The Experts below are selected from a list of 34056 Experts worldwide ranked by ideXlab platform
Nadia Chuzhanova - One of the best experts on this subject based on the ideXlab platform.
-
RESEARCH ARTICLE Breakpoint Analysis of the Pericentric Inversion Distinguishing Human Chromosome 4 From the Homologous Chromosome in the Chimpanzee (Pan
2014Co-Authors: Hildegard Kehrer-sawatzki, Violaine Goidts, Nadia Chuzhanova, Catharina N S, Justyna M, Communicated Haig, H. KazazianAbstract: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 anB5-kb inverted repeat in the breakpoint regions. This inverted repeat is inexac
-
identification of recurrent type 2 nf1 microdeletions reveals a mitotic nonallelic homologous recombination hotspot underlying a human genomic disorder
Human Mutation, 2012Co-Authors: Julia Vogt, Nadia Chuzhanova, David Neil Cooper, Tanja Mussotter, Kathrin Bengesser, Josef Högel, Kathleen Claes, Jenneke Van Den Ende, Victorfelix Mautner, Ludwine MessiaenAbstract:Nonallelic homologous recombination (NAHR) is one of the major mechanisms underlying copy number variation in the human genome. Although several disease-associated meiotic NAHR Breakpoints have been analyzed in great detail, hotspots for mitotic NAHR are not well characterized. Type-2 NF1 microdeletions, which are predominantly of postzygotic origin, constitute a highly informative model with which to investigate the features of mitotic NAHR. Here, a custom-designed MLPA- and PCR-based approach was used to identify 23 novel NAHR-mediated type-2 NF1 deletions. Breakpoint analysis of these 23 type-2 deletions, together with 17 NAHR-mediated type-2 deletions identified previously, revealed that the Breakpoints are nonuniformly distributed within the paralogous SUZ12 and SUZ12P sequences. Further, the analysis of this large group of type-2 deletions revealed breakpoint recurrence within short segments (ranging in size from 57 to 253-bp) as well as the existence of a novel NAHR hotspot of 1.9-kb (termed PRS4). This hotspot harbored 20% (8/40) of the type-2 deletion Breakpoints and contains the 253-bp recurrent breakpoint region BR6 in which four independent type-2 deletion Breakpoints were identified. Our findings indicate that a combination of an open chromatin conformation and short non-B DNA-forming repeats may predispose to recurrent mitotic NAHR events between SUZ12 and its pseudogene. Hum Mutat 33:1599–1609, 2012. © 2012 Wiley Periodicals, Inc.
-
Molecular characterisation of the pericentric inversion that distinguishes human chromosome 5 from the homologous chimpanzee chromosome
Human Genetics, 2005Co-Authors: Justyna M Szamalek, Violaine Goidts, Horst Hameister, Nadia Chuzhanova, David Neil Cooper, Hildegard Kehrer-sawatzkiAbstract: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.
-
breakpoint analysis of the pericentric inversion distinguishing human chromosome 4 from the homologous chromosome in the chimpanzee pan troglodytes
Human Mutation, 2005Co-Authors: Hildegard Kehrersawatzki, Stefan Müller, C A Sandig, Violaine Goidts, Nadia Chuzhanova, Justyna M Szamalek, Simone Tanzer, Matthias Platzer, David Neil Cooper, Horst HameisterAbstract: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.
-
translocation and gross deletion Breakpoints in human inherited disease and cancer i nucleotide composition and recombination associated motifs
Human Mutation, 2003Co-Authors: Shaun S Abeysinghe, Nadia Chuzhanova, Michael Krawczak, Edward V Ball, David Neil CooperAbstract:Translocations and gross deletions are important causes of both cancer and inherited disease. Such gene rearrangements are nonrandomly distributed in the human genome as a consequence of selection for growth advantage and/or the inherent potential of some DNA sequences to be frequently involved in breakage and recombination. Using the Gross Rearrangement Breakpoint Database [GRaBD; www.uwcm.ac.uk/uwcm/mg/grabd/grabd.html] (containing 397 germ-line and somatic DNA breakpoint junction sequences derived from 219 different rearrangements underlying human inherited disease and cancer), we have analyzed the sequence context of translocation and deletion Breakpoints in a search for general characteristics that might have rendered these sequences prone to rearrangement. The oligonucleotide composition of breakpoint junctions and a set of reference sequences, matched for length and genomic location, were compared with respect to their nucleotide composition. Deletion Breakpoints were found to be AT-rich whereas by comparison, translocation Breakpoints were GC-rich. Alternating purine-pyrimidine sequences were found to be significantly over-represented in the vicinity of deletion Breakpoints while polypyrimidine tracts were over-represented at translocation Breakpoints. A number of recombination-associated motifs were found to be over-represented at translocation Breakpoints (including DNA polymerase pause sites/frameshift hotspots, immunoglobulin heavy chain class switch sites, heptamer/nonamer V(D)J recombination signal sequences, translin binding sites, and the χ element) but, with the exception of the translin-binding site and immunoglobulin heavy chain class switch sites, none of these motifs were over-represented at deletion Breakpoints. Alu sequences were found to span both Breakpoints in seven cases of gross deletion that may thus be inferred to have arisen by homologous recombination. Our results are therefore consistent with a role for homologous unequal recombination in deletion mutagenesis and a role for nonhomologous recombination in the generation of translocations. Hum Mutat 22:229–244, 2003. © 2003 Wiley-Liss, Inc.
David Neil Cooper - One of the best experts on this subject based on the ideXlab platform.
-
identification of recurrent type 2 nf1 microdeletions reveals a mitotic nonallelic homologous recombination hotspot underlying a human genomic disorder
Human Mutation, 2012Co-Authors: Julia Vogt, Nadia Chuzhanova, David Neil Cooper, Tanja Mussotter, Kathrin Bengesser, Josef Högel, Kathleen Claes, Jenneke Van Den Ende, Victorfelix Mautner, Ludwine MessiaenAbstract:Nonallelic homologous recombination (NAHR) is one of the major mechanisms underlying copy number variation in the human genome. Although several disease-associated meiotic NAHR Breakpoints have been analyzed in great detail, hotspots for mitotic NAHR are not well characterized. Type-2 NF1 microdeletions, which are predominantly of postzygotic origin, constitute a highly informative model with which to investigate the features of mitotic NAHR. Here, a custom-designed MLPA- and PCR-based approach was used to identify 23 novel NAHR-mediated type-2 NF1 deletions. Breakpoint analysis of these 23 type-2 deletions, together with 17 NAHR-mediated type-2 deletions identified previously, revealed that the Breakpoints are nonuniformly distributed within the paralogous SUZ12 and SUZ12P sequences. Further, the analysis of this large group of type-2 deletions revealed breakpoint recurrence within short segments (ranging in size from 57 to 253-bp) as well as the existence of a novel NAHR hotspot of 1.9-kb (termed PRS4). This hotspot harbored 20% (8/40) of the type-2 deletion Breakpoints and contains the 253-bp recurrent breakpoint region BR6 in which four independent type-2 deletion Breakpoints were identified. Our findings indicate that a combination of an open chromatin conformation and short non-B DNA-forming repeats may predispose to recurrent mitotic NAHR events between SUZ12 and its pseudogene. Hum Mutat 33:1599–1609, 2012. © 2012 Wiley Periodicals, Inc.
-
Molecular characterisation of the pericentric inversion that distinguishes human chromosome 5 from the homologous chimpanzee chromosome
Human Genetics, 2005Co-Authors: Justyna M Szamalek, Violaine Goidts, Horst Hameister, Nadia Chuzhanova, David Neil Cooper, Hildegard Kehrer-sawatzkiAbstract: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.
-
breakpoint analysis of the pericentric inversion distinguishing human chromosome 4 from the homologous chromosome in the chimpanzee pan troglodytes
Human Mutation, 2005Co-Authors: Hildegard Kehrersawatzki, Stefan Müller, C A Sandig, Violaine Goidts, Nadia Chuzhanova, Justyna M Szamalek, Simone Tanzer, Matthias Platzer, David Neil Cooper, Horst HameisterAbstract: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.
-
translocation and gross deletion Breakpoints in human inherited disease and cancer i nucleotide composition and recombination associated motifs
Human Mutation, 2003Co-Authors: Shaun S Abeysinghe, Nadia Chuzhanova, Michael Krawczak, Edward V Ball, David Neil CooperAbstract:Translocations and gross deletions are important causes of both cancer and inherited disease. Such gene rearrangements are nonrandomly distributed in the human genome as a consequence of selection for growth advantage and/or the inherent potential of some DNA sequences to be frequently involved in breakage and recombination. Using the Gross Rearrangement Breakpoint Database [GRaBD; www.uwcm.ac.uk/uwcm/mg/grabd/grabd.html] (containing 397 germ-line and somatic DNA breakpoint junction sequences derived from 219 different rearrangements underlying human inherited disease and cancer), we have analyzed the sequence context of translocation and deletion Breakpoints in a search for general characteristics that might have rendered these sequences prone to rearrangement. The oligonucleotide composition of breakpoint junctions and a set of reference sequences, matched for length and genomic location, were compared with respect to their nucleotide composition. Deletion Breakpoints were found to be AT-rich whereas by comparison, translocation Breakpoints were GC-rich. Alternating purine-pyrimidine sequences were found to be significantly over-represented in the vicinity of deletion Breakpoints while polypyrimidine tracts were over-represented at translocation Breakpoints. A number of recombination-associated motifs were found to be over-represented at translocation Breakpoints (including DNA polymerase pause sites/frameshift hotspots, immunoglobulin heavy chain class switch sites, heptamer/nonamer V(D)J recombination signal sequences, translin binding sites, and the χ element) but, with the exception of the translin-binding site and immunoglobulin heavy chain class switch sites, none of these motifs were over-represented at deletion Breakpoints. Alu sequences were found to span both Breakpoints in seven cases of gross deletion that may thus be inferred to have arisen by homologous recombination. Our results are therefore consistent with a role for homologous unequal recombination in deletion mutagenesis and a role for nonhomologous recombination in the generation of translocations. Hum Mutat 22:229–244, 2003. © 2003 Wiley-Liss, Inc.
-
translocation and gross deletion Breakpoints in human inherited disease and cancer i nucleotide composition and recombination associated motifs
Human Mutation, 2003Co-Authors: Shaun S Abeysinghe, Nadia Chuzhanova, Michael Krawczak, Edward V Ball, David Neil CooperAbstract:Translocations and gross deletions are important causes of both cancer and inherited disease. Such gene rearrangements are nonrandomly distributed in the human genome as a consequence of selection for growth advantage and/or the inherent potential of some DNA sequences to be frequently involved in breakage and recombination. Using the Gross Rearrangement Breakpoint Database [GRaBD; www.uwcm.ac.uk/uwcm/mg/grabd/grabd.html] (containing 397 germ-line and somatic DNA breakpoint junction sequences derived from 219 different rearrangements underlying human inherited disease and cancer), we have analyzed the sequence context of translocation and deletion Breakpoints in a search for general characteristics that might have rendered these sequences prone to rearrangement. The oligonucleotide composition of breakpoint junctions and a set of reference sequences, matched for length and genomic location, were compared with respect to their nucleotide composition. Deletion Breakpoints were found to be AT-rich whereas by comparison, translocation Breakpoints were GC-rich. Alternating purine-pyrimidine sequences were found to be significantly over-represented in the vicinity of deletion Breakpoints while polypyrimidine tracts were over-represented at translocation Breakpoints. A number of recombination-associated motifs were found to be over-represented at translocation Breakpoints (including DNA polymerase pause sites/frameshift hotspots, immunoglobulin heavy chain class switch sites, heptamer/nonamer V(D)J recombination signal sequences, translin binding sites, and the chi element) but, with the exception of the translin-binding site and immunoglobulin heavy chain class switch sites, none of these motifs were over-represented at deletion Breakpoints. Alu sequences were found to span both Breakpoints in seven cases of gross deletion that may thus be inferred to have arisen by homologous recombination. Our results are therefore consistent with a role for homologous unequal recombination in deletion mutagenesis and a role for nonhomologous recombination in the generation of translocations.
Horst Hameister - One of the best experts on this subject based on the ideXlab platform.
-
Molecular characterisation of the pericentric inversion that distinguishes human chromosome 5 from the homologous chimpanzee chromosome
Human Genetics, 2005Co-Authors: Justyna M Szamalek, Violaine Goidts, Horst Hameister, Nadia Chuzhanova, David Neil Cooper, Hildegard Kehrer-sawatzkiAbstract: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.
-
breakpoint analysis of the pericentric inversion distinguishing human chromosome 4 from the homologous chromosome in the chimpanzee pan troglodytes
Human Mutation, 2005Co-Authors: Hildegard Kehrersawatzki, Stefan Müller, C A Sandig, Violaine Goidts, Nadia Chuzhanova, Justyna M Szamalek, Simone Tanzer, Matthias Platzer, David Neil Cooper, Horst HameisterAbstract: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.
Margaret R Wallace - One of the best experts on this subject based on the ideXlab platform.
-
fine mapping of chromosome 17 translocation Breakpoints 900 kb upstream of sox9 in acampomelic campomelic dysplasia and a mild familial skeletal dysplasia
American Journal of Human Genetics, 2005Co-Authors: Katherine L Hillharfe, Lee M Kaplan, Heather J Stalker, Roberto T Zori, Gerd Scherer, Margaret R WallaceAbstract:Previously, our group reported a five-generation family in which a balanced t(13;17) translocation is associated with a spectrum of skeletal abnormalities, including Robin sequence, hypoplastic scapulae, and a missing pair of ribs. Using polymerase chain reaction (PCR) with chromosome-specific markers to analyze DNA from somatic cell hybrids containing the derivative translocation chromosomes, we narrowed the breakpoint on each chromosome. Subsequent sequencing of PCR products spanning the Breakpoints identified the breaks precisely. The chromosome 17 breakpoint maps ∼932 kb upstream of the sex-determining region Y (SRY)–related high-mobility group box gene (SOX9) within a noncoding transcript represented by two IMAGE cDNA clones. A growing number of reports have implicated chromosome 17 Breakpoints at a distance of up to 1 Mb from SOX9 in some cases of campomelic dysplasia (CD). Although this multigeneration family has a disorder that shares some features with CD, their phenotype is significantly milder than any reported cases of (nonmosaic) CD. Therefore, this case may represent an etiologically distinct skeletal dysplasia or may be an extremely mild familial example of CD, caused by the most proximal translocation breakpoint from SOX9 reported to date. In addition, we have refined the breakpoint in an acampomelic CD case described elsewhere and have found that it lies ∼900 kb upstream of SOX9.
Justyna M Szamalek - One of the best experts on this subject based on the ideXlab platform.
-
Molecular characterisation of the pericentric inversion that distinguishes human chromosome 5 from the homologous chimpanzee chromosome
Human Genetics, 2005Co-Authors: Justyna M Szamalek, Violaine Goidts, Horst Hameister, Nadia Chuzhanova, David Neil Cooper, Hildegard Kehrer-sawatzkiAbstract: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.
-
breakpoint analysis of the pericentric inversion distinguishing human chromosome 4 from the homologous chromosome in the chimpanzee pan troglodytes
Human Mutation, 2005Co-Authors: Hildegard Kehrersawatzki, Stefan Müller, C A Sandig, Violaine Goidts, Nadia Chuzhanova, Justyna M Szamalek, Simone Tanzer, Matthias Platzer, David Neil Cooper, Horst HameisterAbstract: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.
