Principles of genome evolution in the Drosophila melanogaster species group.

That closely related species often differ by chromosomal inversions was discovered by Sturtevant and Plunkett in 1926. Our knowledge of how these inversions originate is still very limited, although a prevailing view is that they are facilitated by ectopic recombination events between inverted repetitive sequences. The availability of genome sequences of related species now allows us to study in detail the mechanisms that generate interspecific inversions. We have analyzed the breakpoint regions of the 29 inversions that differentiate the chromosomes of Drosophila melanogaster and two closely related species, D. simulans and D. yakuba, and reconstructed the molecular events that underlie their origin. Experimental and computational analysis revealed that the breakpoint regions of 59% of the inversions (17/29) are associated with inverted duplications of genes or other nonrepetitive sequences. In only two cases do we find evidence for inverted repetitive sequences in inversion breakpoints. We propose that the presence of inverted duplications associated with inversion breakpoint regions is the result of staggered breaks, either isochromatid or chromatid, and that this, rather than ectopic exchange between inverted repetitive sequences, is the prevalent mechanism for the generation of inversions in the melanogaster species group. Outgroup analysis also revealed evidence for widespread breakpoint recycling. Lastly, we have found that expression domains in D. melanogaster may be disrupted in D. yakuba, bringing into question their potential adaptive significance

CYNTENATOR: Progressive Gene Order Alignment of 17 Vertebrate Genomes

Whole genome gene order evolution in higher eukaryotes was initially considered as a random process. Gene order conservation or conserved synteny was seen as a feature of common descent and did not imply the existence of functional constraints. This view had to be revised in the light of results from sequencing dozens of vertebrate genomes

Gene synteny comparisons between different vertebrates provide new insights into breakage and fusion events during mammalian karyotype evolution

<p>Abstract</p> <p>Background</p> <p>Genome comparisons have made possible the reconstruction of the eutherian ancestral karyotype but also have the potential to provide new insights into the evolutionary inter-relationship of the different eutherian orders within the mammalian phylogenetic tree. Such comparisons can additionally reveal (i) the nature of the DNA sequences present within the evolutionary breakpoint regions and (ii) whether or not the evolutionary breakpoints occur randomly across the genome. Gene synteny analysis (E-painting) not only greatly reduces the complexity of comparative genome sequence analysis but also extends its evolutionary reach.</p> <p>Results</p> <p>E-painting was used to compare the genome sequences of six different mammalian species and chicken. A total of 526 evolutionary breakpoint intervals were identified and these were mapped to a median resolution of 120 kb, the highest level of resolution so far obtained. A marked correlation was noted between evolutionary breakpoint frequency and gene density. This correlation was significant not only at the chromosomal level but also sub-chromosomally when comparing genome intervals of lengths as short as 40 kb. Contrary to previous findings, a comparison of evolutionary breakpoint locations with the chromosomal positions of well mapped common fragile sites and cancer-associated breakpoints failed to reveal any evidence for significant co-location. Primate-specific chromosomal rearrangements were however found to occur preferentially in regions containing segmental duplications and copy number variants.</p> <p>Conclusion</p> <p>Specific chromosomal regions appear to be prone to recurring rearrangement in different mammalian lineages ('breakpoint reuse') even if the breakpoints themselves are likely to be non-identical. The putative ancestral eutherian genome, reconstructed on the basis of the synteny analysis of 7 vertebrate genome sequences, not only confirmed the results of previous molecular cytogenetic studies but also increased the definition of the inferred structure of ancestral eutherian chromosomes. For the first time in such an analysis, the opossum was included as an outgroup species. This served to confirm our previous model of the ancestral eutherian genome since all ancestral syntenic segment associations were also noted in this marsupial.</p

Recurring genomic breaks in independent lineages support genomic fragility

BACKGROUND: Recent findings indicate that evolutionary breaks in the genome are not randomly distributed, and that certain regions, so-called fragile regions, are predisposed to breakages. Previous approaches to the study of genomic fragility have examined the distribution of breaks, as well as the coincidence of breaks with segmental duplications and repeats, within a single species. In contrast, we investigate whether this regional fragility is an inherent genomic characteristic and is thus conserved over multiple independent lineages. RESULTS: We do this by quantifying the extent to which certain genomic regions are disrupted repeatedly in independent lineages. Our investigation, based on Human, Chimp, Mouse, Rat, Dog and Chicken, suggests that the propensity of a chromosomal region to break is significantly correlated among independent lineages, even when covariates are considered. Furthermore, the fragile regions are enriched for segmental duplications. CONCLUSION: Based on a novel methodology, our work provides additional support for the existence of fragile regions

Is mammalian chromosomal evolution driven by regions of genome fragility?

BACKGROUND: A fundamental question in comparative genomics concerns the identification of mechanisms that underpin chromosomal change. In an attempt to shed light on the dynamics of mammalian genome evolution, we analyzed the distribution of syntenic blocks, evolutionary breakpoint regions, and evolutionary breakpoints taken from public databases available for seven eutherian species (mouse, rat, cattle, dog, pig, cat, and horse) and the chicken, and examined these for correspondence with human fragile sites and tandem repeats. RESULTS: Our results confirm previous investigations that showed the presence of chromosomal regions in the human genome that have been repeatedly used as illustrated by a high breakpoint accumulation in certain chromosomes and chromosomal bands. We show, however, that there is a striking correspondence between fragile site location, the positions of evolutionary breakpoints, and the distribution of tandem repeats throughout the human genome, which similarly reflect a non-uniform pattern of occurrence. CONCLUSION: These observations provide further evidence that certain chromosomal regions in the human genome have been repeatedly used in the evolutionary process. As a consequence, the genome is a composite of fragile regions prone to reorganization that have been conserved in different lineages, and genomic tracts that do not exhibit the same levels of evolutionary plasticity

Finding genomic differences from whole-genome assemblies using SyRI

Genomic differences can range from single nucleotide differences (SNPs) to large complex structural rearrangements. Current methods typically can annotate sequence differences like SNPs and large indels accurately but do not unravel the full complexity of structural rearrangements that include inversions, translocations, and duplications. Structural rearrangements involve changes in location, orientation, or copy-number between highly similar sequences and have been reported to be associated with several biological differences between organisms. However, they are still scantly studied with sequencing technologies as it is still challenging to identify them accurately. Here I present SyRI, a novel computational method for genome-wide identification of structural differences using the pairwise comparison of whole-genome chromosome-level assemblies. SyRI uses a unique approach where it first identifies all syntenic (structurally conserved) regions between two genomes. Since all non-syntenic regions are structural rearrangements by definition, this transforms the difficult problem of rearrangement identification to a comparatively easier problem of rearrangement classification. SyRI analyses the location, orientation, and copy-number of alignments between rearranged regions and selects alignments that best represent the putative rearrangements and result in the highest total alignment score between the genomes. Next, SyRI searches for sequence differences that are distinguished for residing in syntenic or rearranged regions. This distinction is important, as rearranged regions (and sequence differences within them) do not follow Mendelian Law of Segregation and are therefore inherited differently compared to syntenic regions. Using SyRI, I successfully identified rearrangements in human, A. thaliana, yeast, fruit fly, and maize genomes. Further, I also experimentally validated 92% (108/117) of the predicted translocations in A. thaliana using a genetic approach

Reconstructing the Phylogeny of the Human Chromosome 4 Synteny using Comparative Karyology and Genomic Data Analysis

Abstract This work focuses on the evolution of the architecture of human chromosome 4 (HSA4) through the analysis of chromosomal regions that have been conserved over time, and the comparison of regions that have been involved in different rearrangements in placental lineages. As with most elements of the human genome, HSA4 is considered to be evolutionarily stable. A more detailed analysis indicates that the syntenic association has been reshuffled by a series of rearrangements, yielding different chromosomes in various taxa. In its ancestral eutherian state, HSA4 has a syntenic association with HSA8p. We investigated the complex origin of this human chromosome using three different approaches, including: the analysis of chromosome painting features among 157 mammalian species gleaned from published data; the analysis of conserved syntenic orthologous blocks derived from the Ensembl dataset (www.ensembl.org); and the reconstruction of the orthologues of HSA4 in various species, using a maximum parsimony ..

Characterization of the past and current duplication activities in the human 22q11.2 region

<p>Abstract</p> <p>Background</p> <p>Segmental duplications (SDs) on 22q11.2 (LCR22), serve as substrates for meiotic non-allelic homologous recombination (NAHR) events resulting in several clinically significant genomic disorders.</p> <p>Results</p> <p>To understand the duplication activity leading to the complicated SD structure of this region, we have applied the A-Bruijn graph algorithm to decompose the 22q11.2 SDs to 523 fundamental duplication sequences, termed subunits. Cross-species syntenic analysis of primate genomes demonstrates that many of these LCR22 subunits emerged very recently, especially those implicated in human genomic disorders. Some subunits have expanded more actively than others, and young <it>Alu </it>SINEs, are associated much more frequently with duplicated sequences that have undergone active expansion, confirming their role in mediating recombination events. Many copy number variations (CNVs) exist on 22q11.2, some flanked by SDs. Interestingly, two chromosome breakpoints for 13 CNVs (mean length 65 kb) are located in paralogous subunits, providing direct evidence that SD subunits could contribute to CNV formation. Sequence analysis of PACs or BACs identified extra CNVs, specifically, 10 insertions and 18 deletions within 22q11.2; four were more than 10 kb in size and most contained young <it>AluY</it>s at their breakpoints.</p> <p>Conclusions</p> <p>Our study indicates that <it>AluY</it>s are implicated in the past and current duplication events, and moreover suggests that DNA rearrangements in 22q11.2 genomic disorders perhaps do not occur randomly but involve both actively expanded duplication subunits and <it>Alu </it>elements.</p

High rates of genome rearrangements and pathogenicity of Shigella spp.

Shigella are pathogens originating within the Escherichia lineage but frequently classified as a separate genus. Shigella genomes contain numerous insertion sequences (ISs) that lead to pseudogenisation of affected genes and an increase of non-homologous recombination. Here, we study 414 genomes of E. coli and Shigella strains to assess the contribution of genomic rearrangements to Shigella evolution. We found that Shigella experienced exceptionally high rates of intragenomic rearrangements and had a decreased rate of homologous recombination compared to pathogenic and non-pathogenic E. coli. The high rearrangement rate resulted in independent disruption of syntenic regions and parallel rearrangements in different Shigella lineages. Specifically, we identified two types of chromosomally encoded E3 ubiquitin-protein ligases acquired independently by all Shigella strains that also showed a high level of sequence conservation in the promoter and further in the 5′-intergenic region. In the only available enteroinvasive E. coli (EIEC) strain, which is a pathogenic E. coli with a phenotype intermediate between Shigella and non-pathogenic E. coli, we found a rate of genome rearrangements comparable to those in other E. coli and no functional copies of the two Shigella-specific E3 ubiquitin ligases. These data indicate that the accumulation of ISs influenced many aspects of genome evolution and played an important role in the evolution of intracellular pathogens. Our research demonstrates the power of comparative genomics-based on synteny block composition and an important role of non-coding regions in the evolution of genomic islands

The where and wherefore of evolutionary breakpoints

The 'action' in genome-level evolution lies not in the large gene-containing segments that are conserved among related species, but in the breakpoint regions between these segments. Two recent papers in BMC Genomics detail the pattern of repetitive elements associated with breakpoints and the epigenetic conditions under which breakage occurs