and search algorithm are presented to identify the most distinguishing sequences of a pathogen that are absent from all other sequenced genomes. Results are presented that show these "signature" sequences can be used to detect pathogens in complex samples and differentiate them from their non-pathogenic, phylogenetic near neighbors. For microarray, novel pan-genomic design and analysis methods are presented for the characterization of unknown microbial isolates. To demonstrate the effectiveness of these methods, pan-genomic arrays are applied to the study of multiple strains of the foodborne pathogen, Listeria monocytogenes, revealing new insights into the diversity and evolution of the species. Finally, multiple methods are presented for the validation of whole-genome sequence assemblies, which are capable of identifying assembly errors in even finished genomes. These validated assemblies provide the ultimate nucleic acid diagnostic, revealing the entire sequence of a genome