Complex Genomic Rearrangements at the PLP1 Locus Include Triplication and Quadruplication

被引：54

作者：

Beck, Christine R. ^{[1
]}

Carvalho, Claudia M. B. ^{[1
,2
]}

Banser, Linda ^{[3
]}

Gambin, Tomasz ^{[1
]}

Stubbolo, Danielle ^{[3
]}

Yuan, Bo ^{[1
]}

Sperle, Karen ^{[3
]}

McCahan, Suzanne M. ^{[3
,4
]}

Henneke, Marco ^{[5
]}

Seeman, Pavel ^{[6
,7
]}

Garbern, James Y. ^{[8
]}

Hobson, Grace M. ^{[3
,4
,9
]}

Lupski, James R. ^{[1
,10
,11
,12
]}

机构：

[1] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[2] Fiocruz MS, Ctr Pesquisas Rene Rachou, Belo Horizonte, MG, Brazil

[3] Alfred I duPont Hosp Children, Nemours Biomed Res, Wilmington, DE USA

[4] Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA

[5] Univ Gottingen, Univ Med Ctr Gottingen, Dept Pediat & Adolescent Med, Div Pediat Neurol, D-37073 Gottingen, Germany

[6] Charles Univ Prague, Fac Med 2, DNA Lab, Dept Pediat Neurol, Prague, Czech Republic

[7] Motol Univ Hosp, Prague, Czech Republic

[8] Univ Rochester, Med Ctr, Rochester, NY 14642 USA

[9] Univ Delaware, Dept Biol Sci, Newark, DE USA

[10] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[11] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[12] Texas Childrens Hosp, Houston, TX 77030 USA

来源：

PLOS GENETICS | 2015年 / 11卷 / 03期

关键词：

PELIZAEUS-MERZBACHER-DISEASE; LOW-COPY REPEATS; BREAK-INDUCED REPLICATION; INVERTED REPEATS; STRUCTURAL VARIATION; NONRECURRENT REARRANGEMENTS; HOMOLOGOUS RECOMBINATION; MECHANISTIC INSIGHTS; GENE AMPLIFICATION; DNA-SYNTHESIS;

D O I：

10.1371/journal.pgen.1005050

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Inverted repeats (IRs) can facilitate structural variation as crucibles of genomic rearrangement. Complex duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) rearrangements that contain breakpoint junctions within IRs have been recently associated with both MECP2 duplication syndrome (MIM#300260) and Pelizaeus-Merzbacher disease (PMD, MIM#312080). We investigated 17 unrelated PMD subjects with copy number gains at the PLP1 locus including triplication and quadruplication of specific genomic intervals-16/17 were found to have a DUP-TRP/INV-DUP rearrangement product. An IR distal to PLP1 facilitates DUP-TRP/INV-DUP formation as well as an inversion structural variation found frequently amongst normal individuals. We show that a homology-or homeology-driven replicative mechanism of DNA repair can apparently mediate template switches within stretches of microhomology. Moreover, we provide evidence that quadruplication and potentially higher order amplification of a genomic interval can occur in a manner consistent with rolling circle amplification as predicted by the microhomology-mediated break induced replication (MMBIR) model.

引用

页数：26

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