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.     

Comparative mapping between potato (Solanum tuberosum) and Arabidopsis thaliana reveals structurally conserved domains and ancient duplications in the potato genome

A genetic map of potato (Solanum tuberosum) was constructed based on 293 restriction fragment length polymorphism (RFLP) markers including 31 EST markers of Arabidopsis. The in silico comparison of all marker sequences with the Arabidopsis genomic sequence resulted in 189 markers that detected in Arabidopsis 787 loci with sequence conservation. Based on conserved linkage between groups of at least three different markers on the genetic map of potato and the physical map of Arabidopsis, 90 putative syntenic blocks were identified covering 41% of the potato genetic map and 50% of the Arabidopsis physical map. The existence and distribution of syntenic blocks suggested a higher degree of structural conservation in some parts of the potato genome when compared to others. Syntenic blocks were redundant: most potato syntenic blocks were related to several Arabidopsis genome segments and vice versa. Some duplicated potato syntenic blocks correlated well with ancient segmental duplications in Arabidopsis. Syntenic relationships between different genomic segments of potato and the same segment of the Arabidopsis genome indicated that potato genome evolution included ancient intra- and interchromosomal duplications. The partial genome coveridge and the redundancy of syntenic blocks limits the use of synteny for functional comparisons between the crop species potato and the model plant Arabidopsis.     

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.     

Molecular characterisation of the pericentric inversion that distinguishes human chromosome 5 from the homologous chimpanzee chromosome

Human and chimpanzee karyotypes differ by virtue of nine pericentric inversions that serve to distinguish human chromosomes 1, 4, 5, 9, 12, 15, 16, 17, and 18 from their chimpanzee orthologues. In this study, we have analysed the breakpoints of the pericentric inversion characteristic of chimpanzee chromosome 4, the homologue of human chromosome 5. Breakpoint-spanning BAC clones were identified from both the human and chimpanzee genomes by fluorescence in situ hybridisation, and the precise locations of the breakpoints were determined by sequence comparisons. In stark contrast to some other characterised evolutionary rearrangements in primates, this chimpanzee-specific inversion appears not to have been mediated by either gross segmental duplications or low-copy repeats, although micro-duplications were found adjacent to the breakpoints. However, alternating purine–pyrimidine (RY) tracts were detected at the breakpoints, and such sequences are known to adopt non-B DNA conformations that are capable of triggering DNA breakage and genomic rearrangements. Comparison of the breakpoint region of human chromosome 5q15 with the orthologous regions of the chicken, mouse, and rat genomes, revealed similar but non-identical syntenic disruptions in all three species. The clustering of evolutionary breakpoints within this chromosomal region, together with the presence of multiple pathological breakpoints in the vicinity of both 5p15 and 5q15, is consistent with the non-random model of chromosomal evolution and suggests that these regions may well possess intrinsic features that have served to mediate a variety of genomic rearrangements, including the pericentric inversion in chimpanzee chromosome 4.     

Localization of the calcium release channel gene in cattle and horse by in situ hybridization: evidence of a conserved synteny with glucose phosphate isomerase

In situ hybridization techniques were used to localize regionally the calcium release channel (CRC) gene on cattle and horse chromosomes, using a porcine CRC cDNA probe. In cattle, the hybridization signal peaked on the 18q23-q26 bands and in horse on the 10pter region. Previous studies have shown that the glucose phosphate isomerase (GPI) gene localizes at the same site in both species, indicating that the two loci are syntenic. As CRC and GPI are syntenic in human, pig and mouse, the present results in cattle and horse represent another example of synteny conservation in the evolution of mammalian chromosomes.     

The gene map of the Norway rat (Rattus norvegicus) and comparative mapping with mouse and man

The current status of the rat gene map is presented. Mapping information is now available for a total of 214 loci and the number of mapped genes is increasing steadily. The corresponding number of loci quoted at HGM10 was 128. Genes have been assigned to 20 of the 22 chromosomes in the rat. Some aspects of comparative mapping with mouse and man are also discussed. It was found that there is a good correlation between the morphological homologies detectable in rat and mouse chromosomes, on the one hand, and homology at the gene level on the other. For 10 rat synteny groups all the genes so far mapped are syntenic also in the mouse. For the remaining rat synteny groups it appears that the majority of the genes will be syntenic on specific (homologous) mouse chromosomes, with only a few genes dispersed to other members of the mouse karyotype. Furthermore, the data indicate that mouse chromosome 1 genetically corresponds to two rat chromosomes, viz., 9 and 13, equalizing the difference in chromosome number between the two species. Further mappings will show whether the genetic homology will prove to be as extensive as these preliminary results indicate. As might be expected from evolutionary considerations, rat synteny groups are much more dispersed in the human genome. It is clear, however, that many groups of genes have remained syntenic during the period since man and rat shared a common ancestor. One further point was noted. In two cases groups of genes were syntenic in the mouse but dispersed to two chromosomes in rat and man, whereas in a third case a group of genes was syntenic in the rat but dispersed to two chromosomes in mouse and man. This finding argues in favor of the notion that the original gene groups were on separate ancestral chromosomes, which have fused in one rodent species but remained separate in the other and in man.     

The loci for parathyroid hormone and beta-globin are closely linked and map to chromosome 15 in cattle

We report linkage of the loci for beta-globin (HBB) and parathyroid hormone (PTH) in cattle and the assignment of both loci to the bovine chromosome region 15q13-q23. Linkage was analyzed in a family of paternal half-sibs by the use of restriction fragment length polymorphisms detected with bovine probes derived from the HBB and PTH genes. The HBB polymorphism was detected by digestion with restriction endonuclease HindIII and the PTH polymorphism with MspI. The maximum lod score for linkage of PTH with HBB was zeta = 4.52 at theta = 0, suggesting very close linkage of the two loci. The finding of the PTH/HBB linkage is corroborated by the physical assignment of both loci to the region 15q13-q23 by in situ hybridization with bovine genomic probes derived from PTH and HBB, respectively. Since HBB and PTH are syntenic in man and mouse, these results in cattle represent another example of conservation of synteny in the evolution of mammalian chromosomes.     

A centromere-specific retroviral element associated with breaks of synteny in macropodine marsupials

Studies of chromosome evolution have focused heavily on the evolution of conserved syntenic, gene-rich domains. It is obvious, however, that the centromere plays an equally important role in chromosome evolution, through its involvement in fissions, centric fusions, translocations, inversions and centric shifts. It is unclear how the centromere, either as a functioning unit of the chromosome or as a DNA sequence motif, has been involved in these processes. Marsupials of the family Macropodidae (kangaroos, wallabies, rat kangaroos and potoroos) offer unique insights into current theories expositing centromere emergence during karyotypic diversification and speciation. Tracing the genomic distribution of centromeric sequences in a model macropodine (subfamily Macropodinae: kangaroos and wallabies) species, Macropus eugenii (tammar wallaby), indicates these sequences have played an important role in chromosome evolution through possible segmental duplications associated with phylogenetically conserved breaks of synteny, pericentromeric and subtelomeric regions. Hybrids between different kangaroo species provide evidence that the centromere is unstable within this group of mammals and is involved in a large number of chromosome aberrations. A better understanding of the genetic and epigenetic factors that define centromeres and how centromeres may mediate changes in chromosome architecture are critical not only to our understanding of basic cellular functioning but also to our understanding of the process of speciation.     

Mouse ferritin H sequences map to chromosomes 3, 6, and 19

Human and rodent genomes contain multiple copies of ferritin H and L subunit sequences, although it is not yet clear whether there is more than one expressed gene for either of these subunits. We have isolated a cDNA corresponding to mouse ferritin H subunit and observed that the mouse genome contains three to four H-related sequences. This cDNA was used to establish the genomic location of mouse ferritin H subunit genes by chromosomal in situ hybridization. Metaphase chromosomes of concanavalin A-stimulated lymphocytes from a WMP male mouse were examined by in situ hybridization with 3H-labeled cDNA and the chromosomes were identified by R banding (fluorochrome-photolysis-Giemsa method). The results indicate that mouse ferritin H-related sequences map at chromosomes 3, 6, and 19. Homology of synteny between human and mouse suggests that the sequence on mouse chromosome 19 corresponds to the structural H gene.     

Alignment of whole genomes.

A new system for aligning whole genome sequences is described. Using an efficient data structure called a suffix tree, the system is able to rapidly align sequences containing millions of nucleotides. Its use is demonstrated on two strains of Mycoplasma tuberculosis, on two less similar species of Mycoplasma bacteria and on two syntenic sequences from human chromosome 12 and mouse chromosome 6. In each case it found an alignment of the input sequences, using between 30 s and 2 min of computation time. From the system output, information on single nucleotide changes, translocations and homologous genes can easily be extracted. Use of the algorithm should facilitate analysis of syntenic chromosomal regions, strain-to-strain comparisons, evolutionary comparisons and genomic duplications.     

Integrating cytogenetics and genomics in comparative evolutionary studies of cichlid fish

ABSTRACT: BACKGROUND: The availability of a large number of recently sequenced vertebrate genomes opens new avenues to integrate cytogenetics and genomics in comparative and evolutionary studies. Cytogenetic mapping can offer alternative means to identify conserved synteny shared by distinct genomes and also to define genome regions that are still not fine characterized even after wide-ranging nucleotide sequence efforts. An efficient way to perform comparative cytogenetic mapping is based on BAC clones mapping by fluorescence in situ hybridization. In this report, to address the knowledge gap on the genome evolution in cichlid fishes, BAC clones of an Oreochromis niloticus library covering the linkage groups (LG) 1, 3, 5, and 7 were mapped onto the chromosomes of 9 African cichlid species. The cytogenetic mapping data were also integrated with BAC-end sequences information of O. niloticus and comparatively analyzed against the genome of other fish species and vertebrates. RESULTS: The location of BACs from LG1, 3, 5, and 7 revealed a strong chromosomal conservation among the analyzed cichlid species genomes, which evidenced a synteny of the markers of each LG. Comparative in silico analysis also identified large genomic blocks that were conserved in distantly related fish groups and also in other vertebrates. CONCLUSIONS: Although it has been suggested that fishes contain plastic genomes with high rates of chromosomal rearrangements and probably low rates of synteny conservation, our results evidence that large syntenic chromosome segments have been maintained conserved during evolution, at least for the considered markers. Additionally, our current cytogenetic mapping efforts integrated with genomic approaches conduct to a new perspective to address important questions involving chromosome evolution in fishes.     

Conserved synteny between the Ciona genome and human paralogons identifies large duplication events in the molecular evolution of the insulin-relaxin gene family

The aims of the study were to outline the sequence of eventsthat gave rise to the vertebrate insulin-relaxin gene familyand the chromosomal regions in which they reside. We analyzedthe gene content surrounding the human insulin/relaxin geneswith respect to what family they belonged to and if the duplicationhistory of investigated families parallels the evolution ofthe insulin-relaxin family members. Markov Clustering and phylogeneticanalysis were used to determine family identity. More than 15%of the genes belonged to families that have paralogs in theregions, defining two sets of quadruplicate paralogy regions.Thereby, the localization of insulin/relaxin genes in humansis in accordance with those regions on human chromosomes 1,11, 12, 19q (insulin/insulin-like growth factors) and 1, 6p/15q,9/5, 19p (insulin-like factors/relaxins) were formed duringtwo genome duplications. We compared the human genome with thatof Ciona intestinalis, a species that split from the vertebratelineage before the two suggested genome duplications. Two insulin-likeorthologs were discovered in addition to the already describedCi-insulin gene. Conserved synteny between the Ciona regionshosting the insulin-like genes and the two sets of human paralogonsimplies their common origin. Linkage of the two human paralogons,as seen in human chromosome 1, as well as the two regions hostingthe Ciona insulin-like genes suggests that a segmental duplicationgave rise to the region prior to the genome doublings. Thus,preserved gene content provides support that genome duplication(s)in addition to segmental and single-gene duplications shapedthe genomes of extant vertebrates.     

Genomic organization and expression profile of the human and mouse <Emphasis Type="Italic">WAVE</Emphasis> gene family

The WAVE gene family, which contains three members, has been shown to play a major role in the actin polymerization and cytoskeleton organization processes. We have identified the WAVE3 gene from Chromosome (Chr) 13q12, as being involved in one of the breakpoints of a t(1:13)(q21:q12) reciprocal translocation, in a patient with ganglioneuroblastoma (Sossey-Alaoui et al. 2002; Oncogene 21: 5967–5974). We have also reported the cloning of the mouse Wave3. During our analysis of the human gene map, we also noted that WAVE2 maps to Chr region lp35-36, which frequently undergoes loss of heterozygosity and deletion in advanced stage neuroblastoma. These data clearly indicate a possible involvement of the WAVE genes in the pathogenesis of neuroblastoma. In this study, we report the complete genomic organization and expression profile of the three human WAVE genes and their mouse orthologs. We show that the WAVE genes have distinctive expression patterns in both adult and fetal human and mouse tissues. We also show a high level of conservation between these genes, in both the nucleotide and protein sequences. We finally show that the genomic structure is highly conserved among these genes and that the mouse Wave genes map to chromosome regions that have synteny in the human genome. The gene content in these syntenic regions is also conserved, suggesting that the WAVE genes are derived from a common ancient ancestor by genome duplication. The genomic characterization and expression analysis of the WAVE genes provide the basis towards understanding the function of these genes. It also provides the first steps towards the development of mouse models for the role of the WAVE genes in actin and cytoskeleton organization in general, and in the development of neuroblastoma in particular.     

Detailed four-way comparative mapping and gene order analysis of the canine ctvm locus reveals evolutionary chromosome rearrangements

Canine tricuspid valve malformation (CTVM) maps to canine chromosome 9 (CFA9), in a region syntenic with gene-dense human chromosome 17q. To define synteny blocks, we analyzed 148 markers on CFA9 using radiation hybrid mapping and established a four-way comparative map for human, mouse, rat, and dog. We identified a large number of rearrangements, allowing us to reconstruct the evolutionary history of individual synteny blocks and large chromosomal segments. A most parsimonious rearrangement scenario for all four species reveals that human chromosome 17q differs from CFA9 and the syntenic rodent chromosomes through two macroreversals of 9.2 and 23 Mb. Compared to a recovered ancestral gene order, CFA9 has undergone 11 reversals of <3 Mb and 2 reversals of >3 Mb. Interspecies reuse of breakpoints for micro- and macrorearrangements was observed. Gene order and content of the ctvm interval are best extrapolated from murine data, showing that multispecies genome rearrangement scenarios contribute to identifying gene content in canine mapping studies.     

Two patterns of genome organization in mammals: the chromosomal distribution of duplicate genes in human and mouse

Gene duplication occurs repeatedly in the evolution of genomes, and the rearrangement of genomic segments has also occurred repeatedly over the evolution of eukaryotes. We studied the interaction of these two factors in mammalian evolution by comparing the chromosomal distribution of multigene families in human and mouse. In both species, gene families tended to be confined to a single chromosome to a greater extent than expected by chance. The average number of families shared between chromosomes was nearly 60% higher in mouse than in human, and human chromosomes rarely shared large numbers of gene families with more than one or two other chromosomes, whereas mouse chromosomes frequently did so. A higher proportion of duplicate gene pairs on the same chromosome originated from recent duplications in human than in mouse, whereas a higher proportion of duplicate gene pairs on separate chromosomes arose from ancient duplications in human than in mouse. These observations are most easily explained by the hypotheses that (1) most gene duplications arise in tandem and are subsequently separated by segmental rearrangement events, and (2) that the process of segmental rearrangement has occurred at a higher rate in the lineage of mouse than in that of human.     

落叶松-杨栅锈菌基因复制事件及共线性分析

落叶松-杨栅锈菌是一种分布广且危害严重的林木病原真菌.了解基因组内发生的基因复制事件及基因组间的共线性关系,能为最终理解落叶松-杨栅锈菌适应性进化等生物学问题提供帮助.落叶松-杨栅锈菌全基因组水平上基因复制相关研究未见报道,共线性研究报道也较少.本研究利用落叶松-杨栅锈菌全基因组序列分析其基因复制模式.结果表明,落叶松...     

Non-random distribution of Alu-family repeats in human chromosomes

A phage lambda recombinant clone containing at least 8 Alu-family repeats (AFRs) has been isolated from a human genomic library, and DNA from the phage was used as a probe for in situ hybridization on G-banded human metaphase chromosomes of healthy donors and leukemic patients. Some chromosome bands show prominent clusters of silver grains in all individuals examined: 1p34, 1q23, 2q21–22, 10p14, 11p14, 10q21 and 11q14. The data suggest non-random distribution of AFRs in the human genome.     

Genomic arrangement of salinity tolerance QTLs in salmonids: A comparative analysis of Atlantic salmon (Salmo salar) with Arctic charr (Salvelinus alpinus) and rainbow trout (

ABSTRACT: BACKGROUND: Quantitative trait locus (QTL) studies show that variation in salinity tolerance in Arctic charr and rainbow trout has a genetic basis, even though both these species have low to moderate salinity tolerance capacities. QTL were observed to localize to homologous linkage group segments within putative chromosomal regions possessing multiple candidate genes. We compared salinity tolerance QTL in rainbow trout and Arctic charr to those detected in a higher salinity tolerant species, Atlantic salmon. The highly derived karyotype of Atlantic salmon allows for the assessment of whether disparity in salinity tolerance in salmonids is associated with differences in genetic architecture. To facilitate these comparisons, we examined the genomic synteny patterns of key candidate genes in the other model teleost fishes that have experienced three whole-genome duplication (3R) events which preceded a fourth (4R) whole genome duplication event common to all salmonid species. RESULTS: Nine linkage groups contained chromosome-wide significant QTL (AS-2, -4p, -4q, -5, -9, -12p, -12q, -14q -17q, -22, and [MINUS SIGN]23), while a single genome-wide significant QTL was located on AS-4q. Salmonid genomes shared the greatest marker homology with the genome of three-spined stickleback. All linkage group arms in Atlantic salmon were syntenic with at least one stickleback chromosome, while 18 arms had multiple affinities. Arm fusions in Atlantic salmon were often between multiple regions bearing salinity tolerance QTL. Nine linkage groups in Arctic charr and six linkage group arms in rainbow trout currently have no synteny alignments with stickleback chromosomes, while eight rainbow trout linkage group arms were syntenic with multiple stickleback chromosomes. Rearrangements in the stickleback lineage involving fusions of ancestral arm segments could account for the 21 chromosome pairs observed in the stickleback karyotype. CONCLUSIONS: Salinity tolerance in salmonids from three genera is to some extent controlled by the same loci. Synteny between QTL in salmonids and candidate genes in stickleback suggests genetic variation at candidate gene loci could affect salinity tolerance in all three salmonids investigated. Candidate genes often occur in pairs on chromosomes, and synteny patterns indicate these pairs are generally conserved in 2R, 3R, and 4R genomes. Synteny maps also suggest that the Atlantic salmon genome contains three larger syntenic combinations of candidate genes that are not evident in any of the other 2R, 3R, or 4R genomes examined. These larger synteny tracts appear to have resulted from ancestral arm fusions that occurred in the Atlantic salmon ancestor. We hypothesize that the superior hypo-osmoregulatory efficiency that is characteristic of Atlantic salmon may be related to these clusters.     

Isolation and differential expression of two isoforms of the ROBO2/Robo2 axon guidance receptor gene in humans and mice

Expression of Robo receptor molecules is important for axon guidance across the midline of the mammalian central nervous system. Here we describe novel isoform a of human ROBO2, which is initially strongly expressed in the fetal human brain but thereafter only weakly expressed in adult brain and a few other tissues. The known isoform b of ROBO2 shows a more or less ubiquitous expression pattern, suggesting diverse functional roles. The genomic structure and distinct expression patterns of Robo2a and Robo2b have been conserved in the mouse, but in contrast to human ROBO2a mouse Robo2a is also abundant in adult brain. Exons 1 and 2 of human ROBO2a lie in an inherently unstable DNA segment at human chromosome 3p12.3 that is associated with segmental duplications, independent chromosome rearrangements during primate evolution, and homozygous deletion and loss of heterozygosity in various human cancers. The 5' end of mouse Robo2a lies in a <150-kb DNA segment of break in synteny between mouse chromosome 16C3.1 and the human genome.