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Microhomology-mediated mechanisms underlie non-recurrent disease-causing microdeletions of the FOXL2 gene or its regulatory domain

(2013) PLOS GENETICS. 9(3).
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Abstract
Genomic disorders are often caused by recurrent copy number variations (CNVs), with nonallelic homologous recombination (NAHR) as the underlying mechanism. Recently, several microhomology-mediated repair mechanisms-such as microhomology-mediated end-joining (MMEJ), fork stalling and template switching (FoSTeS), microhomology-mediated break-induced replication (MMBIR), serial replication slippage (SRS), and break-induced SRS (BISRS)-were described in the etiology of non-recurrent CNVs in human disease. In addition, their formation may be stimulated by genomic architectural features. It is, however, largely unexplored to what extent these mechanisms contribute to rare, locus-specific pathogenic CNVs. Here, fine-mapping of 42 microdeletions of the FOXL2 locus, encompassing FOXL2 (32) or its regulatory domain (10), serves as a model for rare, locus-specific CNVs implicated in genetic disease. These deletions lead to blepharophimosis syndrome (BPES), a developmental condition affecting the eyelids and the ovary. For breakpoint mapping we used targeted array-based comparative genomic hybridization (aCGH), quantitative PCR (qPCR), long-range PCR, and Sanger sequencing of the junction products. Microhomology, ranging from 1 bp to 66 bp, was found in 91.7% of 24 characterized breakpoint junctions, being significantly enriched in comparison with a random control sample. Our results show that microhomology-mediated repair mechanisms underlie at least 50% of these microdeletions. Moreover, genomic architectural features, like sequence motifs, non-B DNA conformations, and repetitive elements, were found in all breakpoint regions. In conclusion, the majority of these microdeletions result from microhomology-mediated mechanisms like MMEJ, FoSTeS, MMBIR, SRS, or BISRS. Moreover, we hypothesize that the genomic architecture might drive their formation by increasing the susceptibility for DNA breakage or promote replication fork stalling. Finally, our locus-centered study, elucidating the etiology of a large set of rare microdeletions involved in a monogenic disorder, can serve as a model for other clustered, non-recurrent microdeletions in genetic disease.
Keywords
GENOTYPE-PHENOTYPE CORRELATION, COPY NUMBER VARIATION, EPICANTHUS INVERSUS SYNDROME, TIME QUANTITATIVE PCR, B DNA CONFORMATIONS, HUMAN GENOME, STRUCTURAL VARIATION, INTELLECTUAL DISABILITY, DELETION BREAKPOINTS, REARRANGEMENTS

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Chicago
Verdin, Hannah, Barbara D’haene, DIANE BEYSEN, Yana Novikova, Björn Menten, Tom Sante, Pablo Lapunzina, et al. 2013. “Microhomology-mediated Mechanisms Underlie Non-recurrent Disease-causing Microdeletions of the FOXL2 Gene or Its Regulatory Domain.” Plos Genetics 9 (3).
APA
Verdin, H., D’haene, B., BEYSEN, D., Novikova, Y., Menten, B., Sante, T., Lapunzina, P., et al. (2013). Microhomology-mediated mechanisms underlie non-recurrent disease-causing microdeletions of the FOXL2 gene or its regulatory domain. PLOS GENETICS, 9(3).
Vancouver
1.
Verdin H, D’haene B, BEYSEN D, Novikova Y, Menten B, Sante T, et al. Microhomology-mediated mechanisms underlie non-recurrent disease-causing microdeletions of the FOXL2 gene or its regulatory domain. PLOS GENETICS. 2013;9(3).
MLA
Verdin, Hannah, Barbara D’haene, DIANE BEYSEN, et al. “Microhomology-mediated Mechanisms Underlie Non-recurrent Disease-causing Microdeletions of the FOXL2 Gene or Its Regulatory Domain.” PLOS GENETICS 9.3 (2013): n. pag. Print.
@article{3170475,
  abstract     = {Genomic disorders are often caused by recurrent copy number variations (CNVs), with nonallelic homologous recombination (NAHR) as the underlying mechanism. Recently, several microhomology-mediated repair mechanisms-such as microhomology-mediated end-joining (MMEJ), fork stalling and template switching (FoSTeS), microhomology-mediated break-induced replication (MMBIR), serial replication slippage (SRS), and break-induced SRS (BISRS)-were described in the etiology of non-recurrent CNVs in human disease. In addition, their formation may be stimulated by genomic architectural features. It is, however, largely unexplored to what extent these mechanisms contribute to rare, locus-specific pathogenic CNVs. Here, fine-mapping of 42 microdeletions of the FOXL2 locus, encompassing FOXL2 (32) or its regulatory domain (10), serves as a model for rare, locus-specific CNVs implicated in genetic disease. These deletions lead to blepharophimosis syndrome (BPES), a developmental condition affecting the eyelids and the ovary. For breakpoint mapping we used targeted array-based comparative genomic hybridization (aCGH), quantitative PCR (qPCR), long-range PCR, and Sanger sequencing of the junction products. Microhomology, ranging from 1 bp to 66 bp, was found in 91.7\% of 24 characterized breakpoint junctions, being significantly enriched in comparison with a random control sample. Our results show that microhomology-mediated repair mechanisms underlie at least 50\% of these microdeletions. Moreover, genomic architectural features, like sequence motifs, non-B DNA conformations, and repetitive elements, were found in all breakpoint regions. In conclusion, the majority of these microdeletions result from microhomology-mediated mechanisms like MMEJ, FoSTeS, MMBIR, SRS, or BISRS. Moreover, we hypothesize that the genomic architecture might drive their formation by increasing the susceptibility for DNA breakage or promote replication fork stalling. Finally, our locus-centered study, elucidating the etiology of a large set of rare microdeletions involved in a monogenic disorder, can serve as a model for other clustered, non-recurrent microdeletions in genetic disease.},
  articleno    = {e1003358},
  author       = {Verdin, Hannah and D'haene, Barbara and BEYSEN, DIANE and Novikova, Yana and Menten, Bj{\"o}rn and Sante, Tom and Lapunzina, Pablo and Nevado, Julian and Carvalho, Claudio MB and Lupski, James R and De Baere, Elfride},
  issn         = {1553-7404},
  journal      = {PLOS GENETICS},
  language     = {eng},
  number       = {3},
  pages        = {12},
  title        = {Microhomology-mediated mechanisms underlie non-recurrent disease-causing microdeletions of the FOXL2 gene or its regulatory domain},
  url          = {http://dx.doi.org/10.1371/journal.pgen.1003358},
  volume       = {9},
  year         = {2013},
}

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