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PMID: 14639526 Published · ppublish English Comparative Study Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Reciprocal crossovers and a positional preference for strand exchange in recombination events resulting in deletion or duplication of chromosome 17p11.2.

American journal of human genetics ·Vol. 73 ·No. 6 ·2003-12-00 ·Pages 1302-15

Bi W, Park SS, Shaw CJ, Withers MA, Patel PI, Lupski JR

Abstract

Smith-Magenis syndrome (SMS) is caused by an approximately 4-Mb heterozygous interstitial deletion on chromosome 17p11.2 in approximately 80%-90% of affected patients. Three large ( approximately 200 kb), complex, and highly homologous ( approximately 98%) low-copy repeats (LCRs) are located inside or flanking the SMS common deletion. These repeats, also known as "SMS-REPs," are termed "distal," "middle," and "proximal." The directly oriented distal and proximal copies act as substrates for nonallelic homologous recombination resulting in both the deletion associated with SMS and the reciprocal duplication: dup(17)(p11.2p11.2). Using restriction enzyme cis-morphism analyses and direct sequencing, we mapped the regions of strand exchange in 16 somatic-cell hybrids that harbor only the recombinant SMS-REP. Our studies showed that the sites of crossovers were distributed throughout the region of homology between the distal and proximal SMS-REPs. However, despite approximately 170 kb of high homology, 50% of the recombinant junctions occurred in a 12.0-kb region within the KER gene clusters. DNA sequencing of this hotspot (positional preference for strand exchange) in seven recombinant SMS-REPs narrowed the crossovers to an approximately 8-kb interval. Four of them occurred in a 1,655-bp region rich in polymorphic nucleotides that could potentially reflect frequent gene conversion. For further evaluation of the strand exchange frequency in patients with SMS, novel junction fragments from the recombinant SMS-REPs were identified. As predicted by the reciprocal-recombination model, junction fragments were also identified from this hotspot region in patients with dup(17)(p11.2p11.2), documenting reciprocity of the positional preference for strand exchange. Several potential cis-acting recombination-promoting sequences were identified within the hotspot. It is interesting that we found 2.1-kb AT-rich inverted repeats flanking the proximal and middle KER gene clusters but not the distal one. The role of any or all of these in stimulating double-strand breaks around this positional recombination hotspot remains to be explored.

MeSH Terms
Abnormalities, Multiple/genetics Base Sequence Blotting, Southern Chromosome Deletion Chromosome Mapping Chromosomes, Human, Pair 17/genetics Crossing Over, Genetic/genetics DNA Primers Gene Duplication Humans Intellectual Disability/genetics Molecular Sequence Data Restriction Mapping Sequence Analysis, DNA
Chemicals
DNA Primers
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Bi Weimin
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Park Sung-Sup
Shaw Christine J
Withers Marjorie A
Patel Pragna I
Lupski James R
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Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
0002-9297
DOI
10.1086/379979
Published
2003-12-00
Epub
2003-00-24
Pages
1302-15
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC1180396
Subset
IM
Grants
NICHD NIH HHS · HD2406407 · United States
NCRR NIH HHS · M01 RR00188 · United States
NCRR NIH HHS · M01 RR000188 · United States
NICHD NIH HHS · P01 HD38420 · United States
NICHD NIH HHS · R01 HD038420 · United States
Databases
GENBANK
BK001589, BK001590, BK001591
External Links
PubMed source DOI: 10.1086/379979 PMC Full Text View journal details
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