MMBIRFinder: A Tool to Detect Microhomology-Mediated Break-Induced Replication

Overview

Journal IEEE/ACM Trans Comput Biol Bioinform

Specialty Biology

Date 2015 Sep 11

PMID 26357319

Citations 5

Authors

Matthew W Segar

Cynthia J Sakofsky

Anna Malkova

Yunlong Liu

Affiliations

Soon will be listed here.

Abstract

The introduction of next-generation sequencing technologies has radically changed the way we view structural genetic events. Microhomology-mediated break-induced replication (MMBIR) is just one of the many mechanisms that can cause genomic destabilization that may lead to cancer. Although the mechanism for MMBIR remains unclear, it has been shown that MMBIR is typically associated with template-switching events. Currently, to our knowledge, there is no existing bioinformatics tool to detect these template-switching events. We have developed MMBIRFinder, a method that detects template-switching events associated with MMBIR from whole-genome sequenced data. MMBIRFinder uses a half-read alignment approach to identify potential regions of interest. Clustering of these potential regions helps narrow the search space to regions with strong evidence. Subsequent local alignments identify the template-switching events with single-nucleotide accuracy. Using simulated data, MMBIRFinder identified 83 percent of the MMBIR regions within a five nucleotide tolerance. Using real data, MMBIRFinder identified 16 MMBIR regions on a normal breast tissue data sample and 51 MMBIR regions on a triple-negative breast cancer tumor sample resulting in detection of 37 novel template-switching events. Finally, we identified template-switching events residing in the promoter region of seven genes that have been implicated in breast cancer.

Citing Articles

Characteristics and possible mechanisms of formation of microinversions distinguishing human and chimpanzee genomes.

Potapova N, Kondrashov A, Mirkin S Sci Rep. 2022; 12(1):591.

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Cancer cells are highly susceptible to accumulation of templated insertions linked to MMBIR.

Osia B, Alsulaiman T, Jackson T, Kramara J, Oliveira S, Malkova A Nucleic Acids Res. 2021; 49(15):8714-8731.

PMID: 34379776 PMC: 8421209. DOI: 10.1093/nar/gkab685.

Genome Editing in Trees: From Multiple Repair Pathways to Long-Term Stability.

Bewg W, Ci D, Tsai C Front Plant Sci. 2018; 9:1732.

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Two large deletions extending beyond either end of the RHD gene and their red cell phenotypes.

Srivastava K, Stiles D, Wagner F, Flegel W J Hum Genet. 2017; 63(1):27-35.

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Translesion Polymerases Drive Microhomology-Mediated Break-Induced Replication Leading to Complex Chromosomal Rearrangements.

Sakofsky C, Ayyar S, Deem A, Chung W, Ira G, Malkova A Mol Cell. 2015; 60(6):860-72.

PMID: 26669261 PMC: 4688117. DOI: 10.1016/j.molcel.2015.10.041.

References

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

Llorente B, Smith C, Symington L . Break-induced replication: what is it and what is it for?. Cell Cycle. 2008; 7(7):859-64. DOI: 10.4161/cc.7.7.5613. View

Negrini S, Gorgoulis V, Halazonetis T . Genomic instability--an evolving hallmark of cancer. Nat Rev Mol Cell Biol. 2010; 11(3):220-8. DOI: 10.1038/nrm2858. View

Jiang Y, Wang Y, Brudno M . PRISM: pair-read informed split-read mapping for base-pair level detection of insertion, deletion and structural variants. Bioinformatics. 2012; 28(20):2576-83. DOI: 10.1093/bioinformatics/bts484. View

Hastings P, Ira G, Lupski J . A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genet. 2009; 5(1):e1000327. PMC: 2621351. DOI: 10.1371/journal.pgen.1000327. View

Sakofsky C, Ayyar S, Malkova A . Break-induced replication and genome stability. Biomolecules. 2013; 2(4):483-504. PMC: 3678771. DOI: 10.3390/biom2040483. View

Medvedev P, Stanciu M, Brudno M . Computational methods for discovering structural variation with next-generation sequencing. Nat Methods. 2009; 6(11 Suppl):S13-20. DOI: 10.1038/nmeth.1374. View

Deem A, Keszthelyi A, Blackgrove T, Vayl A, Coffey B, Mathur R . Break-induced replication is highly inaccurate. PLoS Biol. 2011; 9(2):e1000594. PMC: 3039667. DOI: 10.1371/journal.pbio.1000594. View

Bosco G, Haber J . Chromosome break-induced DNA replication leads to nonreciprocal translocations and telomere capture. Genetics. 1998; 150(3):1037-47. PMC: 1460379. DOI: 10.1093/genetics/150.3.1037. View

10.

Smith C, Llorente B, Symington L . Template switching during break-induced replication. Nature. 2007; 447(7140):102-5. DOI: 10.1038/nature05723. View

11.

Yatsenko S, Hixson P, Roney E, Scott D, Schaaf C, Ng Y . Human subtelomeric copy number gains suggest a DNA replication mechanism for formation: beyond breakage-fusion-bridge for telomere stabilization. Hum Genet. 2012; 131(12):1895-910. PMC: 3493700. DOI: 10.1007/s00439-012-1216-9. View

12.

Kryh H, Abrahamsson J, Jegeras E, Sjoberg R, Devenney I, Kogner P . MYCN amplicon junctions as tumor-specific targets for minimal residual disease detection in neuroblastoma. Int J Oncol. 2011; 39(5):1063-71. DOI: 10.3892/ijo.2011.1120. View

13.

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N . The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009; 25(16):2078-9. PMC: 2723002. DOI: 10.1093/bioinformatics/btp352. View

14.

McEachern M, Haber J . Break-induced replication and recombinational telomere elongation in yeast. Annu Rev Biochem. 2006; 75:111-35. DOI: 10.1146/annurev.biochem.74.082803.133234. View

15.

Luo C, Tsementzi D, Kyrpides N, Read T, Konstantinidis K . Direct comparisons of Illumina vs. Roche 454 sequencing technologies on the same microbial community DNA sample. PLoS One. 2012; 7(2):e30087. PMC: 3277595. DOI: 10.1371/journal.pone.0030087. View

16.

Rausch T, Zichner T, Schlattl A, Stutz A, Benes V, Korbel J . DELLY: structural variant discovery by integrated paired-end and split-read analysis. Bioinformatics. 2012; 28(18):i333-i339. PMC: 3436805. DOI: 10.1093/bioinformatics/bts378. View

17.

Mosca E, Alfieri R, Merelli I, Viti F, Calabria A, Milanesi L . A multilevel data integration resource for breast cancer study. BMC Syst Biol. 2010; 4:76. PMC: 2900226. DOI: 10.1186/1752-0509-4-76. View

18.

Cock P, Fields C, Goto N, Heuer M, Rice P . The Sanger FASTQ file format for sequences with quality scores, and the Solexa/Illumina FASTQ variants. Nucleic Acids Res. 2009; 38(6):1767-71. PMC: 2847217. DOI: 10.1093/nar/gkp1137. View

19.

Malkova A, Haber J . Mutations arising during repair of chromosome breaks. Annu Rev Genet. 2012; 46:455-73. DOI: 10.1146/annurev-genet-110711-155547. View

20.

Cappadocia L, Parent J, Zampini E, Lepage E, Sygusch J, Brisson N . A conserved lysine residue of plant Whirly proteins is necessary for higher order protein assembly and protection against DNA damage. Nucleic Acids Res. 2011; 40(1):258-69. PMC: 3245945. DOI: 10.1093/nar/gkr740. View