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PMID: 21205869 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

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

Genome research ·Vol. 21 ·No. 1 ·2011-01-00 ·Pages 33-46

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 SH, Shaw CA, Lupski JR, Cheung SW

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."

MeSH Terms
Chromosome Breakage Chromosome Disorders/genetics,pathology Chromosome Mapping/methods Chromosomes, Human, Pair 11/genetics Chromosomes, Human, Pair 4/genetics Comparative Genomic Hybridization Family Female Humans Male Molecular Sequence Data Multigene Family Oligonucleotide Array Sequence Analysis Phenotype Polymerase Chain Reaction/methods Receptors, Odorant/genetics Recombination, Genetic Segmental Duplications, Genomic/genetics Sequence Analysis, DNA Translocation, Genetic
Chemicals
Receptors, Odorant
Authors & Affiliations
23 authors, click to expand affiliations / ORCID
Ou Zhishuo
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
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
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Article Info
Journal
Genome research
Abbr.
Genome Res
ISSN
1549-5469
DOI
10.1101/gr.111609.110
Published
2011-01-00
Pages
33-46
Language
English
Region
United States
NLM ID
9518021
PMCID
PMC3012924
Subset
IM
Grants
NCRR NIH HHS · M01 RR000188 · United States
NINDS NIH HHS · R01 NS058529 · United States
Databases
GENBANK
HM989976, HM989977
GEO
GSM578535, GSM578536, GSM578537, GSM578538, GSM578539, GSM578540, GSM578936, GSM578937, GSM578938, GSM578939, GSM578940, GSM578965, GSM579028
External Links
PubMed source DOI: 10.1101/gr.111609.110 PMC Full Text View journal details
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