Observation and prediction of recurrent human translocations mediated by NAHR between nonhomologous chromosomes

Zhishuo Ou, Paweł Stankiewicz, Zhilian Xia, Amy M. Breman, Brian Dawson, Joanna Wiszniewska, Przemyslaw Szafranski, M. Lance Cooper, Mitchell Rao, Lina Shao, Sarah T. South, Karlene Coleman, Paul M. Fernhoff, Marcel J. Deray, Sally Rosengren, Elizabeth R. Roeder, Victoria B. Enciso, A. Craig Chinault, Ankita Patel, Sung Hae L. Kang & 3 others Chad A. Shaw, James R. Lupski, Sau W. Cheung

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Abstract

Four unrelated families with the same unbalanced translocation der(4)t(4;11)(p16.2;p15.4) were analyzed. Both of the breakpoint regions in 4p16.2 and 11p15.4 were narrowed to large ∼359-kb and ∼215-kb low-copy repeat (LCR) clusters, respectively, by aCGH and SNP array analyses. DNA sequencing enabled mapping the breakpoints of one translocation to 24 bp within interchromosomal paralogous LCRs of ∼130 kb in length and 94.7% DNA sequence identity located in olfactory receptor gene clusters, indicating nonallelic homologous recombination (NAHR) as the mechanism for translocation formation. To investigate the potential involvement of interchromosomal LCRs in recurrent chromosomal translocation formation, we performed computational genome-wide analyses and identified 1143 interchromosomal LCR substrate pairs, >5 kb in size and sharing >94% sequence identity that can potentially mediate chromosomal translocations. Additional evidence for interchromosomal NAHR mediated translocation formation was provided by sequencing the breakpoints of another recurrent translocation, der(8)t(8;12)(p23.1;p13.31). The NAHR sites were mapped within 55 bp in ∼7.8-kb paralogous subunits of 95.3% sequence identity located in the ∼579-kb (chr 8) and ∼287-kb (chr 12) LCR clusters. We demonstrate that NAHR mediates recurrent constitutional translocations t(4;11) and t(8;12) and potentially many other interchromosomal translocations throughout the human genome. Furthermore, we provide a computationally determined genome-wide "recurrent translocation map."

Original languageEnglish (US)
Pages (from-to)33-46
Number of pages14
JournalGenome Research
Volume21
Issue number1
DOIs
StatePublished - Jan 1 2011
Externally publishedYes

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Homologous Recombination
Genomic Segmental Duplications
Chromosomes
Observation
Genetic Translocation
Odorant Receptors
Genome
Human Genome
Multigene Family
DNA Sequence Analysis
Single Nucleotide Polymorphism

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Observation and prediction of recurrent human translocations mediated by NAHR between nonhomologous chromosomes. / Ou, Zhishuo; Stankiewicz, Paweł; Xia, Zhilian; Breman, Amy M.; Dawson, Brian; Wiszniewska, Joanna; Szafranski, Przemyslaw; Cooper, M. Lance; Rao, Mitchell; Shao, Lina; South, Sarah T.; Coleman, Karlene; Fernhoff, Paul M.; Deray, Marcel J.; Rosengren, Sally; Roeder, Elizabeth R.; Enciso, Victoria B.; Chinault, A. Craig; Patel, Ankita; Kang, Sung Hae L.; Shaw, Chad A.; Lupski, James R.; Cheung, Sau W.

In: Genome Research, Vol. 21, No. 1, 01.01.2011, p. 33-46.

Research output: Contribution to journalArticle

Ou, Z, Stankiewicz, P, Xia, Z, Breman, AM, Dawson, B, Wiszniewska, J, Szafranski, P, Cooper, ML, Rao, M, Shao, L, South, ST, Coleman, K, Fernhoff, PM, Deray, MJ, Rosengren, S, Roeder, ER, Enciso, VB, Chinault, AC, Patel, A, Kang, SHL, Shaw, CA, Lupski, JR & Cheung, SW 2011, 'Observation and prediction of recurrent human translocations mediated by NAHR between nonhomologous chromosomes', Genome Research, vol. 21, no. 1, pp. 33-46. https://doi.org/10.1101/gr.111609.110
Ou, Zhishuo ; Stankiewicz, Paweł ; Xia, Zhilian ; Breman, Amy M. ; Dawson, Brian ; Wiszniewska, Joanna ; Szafranski, Przemyslaw ; Cooper, M. Lance ; Rao, Mitchell ; Shao, Lina ; South, Sarah T. ; Coleman, Karlene ; Fernhoff, Paul M. ; Deray, Marcel J. ; Rosengren, Sally ; Roeder, Elizabeth R. ; Enciso, Victoria B. ; Chinault, A. Craig ; Patel, Ankita ; Kang, Sung Hae L. ; Shaw, Chad A. ; Lupski, James R. ; Cheung, Sau W. / Observation and prediction of recurrent human translocations mediated by NAHR between nonhomologous chromosomes. In: Genome Research. 2011 ; Vol. 21, No. 1. pp. 33-46.
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T1 - Observation and prediction of recurrent human translocations mediated by NAHR between nonhomologous chromosomes

AU - Ou, Zhishuo

AU - Stankiewicz, Paweł

AU - Xia, Zhilian

AU - Breman, Amy M.

AU - Dawson, Brian

AU - Wiszniewska, Joanna

AU - Szafranski, Przemyslaw

AU - Cooper, M. Lance

AU - Rao, Mitchell

AU - Shao, Lina

AU - South, Sarah T.

AU - Coleman, Karlene

AU - Fernhoff, Paul M.

AU - Deray, Marcel J.

AU - Rosengren, Sally

AU - Roeder, Elizabeth R.

AU - Enciso, Victoria B.

AU - Chinault, A. Craig

AU - Patel, Ankita

AU - Kang, Sung Hae L.

AU - Shaw, Chad A.

AU - Lupski, James R.

AU - Cheung, Sau W.

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N2 - Four unrelated families with the same unbalanced translocation der(4)t(4;11)(p16.2;p15.4) were analyzed. Both of the breakpoint regions in 4p16.2 and 11p15.4 were narrowed to large ∼359-kb and ∼215-kb low-copy repeat (LCR) clusters, respectively, by aCGH and SNP array analyses. DNA sequencing enabled mapping the breakpoints of one translocation to 24 bp within interchromosomal paralogous LCRs of ∼130 kb in length and 94.7% DNA sequence identity located in olfactory receptor gene clusters, indicating nonallelic homologous recombination (NAHR) as the mechanism for translocation formation. To investigate the potential involvement of interchromosomal LCRs in recurrent chromosomal translocation formation, we performed computational genome-wide analyses and identified 1143 interchromosomal LCR substrate pairs, >5 kb in size and sharing >94% sequence identity that can potentially mediate chromosomal translocations. Additional evidence for interchromosomal NAHR mediated translocation formation was provided by sequencing the breakpoints of another recurrent translocation, der(8)t(8;12)(p23.1;p13.31). The NAHR sites were mapped within 55 bp in ∼7.8-kb paralogous subunits of 95.3% sequence identity located in the ∼579-kb (chr 8) and ∼287-kb (chr 12) LCR clusters. We demonstrate that NAHR mediates recurrent constitutional translocations t(4;11) and t(8;12) and potentially many other interchromosomal translocations throughout the human genome. Furthermore, we provide a computationally determined genome-wide "recurrent translocation map."

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