Enrichment of segmental duplications in regions of breaks of synteny between the human and mouse genomes suggest their involvement in evolutionary rearrangements.

The sequence of the mouse genome allows one to compare the conservation of synteny between the human and mouse genome and exploration of regions that might have been involved in major rearrangements during the evolution of these two species (evolutionary genome rearrangements). Recent segmental duplications (or duplicons) are paralogous DNA sequences with high sequence identity that account for about 3.5-5% of the human genome and have emerged during the past approximately 35 million years of evolution. These regions are susceptible to illegitimate recombination leading to rearrangements that result in genomic disorders or genomic mutations. A catalogue of several hundred segmental duplications potentially leading to genomic rearrangements has been reported. The authors and others have observed that some chromosome regions involved in genomic disorders are shuffled in orientation and order in the mouse genome and that regions flanked by segmental duplications are often polymorphic. We have compared the human and mouse genome sequences and demonstrate here that recent segmental duplications correlate with breaks of synteny between these two species. We also observed that nine primary regions involved in human genomic disorders show changes in the order or the orientation of mouse/human synteny segments, were often flanked by segmental duplications in the human sequence. We found that 53% of all evolutionary rearrangement breakpoints associate with segmental duplications, as compared with 18% expected in a random location of breaks along the chromosome (P<0.0001). Our data suggest that segmental duplications have participated in the recent evolution of the human genome, as driving forces for evolutionary rearrangements, chromosome structure polymorphisms and genomic disorders.

Armengol L ，Pujana MA ，Cheung J ，Scherer SW ，Estivill X ... -  《HUMAN MOLECULAR GENETICS》

Segmental duplication density decrease with distance to human-mouse breaks of synteny.

Segmental duplications are large genomic segments of recent origin and nearly identical sequence. Segmental duplications account for up to 5% of the human genome and they are often involved in genomic rearrangements and human disease. We developed a rapid computational method to characterize segmental duplications in the mouse and the human genomes according to four sequence assemblies for each species. Segmental duplication content in the mouse genome assemblies has largely changed over the four releases (from 0.2 to 1.2%, 4.5 and 3.0%), while in the four human assemblies duplication content was 4.8, 3.5, 3.7 and 3.7%, respectively. This suggests that cataloguing and assembling duplications has been challenging in both genomes and any interpretation of comparative analyses of duplication content must keep this in perspective to avoid artifacts. Human and mouse segmental duplications are more frequent than expected in regions where there is a syntenic discontinuity and the duplication content in syntenic regions decreases significantly with distance from breakpoints of synteny. These observations indicate that in mouse and human the frequency of segmental duplications is strongly correlated with distance to human and mouse syntenic breaks or the most dynamic regions in evolution..

Sainz J ，Rovensky P ，Gudjonsson SA ，Thorleifsson G ，Stefansson K ，Gulcher JR ... -  《EUROPEAN JOURNAL OF HUMAN GENETICS》

Murine segmental duplications are hot spots for chromosome and gene evolution.

Mouse and rat genomic sequences permit us to obtain a global view of evolutionary rearrangements that have occurred between the two species and to define hallmarks that might underlie these events. We present a comparative study of the sequence assemblies of mouse and rat genomes and report an enrichment of rodent-specific segmental duplications in regions where synteny is not preserved. We show that segmental duplications present higher rates of molecular evolution and that genes in rearranged regions have evolved faster than those located elsewhere. Previous studies have shown that synteny breakpoints between the mouse and the human genomes are enriched in human segmental duplications, suggesting a causative connection between such structures and evolutionary rearrangements. Our work provides further evidence to support the role of segmental duplications in chromosomal rearrangements in the evolution of the architecture of mammalian chromosomes and in the speciation processes that separate the mouse and the rat.

Armengol L ，Marquès-Bonet T ，Cheung J ，Khaja R ，González JR ，Scherer SW ，Navarro A ，Estivill X ... -  《GENOMICS》

Analysis of segmental duplications, mouse genome synteny and recurrent cancer-associated amplicons in human chromosome 6p21-p12.

It has been proposed that regions of microhomology in the human genome could facilitate genomic rearrangements, copy number transitions, and rapid genomic change during tumor progression. To investigate this idea, this study examines the role of repetitive sequence elements, and corresponding syntenic mouse genomic features, in targeting cancer-associated genomic instability of specific regions of the human genome. Automated database-mining algorithms designed to search for frequent copy number transitions and genomic breakpoints were applied to 2 publicly-available online databases and revealed that 6p21-p12 is one of the regions of the human genome most frequently involved in tumor-specific alterations. In these analyses, 6p21-p12 exhibited the highest frequency of genomic amplification in osteosarcomas. Analysis of repetitive elements in regions of homology between human chromosome 6p and the syntenic regions of the mouse genome revealed a strong association between the location of segmental duplications greater than 5 kilobase-pairs and the position of discontinuities at the end of the syntenic region. The presence of clusters of segmental duplications flanking these syntenic regions also correlated with a high frequency of amplification and genomic alteration. Collectively, the experimental findings, in silico analyses, and comparative genomic studies presented here suggest that segmental duplications may facilitate cancer-associated copy number transitions and rearrangements at chromosome 6p21-p12. This process may involve homology-dependent DNA recombination and/or repair, which may also contribute towards the overall plasticity of the human genome.

Martin JW ，Yoshimoto M ，Ludkovski O ，Thorner PS ，Zielenska M ，Squire JA ，Nuin PA ... -  《-》

Evolutionarily plastic regions at human 3p21.3 coincide with tumor breakpoints identified by the "elimination test".

We have previously found with the microcell hybrid-based "elimination test" that human chromosome 3 transferred into murine or human tumor cells regularly lost certain 3p regions during tumor growth in SCID mice. The most common eliminated region, CER1, is approximately 2.4 Mb at 3p21.3. CER1 breakpoints were clustered in approximately 200-kb regions at both telomeric and centromeric borders. We have also shown, earlier, that tumor-related deletions often coincide with human/mouse synteny breakpoints on 3p12-p22. Here we describe the results of a comparative genomic analysis on the CER1 region in Caenorhabditis elegans, Drosophila melanogaster, Fugu rubripes, Gallus gallus, Mus musculus, Rattus norvegicus, and Canis familiaris. First, four independent synteny breaks were found within the CER1 telomeric breakpoint cluster region, comparing human, dog, and chicken genomes, and two independent synteny breaks within the CER1 centromeric breakpoint cluster region, comparing human, mouse, and chicken genomes, suggesting a nonrandom involvement of tumor breakpoint regions in chromosome evolution. Second, both CER1 breakpoint cluster regions show recent tandem duplications (seven Zn finger protein family genes at the telomeric and eight chemokine receptor genes at the centromeric side). Finally, all genes from these regions underwent horizontal evolution in mammals, with formation of new genes and expansion of gene families, which were displayed in the human genome as tandem gene duplications and pseudogene insertions. In contrast the CER1 middle region contained evolutionarily well-conserved solitary genes and a minimal amount of retroposed genes. The coincidence of evolutionary plasticity with CER1 breakpoints may suggest that regional structural instability is expressed in both evolutionary and cancer-associated chromosome rearrangements.

Darai E ，Kost-Alimova M ，Kiss H ，Kansoul H ，Klein G ，Imreh S ... -  《GENOMICS》