Megabase Length Hypermutation Accompanies Human Structural Variation at 17p11.2

Beck, Christine R.; Carvalho, Claudia M.B.; Akdemir, Zeynep Coban; Sedlazeck, Fritz J.; Song, Xiaofei; Meng, Qingchang; Hu, Jianhong; Doddapaneni, Harshavardhan; Chong, Zechen; Chen, Edward S.; Thornton, P. C.; Liu, Pengfei; Yuan, Bo; Withers, Marjorie; Jhangiani, Shalini N.; Kalra, Dipak; Walker, Kimberly; English, Adam C.; Han, Yi; Chen, Ken; Muzny, Donna M.; Ira, Grzegorz; Shaw, Chad A.; Gibbs, Richard A.; Hastings, P. J.; Lupski, James R.

doi:10.1016/j.cell.2019.01.045

Cited by 67 publications

(72 citation statements)

References 82 publications

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“…The result of our study has shown that there were no significant homologies between proximal and distal breakpoints, and microhomologies were frequently observed at the duplication junctions, along with sequence insertions. The presence of microhomology at the junctions and their position within stem‐loop structures support the concept that SNCA duplication arose from stalled replication forks, which then restarted at ectopic sites upon minimal pairing with an acceptor template, as described by the FoSTeS/MMBIR models of replication repair . Template switching may be reiterative, as suggested by case 5, where the microinsertion may have been acquired from either chromosome 6 or 21, and case 4, in which the ATTTGTCAA motif was copied twice.…”

Section: Discussionmentioning

confidence: 57%

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Replication‐Based Rearrangements Are a Common Mechanism for SNCA Duplication in Parkinson's Disease

Seo

Bacolla

Yoo³

et al. 2020

Movement Disorders

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Background SNCA multiplication is a genomic cause of familial PD, showing dosage‐dependent toxicity. Until now, nonallelic homologous recombination was suggested as the mechanism of SNCA duplication, based on various types of repetitive elements found in the spanning region of the breakpoints. However, the sequence at the breakpoint was analyzed only for 1 case. Objectives We have analyzed the breakpoint sequences of 6 patients with PD who had duplicated SNCA using whole‐genome sequencing data to elucidate the mechanism of SNCA duplication. Methods Six patient samples with SNCA duplication underwent whole‐genome sequencing. The duplicated regions were defined with nucleotide‐resolution breakpoints, which were confirmed by junction polymerase chain reaction and Sanger sequencing. The search for potential non‐B DNA‐forming sequences and stem‐loop structure predictions was conducted. Results Duplicated regions ranged from the smallest region of 718.3 kb to the largest one of 4,162 kb. Repetitive elements were found at 8 of the 12 breakpoint sequences on each side of the junction, but none of the pairs shared overt homologies. Five of these six junctions had microhomologies (2–4 bp) at the breakpoint, and a short stretch of sequences was inserted in 3 cases. All except one junction were located within or next to stem‐loop structures. Conclusion Our study has determined that homologous recombination mechanisms involving repetitive elements are not the main cause of the duplication of SNCA. The presence of microhomology at the junctions and their position within stem‐loop structures suggest that replication‐based rearrangements may be a common mechanism for SNCA amplification. © 2020 International Parkinson and Movement Disorder Society

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Section: Discussionmentioning

confidence: 57%

“…Local rates of hypermutation and DNA structural features have been shown to predispose to nonrecurrent structural variations . A map of common SNPs along chromosome 4 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Replication‐Based Rearrangements Are a Common Mechanism for SNCA Duplication in Parkinson's Disease

Seo

Bacolla

Yoo³

et al. 2020

Movement Disorders

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“…Nucleotide identity of 100% between the proximal and distal reference strands leading to the junction was considered microhomology when found in a subtractive state in the patient's DNA sequence (i.e., identical sequence found once only in the patient's DNA at the deletion junction; Carvalho & Lupski, ). Microhomeology was defined as imperfect matches leading to the junction (cutoff of 70% identity with a maximum two‐nucleotide gap followed by at least two perfectly matched nucleotides; adapted from Beck et al, ; Liu et al, ). Microhomeology at the breakpoint‐junctions was recently reported as a feature associated with the replication‐based mechanism of SV formation (Bahrambeigi et al, ; Liu et al, ).…”

Section: Methodsmentioning

confidence: 99%

Xq22 deletions and correlation with distinct neurological disease traits in females: Further evidence for a contiguous gene syndrome

et al. 2019

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Xq22 deletions that encompass PLP1 (Xq22‐PLP1‐DEL) are notable for variable expressivity of neurological disease traits in females ranging from a mild late‐onset form of spastic paraplegia type 2 (MIM# 312920), sometimes associated with skewed X‐inactivation, to an early‐onset neurological disease trait (EONDT) of severe developmental delay, intellectual disability, and behavioral abnormalities. Size and gene content of Xq22‐PLP1‐DEL vary and were proposed as potential molecular etiologies underlying variable expressivity in carrier females where two smallest regions of overlap (SROs) were suggested to influence disease. We ascertained a cohort of eight unrelated patients harboring Xq22‐PLP1‐DEL and performed high‐density array comparative genomic hybridization and breakpoint‐junction sequencing. Molecular characterization of Xq22‐PLP1‐DEL from 17 cases (eight herein and nine published) revealed an overrepresentation of breakpoints that reside within repeats (11/17, ~65%) and the clustering of ~47% of proximal breakpoints in a genomic instability hotspot with characteristic non‐B DNA density. These findings implicate a potential role for genomic architecture in stimulating the formation of Xq22‐PLP1‐DEL. The correlation of Xq22‐PLP1‐DEL gene content with neurological disease trait in female cases enabled refinement of the associated SROs to a single genomic interval containing six genes. Our data support the hypothesis that genes contiguous to PLP1 contribute to EONDT.

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“…62,63 Microhomology has been reported as a signature for a class of DNA replication errors that can generate CNVs (see Discussion). 64,65 As a positive control for our aCGH analysis, we also included a known SNCA triplication sample from the index family in which SNCA locus multiplication was first discovered as a cause for PD. [38][39][40][41] Breakpoint sequencing revealed that this copy number alteration is a 1.7 Mb complex genomic rearrangement ( Figure 1B), consisting of a duplication-inverted triplication-duplication (DUP-TRP/INV-DUP).…”

Section: Copy Number Variantsmentioning

confidence: 99%

Integrated Sequencing & Array Comparative Genomic Hybridization in Familial Parkinson’s Disease

Robak

Du²,

Yuan³

et al. 2019

Preprint

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Background: Parkinson's disease (PD) is a genetically heterogeneous condition; both single nucleotide variants (SNVs) and copy number variants (CNVs) are important genetic risk factors.We examined the utility of combining exome sequencing and genome-wide array-based comparative genomic hybridization (aCGH) for identification of PD genetic risk factors. Methods:We performed exome sequencing on 110 subjects with PD and a positive family history; 99 subjects were also evaluated using genome-wide aCGH. We interrogated exome sequencing and array comparative genomic hybridization data for pathogenic SNVs and CNVs at Mendelian PD gene loci. SNVs were confirmed via Sanger sequencing. CNVs were confirmed with custom-designed high-density aCGH, droplet digital PCR, and breakpoint sequencing. Results:Using exome sequencing, we discovered individuals with known pathogenic single nucleotide variants in GBA (p.E365K, p.T408M, p.N409S, p.L483P) and LRRK2 (p.R1441G and p.G2019S). Two subjects were each double heterozygotes for variants in GBA and LRRK2.Based on aCGH, we additionally discovered cases with an SNCA duplication and heterozygous intragenic GBA deletion. Five additional subjects harbored both SNVs (p.N52fs, p.T240M, p.P437L, p.W453*) and likely disrupting CNVs at the PARK2 locus, consistent with compound heterozygosity. In nearly all cases, breakpoint sequencing revealed microhomology, a mutational signature consistent with CNV formation due to DNA replication errors. Conclusions:Integrated exome sequencing and aCGH yielded a genetic diagnosis in 19.3% of our familial PD cohort. Our analyses highlight potential mechanisms for SNCA and PARK2 CNV formation, uncover multilocus pathogenic variation, and identify novel SNVs and CNVs for further investigation as potential PD risk alleles.

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Megabase Length Hypermutation Accompanies Human Structural Variation at 17p11.2

Cited by 67 publications

References 82 publications

Replication‐Based Rearrangements Are a Common Mechanism for SNCA Duplication in Parkinson's Disease

Replication‐Based Rearrangements Are a Common Mechanism for SNCA Duplication in Parkinson's Disease

Xq22 deletions and correlation with distinct neurological disease traits in females: Further evidence for a contiguous gene syndrome

Integrated Sequencing & Array Comparative Genomic Hybridization in Familial Parkinson’s Disease

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