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1.
EMBO J ; 30(1): 43-56, 2011 Jan 05.
Article in English | MEDLINE | ID: mdl-21102556

ABSTRACT

The evolutionarily conserved Notch signal transduction pathway regulates fundamental cellular processes during embryonic development and in the adult. Ligand binding induces presenilin-dependent cleavage of the receptor and a subsequent nuclear translocation of the Notch intracellular domain (NICD). In the nucleus, NICD binds to the recombination signal sequence-binding protein J (RBP-J)/CBF-1 transcription factor to induce expression of Notch target genes. Here, we report the identification and functional characterization of RBP-J interacting and tubulin associated (RITA) (C12ORF52) as a novel RBP-J/CBF-1-interacting protein. RITA is a highly conserved 36 kDa protein that, most interestingly, binds to tubulin in the cytoplasm and shuttles rapidly between cytoplasm and nucleus. This shuttling RITA exports RBP-J/CBF-1 from the nucleus. Functionally, we show that RITA can reverse a Notch-induced loss of primary neurogenesis in Xenopus laevis. Furthermore, RITA is able to downregulate Notch-mediated transcription. Thus, we propose that RITA acts as a negative modulator of the Notch signalling pathway, controlling the level of nuclear RBP-J/CBF-1, where its amounts are limiting.


Subject(s)
Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism , Microtubule-Associated Proteins/metabolism , Receptors, Notch/metabolism , Xenopus Proteins/metabolism , Xenopus laevis/metabolism , Active Transport, Cell Nucleus , Animals , Centrosome/ultrastructure , Cytoplasm/metabolism , Cytoplasm/ultrastructure , Gene Expression , HeLa Cells , Humans , Immunoglobulin J Recombination Signal Sequence-Binding Protein/genetics , Microtubule-Associated Proteins/analysis , Microtubule-Associated Proteins/genetics , Neurogenesis , Protein Binding , Protein Transport , Receptor, Notch1/genetics , Receptor, Notch1/metabolism , Receptors, Notch/genetics , Transcription, Genetic , Tubulin/metabolism , Xenopus Proteins/analysis , Xenopus Proteins/genetics , Xenopus laevis/genetics
2.
Chromosome Res ; 17(6): 811-20, 2009.
Article in English | MEDLINE | ID: mdl-19731051

ABSTRACT

Previous studies have revealed an enrichment of reproduction- and brain-related genes on the human X chromosome. In the present study, we investigated the evolutionary history that underlies this functional specialization. To do so, we analyzed the orthologous building blocks of the mammalian X chromosome in the chicken genome. We used Affymetrix chicken genome microarrays to determine tissue-selective gene expression in several tissues of the chicken, including testis and brain. Subsequently, chromosomal distribution of genes with tissue-selective expression was determined. These analyzes provided several new findings. Firstly, they showed that chicken chromosomes orthologous to the mammalian X chromosome exhibited an increased concentration of genes expressed selectively in brain. More specifically, the highest concentration of brain-selectively expressed genes was found on chicken chromosome GGA12, which shows orthology to the X chromosomal regions with the highest enrichment of non-syndromic X-linked mental retardation (MRX) genes. Secondly, and in contrast to the first finding, no enrichment of testis-selective genes could be detected on these chicken chromosomes. These findings indicate that the accumulation of brain-related genes on the prospective mammalian X chromosome antedates the divergence of sauropsid and synapsid lineages 315 million years ago, whereas the accumulation of testis-related genes on the mammalian X chromosome is more recent and due to adaptational changes.


Subject(s)
Brain/metabolism , Chickens/genetics , Evolution, Molecular , Genes/physiology , Testis/metabolism , X Chromosome/genetics , Animals , Chromosome Mapping , Gene Expression Profiling , Male , Oligonucleotide Array Sequence Analysis , Organ Specificity , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction
3.
BMC Evol Biol ; 9: 84, 2009 Apr 24.
Article in English | MEDLINE | ID: mdl-19393055

ABSTRACT

BACKGROUND: 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. RESULTS: 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. CONCLUSION: 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.


Subject(s)
Chromosome Breakage , Chromosomes/genetics , Evolution, Molecular , Mammals/genetics , Synteny/genetics , Vertebrates/genetics , Animals , Humans , Phylogeny
4.
J Mol Diagn ; 11(2): 131-9, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19196998

ABSTRACT

In monogenic disorders, the functional evaluation of rare, unclassified variants helps to assess their pathogenic relevance and can improve differential diagnosis and predictive testing. We characterized six rare APC variants in patients with familial adenomatous polyposis at the mRNA level. APC variants c.531 + 5G>C and c.532-8G>A in intron 4, c.1409-2_1409delAGG in intron 10, c.1548G>A in exon 11, and a large duplication of exons 10 and 11 result in a premature stop codon attributable to aberrant transcripts whereas the variant c.1742A>G leads to the in-frame deletion of exon 13 and results in the removal of a functional motif. Mutation c.1548G>A was detected in the index patient but not in his affected father, suggesting mutational mosaicism. A literature review shows that most of the rare APC variants detected by routine diagnostics and further analyzed at the transcript level were evaluated as pathogenic. The majority of rare APC variants, particularly those located close to exon-intron boundaries, could be classified as pathogenic because of aberrant splicing. Our study shows that the characterization of rare variants at the mRNA level is crucial for the evaluation of pathogenicity and underlying mutational mechanisms, and could lead to better treatment modalities.


Subject(s)
Adenomatous Polyposis Coli/diagnosis , Adenomatous Polyposis Coli/genetics , Genes, APC , Mutation , RNA, Messenger/analysis , DNA Mutational Analysis , Humans , RNA, Messenger/genetics
5.
Comp Funct Genomics ; : 43070, 2007.
Article in English | MEDLINE | ID: mdl-17538687

ABSTRACT

It has been suggested that there are special evolutionary forces that act on sex chromosomes. Hemizygosity of the X chromosome in male mammals has led to selection for male-advantage genes, and against genes posing extreme risks of tumor development. A similar bias against cancer genes should also apply to the Z chromosome that is present as a single copy in female birds. Using comparative database analysis, we found that there was no significant underrepresentation of cancer genes on the chicken Z, nor on the Z-orthologous regions of human chromosomes 5 and 9. This result does not support the hypothesis that genes involved in cancer are selected against on the sex chromosomes.

6.
PLoS Genet ; 2(10): e182, 2006 Oct.
Article in English | MEDLINE | ID: mdl-17069464

ABSTRACT

Genomic imprinting, representing parent-specific expression of alleles at a locus, raises many questions about how--and especially why--epigenetic silencing of mammalian genes evolved. We present the first in-depth study of how a human imprinted domain evolved, analyzing a domain containing several imprinted genes that are involved in human disease. Using comparisons of orthologous genes in humans, marsupials, and the platypus, we discovered that the Prader-Willi/Angelman syndrome region on human Chromosome 15q was assembled only recently (105-180 million years ago). This imprinted domain arose after a region bearing UBE3A (Angelman syndrome) fused with an unlinked region bearing SNRPN (Prader-Willi syndrome), which had duplicated from the non-imprinted SNRPB/B'. This region independently acquired several retroposed gene copies and arrays of small nucleolar RNAs from different parts of the genome. In their original configurations, SNRPN and UBE3A are expressed from both alleles, implying that acquisition of imprinting occurred after their rearrangement and required the evolution of a control locus. Thus, the evolution of imprinting in viviparous mammals is ongoing.


Subject(s)
Genomic Imprinting/genetics , Marsupialia/genetics , Platypus/genetics , Alleles , Animals , Autoantigens/genetics , Chromosome Mapping , Chromosomes, Mammalian/genetics , Genome, Human/genetics , Humans , In Situ Hybridization, Fluorescence , Mice , Ribonucleoproteins, Small Nuclear/genetics , Sequence Analysis, DNA , Sequence Homology , Ubiquitin-Protein Ligases/genetics , snRNP Core Proteins
7.
Hum Genet ; 120(2): 270-84, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16838144

ABSTRACT

The structural diversity of the human genome is much higher than previously assumed although its full extent remains unknown. To investigate the association between segmental duplications that display constitutive copy number differences (CNDs) between humans and the great apes and those which exhibit polymorphic copy number variations (CNVs) between humans, we analysed a BAC array enriched with segmental duplications displaying such CNDs. This study documents for the first time that in addition to human-specific gains common to all humans, these duplication clusters (DCs) also exhibit polymorphic CNVs > 40 kb. Segmental duplication is known to have been a frequent event during human genome evolution. Importantly, among the CNV-associated genes identified here, those involved in transcriptional regulation were found to be significantly overrepresented. Complex patterns of variation were evident at sites of DCs, manifesting as inter-individual differentially sized copy number alterations at the same genomic loci. Thus, CNVs associated with segmental duplications do not simply represent insertion/deletion polymorphisms, but rather constitute a wide variety of rearrangements involving differential amplification and partial gains and losses with high inter-individual variability. Although the number of CNVs was not found to differ between Africans and Caucasians/Asians, the average number of variant patterns per locus was significantly lower in Africans. Thus, complex variation patterns characterizing segmental duplications result from relatively recent genomic rearrangements. The high number of these rearrangements, some of which are potentially recurrent, together with differences in population size and expansion dynamics, may account for the greater diversity of CNV in Caucasians/Asians as compared with Africans.


Subject(s)
Gene Dosage , Genome, Human , Animals , Asian People/genetics , Black People/genetics , Chromosomes, Artificial, Bacterial , Evolution, Molecular , Genome , Humans , Pan troglodytes/genetics , White People/genetics
8.
Hum Genet ; 120(1): 126-38, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16775709

ABSTRACT

The human and chimpanzee genomes are distinguishable in terms of ten gross karyotypic differences including nine pericentric inversions and a chromosomal fusion. Seven of these large pericentric inversions are chimpanzee-specific whereas two of them, involving human chromosomes 1 and 18, were fixed in the human lineage after the divergence of humans and chimpanzees. We have performed detailed molecular and computational characterization of the breakpoint regions of the human-specific inversion of chromosome 1. FISH analysis and sequence comparisons together revealed that the pericentromeric region of HSA 1 contains numerous segmental duplications that display a high degree of sequence similarity between both chromosomal arms. Detailed analysis of these regions has allowed us to refine the p-arm breakpoint region to a 154.2 kb interval at 1p11.2 and the q-arm breakpoint region to a 562.6 kb interval at 1q21.1. Both breakpoint regions contain human-specific segmental duplications arranged in inverted orientation. We therefore propose that the pericentric inversion of HSA 1 was mediated by intra-chromosomal non-homologous recombination between these highly homologous segmental duplications that had themselves arisen only recently in the human lineage by duplicative transposition.


Subject(s)
Chromosome Inversion , Chromosomes, Human, Pair 1/genetics , Pan troglodytes/genetics , Synteny , Animals , Cell Line , Cell Lineage/genetics , Centromere/genetics , Chromosome Breakage , Evolution, Molecular , Humans , In Situ Hybridization, Fluorescence/methods , Karyotyping
9.
Trends Genet ; 22(4): 203-10, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16517001

ABSTRACT

From recent work the putative eutherian karyotype from 100 Mya has been derived. Here, we have applied a new in silico technique, electronic chromosome painting (E-painting), on a large data set of genes whose positions are known in human, chicken, zebrafish and pufferfish. E-painting identifies conserved syntenies in the data set, and it enables a stepwise reconstruction of the ancestral vertebrate protokaryotype comprising 11 protochromosomes. During karyotype evolution in land vertebrates interchromosomal rearrangements by translocation are relatively frequent, whereas the karyotypes of birds and fish are much more conserved. Although the human karyotype is one of the most conserved in eutherians, it can no longer be considered highly conserved from a vertebrate-wide perspective.


Subject(s)
Biological Evolution , Vertebrates/genetics , Animals , Chickens/genetics , Chromosome Painting/methods , Fishes/genetics , Humans , Karyotyping/methods , Phylogeny , Tetraodontiformes/genetics , Time Factors , Zebrafish/genetics
10.
Hum Genet ; 119(1-2): 185-98, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16395594

ABSTRACT

Copy number differences (CNDs), and the concomitant differences in gene number, have contributed significantly to the genomic divergence between humans and other primates. To assess its relative importance, the genomes of human, common chimpanzee, bonobo, gorilla, orangutan and macaque were compared by comparative genomic hybridization using a high-resolution human BAC array (aCGH). In an attempt to avoid potential interference from frequent intra-species polymorphism, pooled DNA samples were used from each species. A total of 322 sites of large-scale inter-species CND were identified. Most CNDs were lineage-specific but frequencies differed considerably between the lineages; the highest CND frequency among hominoids was observed in gorilla. The conserved nature of the orangutan genome has already been noted by karyotypic studies and our findings suggest that this degree of conservation may extend to the sub-microscopic level. Of the 322 CND sites identified, 14 human lineage-specific gains were observed. Most of these human-specific copy number gains span regions previously identified as segmental duplications (SDs) and our study demonstrates that SDs are major sites of CND between the genomes of humans and other primates. Four of the human-specific CNDs detected by aCGH map close to the breakpoints of human-specific karyotypic changes [e.g., the human-specific inversion of chromosome 1 and the polymorphic inversion inv(2)(p11.2q13)], suggesting that human-specific duplications may have predisposed to chromosomal rearrangement. The association of human-specific copy number gains with chromosomal breakpoints emphasizes their potential importance in mediating karyotypic evolution as well as in promoting human genomic diversity.


Subject(s)
Gene Dosage , Genome, Human/genetics , Microarray Analysis/methods , Nucleic Acid Hybridization/methods , Animals , Chromosomes, Artificial, Bacterial/genetics , Gene Duplication , Gorilla gorilla/genetics , Humans , In Situ Hybridization, Fluorescence/methods , Macaca/genetics , Pan paniscus/genetics , Pan troglodytes/genetics , Pongo pygmaeus/genetics , Species Specificity
11.
Hum Genet ; 119(1-2): 103-12, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16362346

ABSTRACT

A combination of inter- and intra-species genome comparisons is required to identify and classify the full spectrum of genetic changes, both subtle and gross, that have accompanied the evolutionary divergence of humans and other primates. In this study, gene order comparisons of 11,518 human and chimpanzee orthologous gene pairs were performed to detect regions of inverted gene order that are potentially indicative of small-scale rearrangements such as inversions. By these means, a total of 71 potential micro-rearrangements were detected, nine of which were considered to represent micro-inversions encompassing more than three genes. These putative inversions were then investigated by FISH and/or PCR analyses and the authenticity of five of the nine inversions, ranging in size from approximately 800 kb to approximately 4.4 Mb, was confirmed. These inversions mapped to 1p13.2-13.3, 7p22.1, 7p13-14.1, 18p11.21-11.22 and 19q13.12 and encompass 50, 14, 16, 7 and 16 known genes, respectively. Intriguingly, four of the confirmed inversions turned out to be polymorphic: three were polymorphic in the chimpanzee and one in humans. It is concluded that micro-inversions make a significant contribution to genomic variability in both humans and chimpanzees and inversion polymorphisms may be more frequent than previously realized.


Subject(s)
Gene Rearrangement , Genetic Variation , Genome/genetics , Genomics/methods , Animals , Chromosome Inversion , Chromosome Mapping , Gene Order , Humans , In Situ Hybridization, Fluorescence , Pan troglodytes , Synteny
12.
Genomics ; 87(1): 39-45, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16321504

ABSTRACT

Seven of nine pericentric inversions that distinguish human (HSA) and chimpanzee karyotypes are chimpanzee-specific. In this study we investigated whether the two extant chimpanzee species, Pan troglodytes (common chimpanzee) and Pan paniscus (bonobo), share exactly the same pericentric inversions. The methods applied were FISH with breakpoint-spanning BAC/PAC clones and PCR analyses of the breakpoint junction sequences. Our findings for the homologues to HSA 4, 5, 9, 12, 16, and 17 confirm for the first time at the sequence level that these pericentric inversions have identical breakpoints in the common chimpanzee and the bonobo. Therefore, these inversions predate the separation of the two chimpanzee species 0.86-2 Mya. Further, the inversions distinguishing human and chimpanzee karyotypes may be regarded as early acquisitions, such that they are likely to have been present at the time of human/chimpanzee divergence. According to the chromosomal speciation theory the inversions themselves could have promoted human speciation.


Subject(s)
Chromosome Inversion/genetics , Chromosomes, Human/genetics , Pan paniscus/genetics , Pan troglodytes/genetics , Animals , Base Sequence , Cell Line, Tumor , Humans , In Situ Hybridization, Fluorescence/methods , Karyotyping/methods , Molecular Sequence Data , Species Specificity
13.
Chromosome Res ; 14(8): 899-907, 2006.
Article in English | MEDLINE | ID: mdl-17195924

ABSTRACT

By comparing high-coverage and high-quality whole genome sequence assemblies it is now possible to reconstruct putative ancestral progenitor karyotypes, here called protokaryotypes. For this study we used the recently described electronic chromosome painting technique (E-painting) to reconstruct the karyotype of the 85 million-year-old (MYA) ferungulate ancestor. This model is primarily based on dog (Canis familiaris) and cattle (Bos taurus) genome data and is highly consistent with comparative gene mapping and chromosome painting data. The protokaryotype bears 23 autosomal chromosome pairs and the sex chromosomes and preserves most of the chromosomal associations described previously for the boreo-eutherian protokaryotype. The model indicates that five interchromosomal rearrangements occurred during the transition from the boreo-eutherian to the ferungulate ancestor. From there on 66 further interchromosomal rearrangements took place in the lineage leading to cattle and 61 further interchromosomal rearrangements in the lineage to dog.


Subject(s)
Cattle/genetics , Computer Simulation , Dogs/genetics , Gene Rearrangement/genetics , Karyotyping/methods , Animals , Biological Evolution , Chromosome Painting/methods , Humans
14.
Genome Res ; 15(9): 1232-42, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16140991

ABSTRACT

Analyses of chromosomal rearrangements that have occurred during the evolution of the hominoids can reveal much about the mutational mechanisms underlying primate chromosome evolution. We characterized the breakpoints of the pericentric inversion of chimpanzee chromosome 18 (PTR XVI), which is homologous to human chromosome 16 (HSA 16). A conserved 23-kb inverted repeat composed of satellites, LINE and Alu elements was identified near the breakpoints and could have mediated the inversion by bringing the chromosomal arms into close proximity with each other, thereby facilitating intrachromosomal recombination. The exact positions of the breakpoints may then have been determined by local DNA sequence homologies between the inversion breakpoints, including a 22-base pair direct repeat. The similarly located pericentric inversion of gorilla (GGO) chromosome XVI, was studied by FISH and PCR analysis. The p- and q-arm breakpoints of the inversions in PTR XVI and GGO XVI were found to occur at slightly different locations, consistent with their independent origin. Further, FISH studies of the homologous chromosomal regions in macaque and orangutan revealed that the region represented by HSA BAC RP11-696P19, which spans the inversion breakpoint on HSA 16q11-12, was derived from the ancestral primate chromosome homologous to HSA 1. After the divergence of orangutan from the other great apes approximately 12 million years ago (Mya), a duplication of the corresponding region occurred followed by its interchromosomal transposition to the ancestral chromosome 16q. Thus, the most parsimonious interpretation is that the gorilla and chimpanzee homologs exhibit similar but nonidentical derived pericentric inversions, whereas HSA 16 represents the ancestral form among hominoids.


Subject(s)
Chromosome Inversion , Chromosomes, Human, Pair 16/genetics , Gorilla gorilla/genetics , Pan troglodytes/genetics , Recombination, Genetic , Animals , Base Sequence , Biological Evolution , Cell Line , Chromosome Breakage , Chromosomes, Artificial, Bacterial/genetics , DNA/genetics , Humans , In Situ Hybridization, Fluorescence , Models, Genetic , Molecular Sequence Data , Species Specificity
15.
Genomics ; 86(4): 439-45, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16081245

ABSTRACT

The mammalian genome is organized as a mosaic of isochores, stretches of DNA with a distinct sequence composition. Isochores form the basis of the chromosomal banding pattern, which is tightly correlated with a number of structural and functional features. We have recently demonstrated that the transition from a GC-poor isochore to a GC-rich one in the NF1 gene region occurs within 5 kb and demarcates genomic regions with high and low recombination frequency. We now report that the same transition zone separates early replicating from late replicating chromatin on the molecular level. At the isochore transition the replication fork is stalled in mid-S phase and can be visualized by fiber-FISH techniques as a Y-shaped structure. The switch in GC content and in replication timing is conserved between human and mouse, emphasizing the importance of the transition zones as landmarks of chromosome organization and function.


Subject(s)
Genes, Neurofibromatosis 1/physiology , Isochores/genetics , Animals , Base Composition , Cells, Cultured , DNA Replication , Fibroblasts/cytology , Genetic Variation , Genome, Human , Humans , In Situ Hybridization, Fluorescence , Lymphocytes/cytology , Mice , Recombination, Genetic/genetics
16.
Mamm Genome ; 16(4): 281-9, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15965789

ABSTRACT

The rodent Ellobius lutescens is an exceptional mammal which determines male sex constitutively without the SRY gene and, therefore, may serve as an animal model for human 46,XX female-to-male sex reversal. It was suggested that other factors of the network of sex-determining genes determine maleness in these animals. However, some sex-determining genes like SOX9 and SF1 have already been excluded by segregation analysis as primary sex-determining factors in E. lutescens. In this work, we have cloned and characterized two genes of the PIS (polled intersex syndrome) gene interval, which were reported as candidates in female-to-male sex reversal in hornless goats recently. The genes Foxl2 and Pisrt1 from that interval were identified in E. lutescens DNA and mapped to Chromosome 8. We have excluded linkage of Foxl2 and Pisrt1 loci with the sex of the animals. Hence, the involvement of this gene region in sex determination may be specific for goats and is not a general mechanism of XX sex reversal or XX male sex determination.


Subject(s)
Chromosomes, Mammalian/genetics , DNA-Binding Proteins/genetics , Rodentia/genetics , Sex Determination Processes , Transcription Factors/genetics , Amino Acid Sequence , Animals , Chromosome Mapping , Cloning, Molecular , Cluster Analysis , DNA Primers , Female , In Situ Hybridization, Fluorescence , Lod Score , Male , Molecular Sequence Data , Pedigree , Sequence Analysis, Protein
17.
Hum Genet ; 117(2-3): 168-76, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15883840

ABSTRACT

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.


Subject(s)
Chromosome Inversion , Chromosomes, Human, Pair 5/genetics , Evolution, Molecular , Pan troglodytes/genetics , Animals , Cell Line, Tumor , Humans , Karyotyping
18.
Genomics ; 85(5): 542-50, 2005 May.
Article in English | MEDLINE | ID: mdl-15820305

ABSTRACT

In addition to the fusion of human chromosome 2, nine pericentric inversions are the most conspicuous karyotype differences between humans and chimpanzees. In this study we identified the breakpoint regions of the pericentric inversion of chimpanzee chromosome 11 (PTR 11) homologous to human chromosome 9 (HSA 9). The break in homology between PTR 11p and HSA 9p12 maps to pericentromeric segmental duplications, whereas the breakpoint region orthologous to 9q21.33 is located in intergenic single-copy sequences. Close to the inversion breakpoint in PTR 11q, large blocks of alpha satellites are located, which indicate the presence of the centromere. Since G-banding analysis and the comparative BAC analyses performed in this study imply that the inversion breaks occurred in the region homologous to HSA 9q21.33 and 9p12, but not within the centromere, the structure of PTR 11 cannot be explained by a single pericentric inversion. In addition to this pericentric inversion of PTR 11, further events like centromere repositioning or a second smaller inversion must be assumed to explain the structure of PTR 11 compared with HSA 9.


Subject(s)
Chromosome Inversion/genetics , Chromosomes, Mammalian/genetics , Evolution, Molecular , Pan troglodytes/genetics , Animals , Base Sequence , Blotting, Southern , Chromosome Mapping , Chromosomes, Artificial, Bacterial , Computational Biology , Databases, Genetic , In Situ Hybridization, Fluorescence , Molecular Sequence Data , Sequence Analysis, DNA
19.
Hum Mutat ; 25(1): 45-55, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15580561

ABSTRACT

The study of breakpoints that occurred during primate evolution promises to yield valuable insights into the mechanisms underlying chromosome rearrangements in both evolution and pathology. Karyotypic differences between humans and chimpanzees include nine pericentric inversions, which may have potentiated the parapatric speciation of hominids and chimpanzees 5-6 million years ago. Detailed analysis of the respective chromosomal breakpoints is a prerequisite for any assessment of the genetic consequences of these inversions. The breakpoints of the inversion that distinguishes human chromosome 4 (HSA4) from its chimpanzee counterpart were identified by fluorescence in situ hybridization (FISH) and comparative sequence analysis. These breakpoints, at HSA4p14 and 4q21.3, do not disrupt the protein coding region of a gene, although they occur in regions with an abundance of LINE and LTR-elements. At 30 kb proximal to the breakpoint in 4q21.3, we identified an as yet unannotated gene, C4orf12, that lacks an homologous counterpart in rodents and is expressed at a 33-fold higher level in human fibroblasts as compared to chimpanzee. Seven out of 11 genes that mapped to the breakpoint regions have been previously analyzed using oligonucleotide-microarrays. One of these genes, WDFY3, exhibits a three-fold difference in expression between human and chimpanzee. To investigate whether the genomic architecture might have facilitated the inversion, comparative sequence analysis was used to identify an approximately 5-kb inverted repeat in the breakpoint regions. This inverted repeat is inexact and comprises six subrepeats with 78 to 98% complementarity. (TA)-rich repeats were also noted at the breakpoints. These findings imply that genomic architecture, and specifically high-copy repetitive elements, may have made a significant contribution to hominoid karyotype evolution, predisposing specific genomic regions to rearrangements.


Subject(s)
Chromosome Inversion , Chromosomes, Human, Pair 4 , Chromosomes , Pan troglodytes/genetics , Animals , Base Composition , Cell Line , Centromere , Chromosome Breakage , Chromosomes, Artificial, Bacterial , Evolution, Molecular , Gene Library , Humans , In Situ Hybridization, Fluorescence , Male , Polymerase Chain Reaction , Primates/genetics , Repetitive Sequences, Nucleic Acid , Sequence Alignment , Synteny
20.
Trends Genet ; 20(12): 598-603, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15522454

ABSTRACT

The eutherian X chromosome has one of the most conserved gene arrangements in mammals. Although earlier comparisons with distantly related mammalian groups pointed towards separate origins for the short and long arms, much deeper comparisons are now possible using draft sequences of the chicken genome, in combination with genome sequences from pufferfish and zebrafish. This enables surprising new insights into the origins of the mammalian X chromosome.


Subject(s)
Chromosomes, Human, X , Genome , Animals , Chickens/genetics , Chromosome Mapping , Evolution, Molecular , Humans , Mammals/genetics , Synteny , Tetraodontiformes/genetics , Zebrafish/genetics
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