Nucleotide sequence comparison of a chromosome rearrangement on human chromosome 12 and the corresponding ape chromosomes

Shimada, Makoto; Kim, C. G.; Kitano, Takashi; Ferrell, Robert E.; Kohara, Yuji; Saitou, Naruya

doi:10.1159/000080805

Cited by 19 publications

(15 citation statements)

References 51 publications

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“…The most intriguing finding of this study is the discovery of megabase-sized hypomethylated zones that are co-localized with breakpoints (Murphy et al 2005;Shimada et al 2005;Schibler et al 2006), chromosomal rearrangement breakpoints, fragile sites, tumor suppressors, large genes, and novel tissue-specific genes without mouse homologs in gene-poor regions. These large hypomethylated regions are also AT-rich, low in CPGI, and show low sequence conservation with other genomes.…”

Section: Discussionmentioning

confidence: 72%

Genome-wide mapping and characterization of hypomethylated sites in human tissues and breast cancer cell lines

Shann¹,

Cheng²,

Chiao³

et al. 2008

Genome Res.

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We have developed a method for mapping unmethylated sites in the human genome based on the resistance of TspRI-digested ends to ExoIII nuclease degradation. Digestion with TspRI and methylation-sensitive restriction endonuclease HpaII, followed by ExoIII and single-strand DNA nuclease allowed removal of DNA fragments containing unmethylated HpaII sites. We then used array comparative genomic hybridization (CGH) to map the sequences depleted by these procedures in human genomes derived from five human tissues, a primary breast tumor, and two breast tumor cell lines. Analysis of methylation patterns of the normal tissue genomes indicates that the hypomethylated sites are enriched in the 5Ј end of widely expressed genes, including promoter, first exon, and first intron. In contrast, genomes of the MCF-7 and MDA-MB-231 cell lines show extensive hypomethylation in the intragenic and intergenic regions whereas the primary tumor exhibits a pattern between those of the normal tissue and the cell lines. A striking characteristic of tumor cell lines is the presence of megabase-sized hypomethylated zones. These hypomethylated zones are associated with large genes, fragile sites, evolutionary breakpoints, chromosomal rearrangement breakpoints, tumor suppressor genes, and with regions containing tissue-specific gene clusters or with gene-poor regions containing novel tissue-specific genes. Correlation with microarray analysis shows that genes with a hypomethylated sequence 2 kb up-or downstream of the transcription start site are highly expressed, whereas genes with extensive intragenic and 3Ј untranslated region (UTR) hypomethylation are silenced. The method described herein can be used for large-scale screening of changes in the methylation pattern in the genome of interest.

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Section: Discussionmentioning

confidence: 72%

Genome-wide mapping and characterization of hypomethylated sites in human tissues and breast cancer cell lines

Shann¹,

Cheng²,

Chiao³

et al. 2008

Genome Res.

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“…www.genome.org genome sequencing and comparative studies (Leveau et al 2004;Magrini et al 2004;Moon and Magor 2004;Jansen et al 2005;Shimada et al 2005;Tuzun et al 2005). Fosmids offer a number of advantages over BACs.…”

Section: Genome Research 401mentioning

confidence: 99%

Decoding the fine-scale structure of a breast cancer genome and transcriptome

Volik¹,

Raphael²,

Huang³

et al. 2006

Genome Res.

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A comprehensive understanding of cancer is predicated upon knowledge of the structure of malignant genomes underlying its many variant forms and the molecular mechanisms giving rise to them. It is well established that solid tumor genomes accumulate a large number of genome rearrangements during tumorigenesis. End Sequence Profiling (ESP) maps and clones genome breakpoints associated with all types of genome rearrangements elucidating the structural organization of tumor genomes. Here we extend the ESP methodology in several directions using the breast cancer cell line MCF-7. First, targeted ESP is applied to multiple amplified loci, revealing a complex process of rearrangement and coamplification in these regions reminiscent of breakage/fusion/bridge cycles. Second, genome breakpoints identified by ESP are confirmed using a combination of DNA sequencing and PCR. Third, in vitro functional studies assign biological function to a rearranged tumor BAC clone, demonstrating that it encodes antiapoptotic activity. Finally, ESP is extended to the transcriptome identifying four novel fusion transcripts and providing evidence that expression of fusion genes may be common in tumors. These results demonstrate the distinct advantages of ESP including: (1) the ability to detect all types of rearrangements and copy number changes; (2) straightforward integration of ESP data with the annotated genome sequence; (3) immortalization of the genome; (4) ability to generate tumor-specific reagents for in vitro and in vivo functional studies. Given these properties, ESP could play an important role in a tumor genome project.

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“…Human and chimpanzee karyotypes differ by one chromosomal fusion that gave rise to human chromosome 2 (HSA2) from two ancestral chromosomes coupled to the inactivation of one of the two centromeres, at least nine pericentric inversions, and in the content of constitutive heterochromatin (Yunis et al 1980;IJdo et al 1991;Baldini et al 1993;Nickerson and Nelson 1998). Seven of these inversions, mapping to human chromosomes 4, 5, 9, 12, 15, 16, and 17, are specific to the chimpanzee lineage (Marzella et al 2000;Kehrer-Sawatzki et al 2002;Locke et al 2003;Goidts et al 2005;Kehrer-Sawatzki et al 2005a,b,c;Shimada et al 2005;Szamalek et al 2005), while the remaining two, mapping to HSA1 and HSA18, appeared in the human lineage after separation from the chimpanzee (Yunis and Prakash 1982;McConkey 1997;Dennehey et al 2004;Weise et al 2005;Szamalek et al 2006). These reorganized structures became fixed during evolution either by providing an advantage or by mere genetic drift.…”

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confidence: 99%

Novel H3K4me3 marks are enriched at human- and chimpanzee-specific cytogenetic structures

2014

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Human and chimpanzee genomes are 98.8% identical within comparable sequences. However, they differ structurally in nine pericentric inversions, one fusion that originated human chromosome 2, and content and localization of heterochromatin and lineage-specific segmental duplications. The possible functional consequences of these cytogenetic and structural differences are not fully understood and their possible involvement in speciation remains unclear. We show that subtelomeric regions-regions that have a species-specific organization, are more divergent in sequence, and are enriched in genes and recombination hotspots-are significantly enriched for species-specific histone modifications that decorate transcription start sites in different tissues in both human and chimpanzee. The human lineage-specific chromosome 2 fusion point and ancestral centromere locus as well as chromosome 1 and 18 pericentric inversion breakpoints showed enrichment of human-specific H3K4me3 peaks in the prefrontal cortex. Our results reveal an association between plastic regions and potential novel regulatory elements.

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Nucleotide sequence comparison of a chromosome rearrangement on human chromosome 12 and the corresponding ape chromosomes

Cited by 19 publications

References 51 publications

Genome-wide mapping and characterization of hypomethylated sites in human tissues and breast cancer cell lines

Genome-wide mapping and characterization of hypomethylated sites in human tissues and breast cancer cell lines

Decoding the fine-scale structure of a breast cancer genome and transcriptome

Novel H3K4me3 marks are enriched at human- and chimpanzee-specific cytogenetic structures

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