The sequence and analysis of duplication-rich human chromosome 16

Martin, Joel; Han, Cliff; Gordon, Laurie; Terry, Astrid; Prabhakar, Shyam; She, Xinwei; Xie, Gary; Hellsten, Uffe; Chan, Yee Man; Altherr, Michael R.; Couronne, Olivier; Aerts, Andrea; Bajorek, Eva; Black, Steve; Blumer, Heather; Branscomb, Elbert; Brown, Nancy; Bruno, William; Buckingham, Judith M.; Callen, David F.; Campbell, Connie S.; Campbell, Mary L.; Campbell, E.W.; Caoile, Chenier; Challacombe, Jean F.; Chasteen, Leslie; Chertkov, Olga; Han, Chunchun; Christensen, Mari; Clark, Lynn M.; Cohn, Judith D.; Denys, Mirian; Detter, John C.; Dickson, Mark; Dimitrijevic-Bussod, Mira; Escobar, Julio; Fawcett, Joseph J.; Flowers, Dave; Fotopulos, Dea; Glavina, Tijana; Gómez, Marı́a; Gonzales, Eidelyn; Goodstein, David; Goodwin, Lynne; Grady, Deborah L.; Grigoriev, Igor V.; Groza, Matthew; Hammon, Nancy; Hawkins, Trevor; Haydu, Lauren E.; Hildebrand, C.E.; Huang, Wayne; Israni, Sanjay; Jett, Jamie; Jewett, Phillip B.; Kadner, Kristen; Kimball, Heather; Kobayashi, Arthur; Krawczyk, Marie-Claude; Leyba, Tina; Longmire, Jonathan L.; Lopez, Frederick; Lou, Yunian; Lowry, Steve; Ludeman, Thom; Manohar, Chitra F.; Mark, Graham A.; Mcmurray, Kimberly L.; Meincke, Linda; Morgan, Jenna; Moyzis, Robert K.; Mundt, Mark; Munk, A. Christine; Nandkeshwar, Richard D.; Pitluck, Sam; Pollard, Martin; Predki, Paul; Parson-Quintana, B.; Ramı́rez, Lucı́a; Rash, Sam; Retterer, James; Ricke, Darrell O.; Robinson, Donna L.; Rodríguez, Álex; Salamov, Asaf; Saunders, Elizabeth; Scott, Duncan; Shough, Timothy; Stallings, Raymond L.; Stalvey, Malinda; Sutherland, Robert; Tapia, Roxanne; Tesmer, Judith G.; Thayer, Nina; Thompson, Linda S.; Tice, Hope; Torney, David C.; Tran-Gyamfi, Mary Bao; Tsai, Ming Jer; Ulanovsky, Levy E.; Ustaszewska, Anna; Vo, Nu; White, Paul S.; Williams, Albert L.; Wills, Patricia L.; Wu, Jung-Rung; Wu, Kevin; Yang, Joan; deJong, Pieter J.; Bruce, David; Doggett, Norman A.; Deaven, Larry L.; Schmutz, Jeremy; Grimwood, Jane; Richardson, Paul M.; Rokhsar, Daniel S.; Eichler, Evan E.; Gilna, Paul; Lucas, Susan; Myers, R; Rubin, Edward M.; Pennacchio, Len A.

doi:10.1038/nature03187

Cited by 153 publications

(94 citation statements)

References 48 publications

(45 reference statements)

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“…The ascertainment of exact breakpoints is complicated by the multiple LCRs in the region ( Figure 2); however, the CNVs can be categorized into five categories: (1) a recurrent B1.3 Mb duplication and the reciprocal deletion with telomeric breakpoints between genomic coordinates 14 650 000 and 14 900 000 (hg18) and centromeric breakpoints between 16 200 000 and 16 800 000, (2) a recurrent B1. 16 Mb duplication with telomeric breakpoints between 14 650 000 and 15 100 000 and centromeric breakpoints at B16 200 000, (3) a larger nonrecurrent duplication with breakpoints between 14 669 916-14 876 354 and 16 832 012-16 832099, (4) atypical duplications with proximal breakpoints centromeric to 17 500 000 and (5) a recurrent B1.13 deletion with breakpoints between 15 000 000-15 129 000 and 16 200 000-6 800 000 ( Figure 1). All the deletions and duplications were confirmed by FISH analyses.…”

Section: Acghmentioning

confidence: 99%

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Phenotypic manifestations of copy number variation in chromosome 16p13.11

et al. 2010

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The widespread clinical utilization of array comparative genome hybridization, has led to the unraveling of many new copy number variations (CNVs). Although some of these CNVs are clearly pathogenic, the phenotypic consequences of others, such as those in 16p13.11 remain unclear. Whereas deletions of 16p13.11 have been associated with multiple congenital anomalies, the relevance of duplications of the region is still being debated. We report detailed clinical and molecular characterization of 10 patients with duplication and 4 patients with deletion of 16p13.11. We found that patients with duplication of the region have varied clinical features including behavioral abnormalities, cognitive impairment, congenital heart defects and skeletal manifestations, such as hypermobility, craniosynostosis and polydactyly. These features were incompletely penetrant. Patients with deletion of the region presented with microcephaly, developmental delay and behavioral abnormalities as previously described. The CNVs were of varying sizes and were likely mediated by non-allelic homologous recombination between low copy repeats. Our findings expand the repertoire of clinical features observed in patients with CNV in 16p13.11 and strengthen the hypothesis that this is a dosage sensitive region with clinical relevance.

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Section: Acghmentioning

confidence: 99%

“…Chromosome 16 is rich in intrachromosomal segmental duplications or low copy repeats (LCRs) 15,16 that mediate recurrent genomic rearrangements. Recurrent deletions and reciprocal duplications in 16p13.11 have been previously reported.…”

Section: Introductionmentioning

confidence: 99%

Phenotypic manifestations of copy number variation in chromosome 16p13.11

et al. 2010

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“…To date, confirmed and putative CRMs identified through comparative analysis appear to be distinct, single-copy elements within the human genome, with only a tiny proportion displaying local sequence similarity to each other (Margulies et al 2003;Bejerano et al 2004a, b;Martin et al 2004;Sandelin et al 2004;Woolfe et al 2005). These small numbers of nonunique sequences appear to be the product of duplication events and are found to be situated close to genes with clear paralogous relationships.…”

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confidence: 99%

Ancient duplicated conserved noncoding elements in vertebrates: A genomic and functional analysis

McEwen¹,

Woolfe²,

Goode³

et al. 2006

Genome Res.

100

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Fish-mammal genomic comparisons have proved powerful in identifying conserved noncoding elements likely to be cis-regulatory in nature, and the majority of those tested in vivo have been shown to act as tissue-specific enhancers associated with genes involved in transcriptional regulation of development. Although most of these elements share little sequence identity to each other, a small number are remarkably similar and appear to be the product of duplication events. Here, we searched for duplicated conserved noncoding elements in the human genome, using comparisons with Fugu to select putative cis-regulatory sequences. We identified 124 families of duplicated elements, each containing between two and five members, that are highly conserved within and between vertebrate genomes. In 74% of cases, we were able to assign a specific set of paralogous genes with annotation relating to transcriptional regulation and/or development to each family, thus removing much of the ambiguity in identifying associated genes. We find that duplicate elements have the potential to up-regulate reporter gene expression in a tissue-specific manner and that expression domains often overlap, but are not necessarily identical, between family members. Over two thirds of the families are conserved in duplicate in fish and appear to predate the large-scale duplication events thought to have occurred at the origin of vertebrates. We propose a model whereby gene duplication and the evolution of cis-regulatory elements can be considered in the context of increased morphological diversity and the emergence of the modern vertebrate body plan.

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“…MILE, a former name of DEXI, is reported to locate centromerically within flanking repeats (36). Interestingly, chromosome 16 also features one of the highest levels of segmentally duplicated sequence among human autosomes (37). Integration of these similar sequences might be induced by interchromosomal duplication between chromosome 15 and 16.…”

Section: Discussionmentioning

confidence: 99%

Identification of a potent epigenetic biomarker for resistance to camptothecin and poor outcome to irinotecan-based chemotherapy in colon cancer

Miyaki

Suzuki

Koizumi³

et al. 2011

Int J Oncol

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Abstract. Drug resistance remains a major obstacle to successful cancer treatment. Genome-wide comprehensive analysis identified a novel gene, glucocorticoid-induced protein-coding gene (DEXI), which was frequently methylated in colorectal (CRC; 36 of 73 patients; 49%) and gastric (28 of 89 patients; 31%) cancer patients. Here, we show that DEXI methylation is implicated in mechanisms facilitating resistance to camptothecin (CPT) via inhibition of apoptosis. Silencing of DEXI by siRNA significantly reduced CPT-induced apoptosis in a fibroblast cell line (1/6-fold; p<0.01) originally expressing endogenous DEXI. Restored expression of DEXI by 5-aza-2'-deoxycytidine (DAC) significantly enhanced susceptibility to CPT (3-fold; p<0.01) in a colon cancer cell line originally suppressing endogenous DEXI due to almost complete methylation. Exogenous induction of DEXI confirmed that DEXI per se contributed to enhanced susceptibility to CPT. 5-Fluorouracil (5-FU) did not exhibit these synergistic effects by DEXI restoration. Further, to estimate the clinical usefulness of DEXI methylation status as biomarker for drug resistance to irinotecan (CPT-11), 16 CRC patients who underwent FOLFIRI (5-FU + CPT-11) therapy because they were refractory to FOLFOX (5-FU + oxaliplatin) were analyzed. Significantly poor response and outcome were observed in 8 CRC patients harboring DEXI methylation. In 8 CRC patients harboring DEXI methylation disease control rate, progression-free survival and overall survival were 25.0%, 2 and 11.8 months, respectively, whereas in 8 CRC patients without DEXI methylation they were 62.5%, 5.3 and 15 months, respectively (p<0.01). These significant differences were not observed in patients undergoing treatment with FOLFOX. In conclusion, silencing of DEXI leads to resistance, but restored expression enhances susceptibility to CPT in vitro and DEXI methylation results in poor response and outcome to CPT-11-based chemotherapy, suggesting that DEXI is a potent therapeutic target and an epigenetic biomarker for the selection of patients more likely to benefit from CPT-11-based chemotherapy. IntroductionMetastatic colorectal cancer (CRC) varies greatly in clinical outcome, depending on the response to chemotherapies despite recent advances achieved by combining new anticancer agents. One of the key drugs for metastatic CRC is irinotecan (CPT-11), a derivative drug of camptothecin (CPT) (1-4) and potent DNA topoisomerase I (top I) inhibitor that blocks the rejoining step of the cleavage/religation reaction of top I (5). CPT-11 is indispensable to chemotherapy in various cancer treatments and is widely used in combination treatment using 5-fluorouracil (5-FU) and CPT-11 (FOLFIRI) (5), which yields a high response rate (>50%) in first-line treatment for metastatic CRC patients (6). However, progression-free survival (PFS) was estimated to be only 8-9 months when this regimen was given as first-line therapy (6), suggesting that most patients acquired resistance to CPT-11 within <1 year after initial treatment.Seque...

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The sequence and analysis of duplication-rich human chromosome 16

Cited by 153 publications

References 48 publications

Phenotypic manifestations of copy number variation in chromosome 16p13.11

Phenotypic manifestations of copy number variation in chromosome 16p13.11

Ancient duplicated conserved noncoding elements in vertebrates: A genomic and functional analysis

Identification of a potent epigenetic biomarker for resistance to camptothecin and poor outcome to irinotecan-based chemotherapy in colon cancer

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