Structural variation

Structural variation (also genomic structural variation) is the variation in structure of an organism's chromosome. It consists of many kinds of variation in the genome of one species, and usually includes microscopic and submicroscopic types, such as deletions, duplications, copy-number variants, insertions, inversions and translocations. Typically a structure variation affects a sequence length about 1Kb to 3Mb, which is larger than SNPs and smaller than chromosome abnormality (though the definitions have some overlap).[1] The definition of structural variation does not imply anything about frequency or phenotypical effects. Many structural variants are associated with genetic diseases, however many are not.[2][3] Recent research about SVs indicates that SVs are more difficult to detect than SNPs. Approximately 13% of the human genome are defined as structurally variant in the normal population, and there are at least 240 genes that exist as homozygous deletion polymorphisms in human populations, suggesting these genes are dispensable in humans.[3] Rapidly accumulating evidence indicates that structural variations can comprise millions of nucleotides of heterogeneity within every genome, and are likely to make an important contribution to human diversity and disease susceptibility.

Microscopic structural variation

Microscopic means that it can be detected with optical microscopes, such as aneuploidies, marker chromosome, gross rearrangements and variation in chromosome size.[4][5] The frequency in human population is thought to be underestimated due to the fact that some of these are not actually easy to identify. These structural abnormalities exist in 1 every 375 live births by putative information.[6]

Sub-microscopic structural variation

Sub-microscopic structural variants are much harder to detect owing to their small size. The first study in 2004 that used DNA microarrays could detect tens of genetic loci that exhibited copy number variation, deletions and duplications, greater than 100 kilobases in the human genome.[7] However, by 2015 whole genome sequencing studies could detect around 5,000 of structural variants as small as 100 base pairs encompassing approximately 20 megabases in each individual genome.[2][3] These structural variants include deletions, tandem duplications, inversions, mobile element insertions. The mutation rate is also much higher than microscopic structural variants, estimated by two studies at 16% and 20% respectively, both of which are probably underestimates due to the challenges of accurately detecting structural variants.[2][8] It has also been shown that the generation of spontaneous structural variants significantly increases the likelihood of generating further spontaneous single nucleotide variants or indels within 100 kilobases of the structural variation event.[2]

Copy-number variation

Main article: Copy-number variation

Copy-number variation (CNV) is a large category of structural variation, which includes insertions, deletions and duplications. In recent studies, copy-number variations are tested on people who do not have genetic diseases, using methods that are used for quantitative SNP genotyping. Results show that 28% of the suspected regions in the individuals actually do contain copy number variations.[9][10] Also, CNVs in human genome affect more nucleotides than Single Nucleotide Polymorphism (SNP). It is also noteworthy that many of CNVs are not in coding regions. Because CNVs are usually caused by unequal recombination, widespread similar sequences such as LINEs and SINEs may be a common mechanism of CNV creation.[11][12]

Inversion

Main article: Chromosomal inversion

There are several inversions known which are related to human disease. For instance, recurrent 400kb inversion in factor VIII gene is a common cause of haemophilia A,[13] and smaller inversions affecting idunorate 2-sulphatase (IDS) will cause Hunter syndrome.[14] More examples include Angelman syndrome and Sotos syndrome. However, recent research shows that one person can have 56 putative inversions, thus the non-disease inversions are more common than previously supposed. Also in this study it's indicated that inversion breakpoints are commonly associated with segmental duplications.[15] One 900 kb inversion in the chromosome 17 is under positive selection and are predicted to increase its frequency in European population.[16]

Other structural variants

More complex structural variants can occur include a combination of the above in a single event.[2] The most common type of complex structural variation are non-tandem duplications, where sequence is duplicated and inserted in inverted or direct orientation into another part of the genome.[2] Other classes of complex structural variant include deletion-inversion-deletions, duplication-inversion-duplications, and tandem duplications with nested deletions.[2] There are also cryptic translocations and segmental uniparental disomy (UPD). There are increasing reports of these variations, but are more difficult to detect than traditional variations because these variants are balanced and array-based or PCR-based methods are not able to locate them.

Structural variation and phenotypes

Some genetic diseases are suspected to be caused by structural variations, but the relation is not very certain. It is not plausible to divide these variants into two classes as "normal" or "disease", because the actual output of the same variant will also vary. Also, a few of the variants are actually positively selected for (mentioned above). A series of studies have shown that gene disrupting spontaneous (de novo) CNVs disrupt genes approximately four times more frequently in autism than in controls and contribute to approximately 5-10% of cases.[2][17][18][19][20] Inherited variants also contribute to around 5-10% of cases of autism.[2]

Structural variations also have its function in population genetics. Different frequency of a same variation can be used as a genetic mark to infer relationship between populations in different areas. A complete comparison between human and chimpanzee structural variation also suggested that some of these may be fixed in one species because of its adaptative function.[21] There are also deletions related to resistance against malaria and AIDS.[22][23] Also, some highly variable segments are thought to be caused by balancing selection, but there are also studies against this hypothesis.[24]

Database of structural variation

Some of genome browsers and bioinformatic databases have a list of structural variations in human genome with an emphasis on CNVs, and can show them in the genome browsing page, for example, UCSC Genome Browser.[25] Under the page viewing a part of the genome, there are "Common Cell CNVs" and "Structural Var" which can be enabled. On NCBI, there is a special page [26] for structural variation. In that system, both "inner" and "outer" coordinates are shown; they are both not actual breakpoints, but surmised minimal and maximum range of sequence affected by the structural variation. The types are classified as insertion, loss, gain, inversion, LOH, everted, transchr and UPD.

Software

Software using Next-generation sequencing data to detect structural variations.

Name Variations
types		 Method Language(s) Reference URL
GROM-RD CNV read depth C Smith & al.[27] http://grigoriev.rutgers.edu/software/
CNVnator CNV read depth C Abyzov & al.[28] http://sv.gersteinlab.org/cnvnator/
ForestSV Structural variant discovery with random forests aligned paired-end R Michaelson & al.[29] http://sebatlab.ucsd.edu/index.php/software-data
Delly copy number variable deletion
tandem duplication		 short insert paired-ends
long-range mate-pairs
split-reads alignments		 C++ Rausch & al.[30] http://www.korbel.embl.de/software.html
ERDS CNV Zhu & al.[31]
BreakDancer Chen & al.[32] http://breakdancer.sourceforge.net/
VariationHunter Hormozdiari & al.[33] http://compbio.cs.sfu.ca/strvar.htm
inGAP-sv Qi & al.[34] http://ingap.sourceforge.net/
Manta Large SVs (deletions, duplications, inversions, translocations), large insertions, and medium-sized indels (8bp default minimum indel size) Paired and split read alignments C++, Python https://github.com/Illumina/manta
Lumpy Large SVs (deletions, duplications, inversions, translocations), large insertions Paired and split read alignments C++ Ryan M Layer, Colby Chiang, Aaron R Quinlan, and Ira M Hall [35] https://github.com/arq5x/lumpy-sv
GRIDSS Insertions less than ~500bp, deletions, duplications, inversions, translocations, arbitrary breakpoints (such as those occurring in chromothripsis) Paired and split read alignments, breakend assembly Java https://github.com/PapenfussLab/gridss
SV-Bay Large SVs (deletions, duplications, inversions, translocations and 11 more types of SVs) Paired read alignments and read depth Python Iakovishina & al.[36] https://github.com/InstitutCurie/SV-Bay

References

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  2. 1 2 3 4 5 6 7 8 9 Brandler, William M.; Antaki, Danny; Gujral, Madhusudan; Noor, Amina; Rosanio, Gabriel; Chapman, Timothy R.; Barrera, Daniel J.; Lin, Guan Ning; Malhotra, Dheeraj; Watts, Amanda C.; Wong, Lawrence C.; Estabillo, Jasper A.; Gadomski, Therese E.; Hong, Oanh; Fajardo, Karin V. Fuentes; Bhandari, Abhishek; Owen, Renius; Baughn, Michael; Yuan, Jeffrey; Solomon, Terry; Moyzis, Alexandra G.; Maile, Michelle S.; Sanders, Stephan J.; Reiner, Gail E.; Vaux, Keith K.; Strom, Charles M.; Zhang, Kang; Muotri, Alysson R.; Akshoomoff, Natacha; Leal, Suzanne M.; Pierce, Karen; Courchesne, Eric; Iakoucheva, Lilia M.; Corsello, Christina; Sebat, Jonathan (24 March 2016). "Frequency and Complexity of De Novo Structural Mutation in Autism". The American Journal of Human Genetics. 98 (4): 1–13. doi:10.1016/j.ajhg.2016.02.018.
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  4. ↑ Reich, David E.; Schaffner, Stephen F.; Daly, Mark J.; McVean, Gil; Mullikin, James C.; Higgins, John M.; Richter, Daniel J.; Lander, Eric S.; Altshuler, David (2002). "Human genome sequence variation and the influence of gene history, mutation and recombination". Nature Genetics. 32 (1): 135–42. doi:10.1038/ng947. PMID 12161752.
  5. ↑ Gripenberg, Ulla (1964). "Size variation and orientation of the human Y chromosome". Chromosoma. 15 (5): 618–29. doi:10.1007/BF00319995. PMID 14333154.
  6. ↑ Wyandt, H. E.; Tonk, V. S. (2004). Atlas of Human Chromosome Heteromorphisms. Netherlands: Kluwer Academic. ISBN 978-90-481-6296-3.
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  8. ↑ Kloosterman, Wigard P.; Francioli, Laurent C.; Hormozdiari, Fereydoun; Marschall, Tobias; Hehir-Kwa, Jayne Y.; Abdellaoui, Abdel; Lameijer, Eric-Wubbo; Moed, Matthijs H.; Koval, Vyacheslav; Renkens, Ivo; van Roosmalen, Markus J.; Arp, Pascal; Karssen, Lennart C.; Coe, Bradley P.; Handsaker, Robert E.; Suchiman, Eka D.; Cuppen, Edwin; Thung, Djie Tjwan; McVey, Mitch; Wendl, Michael C.; Uitterlinden, André; van Duijn, Cornelia M.; Swertz, Morris A.; Wijmenga, Cisca; van Ommen, GertJan B.; Slagboom, P. Eline; Boomsma, Dorret I.; Schönhuth, Alexander; Eichler, Evan E.; de Bakker, Paul I.W.; Ye, Kai; Guryev, Victor (June 2015). "Characteristics of de novo structural changes in the human genome". Genome Research. 25 (6): 792–801. doi:10.1101/gr.185041.114.
  9. ↑ Sebat, J.; Lakshmi, B; Troge, J; Alexander, J; Young, J; Lundin, P; Månér, S; Massa, H; et al. (2004). "Large-Scale Copy Number Polymorphism in the Human Genome". Science. 305 (5683): 525–8. doi:10.1126/science.1098918. PMID 15273396.
  10. ↑ Iafrate, A John; Feuk, Lars; Rivera, Miguel N; Listewnik, Marc L; Donahoe, Patricia K; Qi, Ying; Scherer, Stephen W; Lee, Charles (2004). "Detection of large-scale variation in the human genome". Nature Genetics. 36 (9): 949–51. doi:10.1038/ng1416. PMID 15286789.
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  12. ↑ Lam, Hugo YK; Mu, Xinmeng Jasmine; Stutz, Adrian M; Tanzer, Andrea; Cayting, Philip D; Snyder, Michael; Kim, Philip M; Korbel, Jan O; Gerstein, Mark B (2010). "Nucleotide-resolution analysis of structural variants using BreakSeq and a breakpoint library". Nature Biotechnology. 28 (1): 47–55. doi:10.1038/nbt.1600. PMC 2951730Freely accessible. PMID 20037582.
  13. ↑ Lakich, Delia; Kazazian, Haig H.; Antonarakis, Stylianos E.; Gitschier, Jane (1993). "Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A". Nature Genetics. 5 (3): 236–41. doi:10.1038/ng1193-236. PMID 8275087.
  14. ↑ Bondeson, Maire-Louise; Dahl, Niklas; Malmgren, Helena; Kleijer, Wim J.; Tönnesen, Tönne; Carlberg, Britt-Marie; Pettersson, Ulf (1995). "Inversion of the IDS gene resulting from recombination with IDS-related sequences in a common cause of the Hunter syndrome". Human Molecular Genetics. 4 (4): 615–21. doi:10.1093/hmg/4.4.615. PMID 7633410.
  15. ↑ Tuzun, Eray; Sharp, Andrew J; Bailey, Jeffrey A; Kaul, Rajinder; Morrison, V Anne; Pertz, Lisa M; Haugen, Eric; Hayden, Hillary; et al. (2005). "Fine-scale structural variation of the human genome". Nature Genetics. 37 (7): 727–32. doi:10.1038/ng1562. PMID 15895083.
  16. ↑ Stefansson, Hreinn; Helgason, Agnar; Thorleifsson, Gudmar; Steinthorsdottir, Valgerdur; Masson, Gisli; Barnard, John; Baker, Adam; Jonasdottir, Aslaug; et al. (2005). "A common inversion under selection in Europeans". Nature Genetics. 37 (2): 129–37. doi:10.1038/ng1508. PMID 15654335.
  17. ↑ Sebat, J.; Lakshmi, B.; Malhotra, D.; Troge, J.; Lese-Martin, C.; Walsh, T.; Yamrom, B.; Yoon, S.; Krasnitz, A.; Kendall, J.; Leotta, A.; Pai, D.; Zhang, R.; Lee, Y.-H.; Hicks, J.; Spence, S. J.; Lee, A. T.; Puura, K.; Lehtimaki, T.; Ledbetter, D.; Gregersen, P. K.; Bregman, J.; Sutcliffe, J. S.; Jobanputra, V.; Chung, W.; Warburton, D.; King, M.-C.; Skuse, D.; Geschwind, D. H.; Gilliam, T. C.; Ye, K.; Wigler, M. (20 April 2007). "Strong Association of De Novo Copy Number Mutations with Autism". Science. 316 (5823): 445–449. doi:10.1126/science.1138659. PMC 2993504Freely accessible. PMID 17363630.
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  19. ↑ Levy, Dan; Ronemus, Michael; Yamrom, Boris; Lee, Yoon-ha; Leotta, Anthony; Kendall, Jude; Marks, Steven; Lakshmi, B.; Pai, Deepa; Ye, Kenny; Buja, Andreas; Krieger, Abba; Yoon, Seungtai; Troge, Jennifer; Rodgers, Linda; Iossifov, Ivan; Wigler, Michael (June 2011). "Rare De Novo and Transmitted Copy-Number Variation in Autistic Spectrum Disorders". Neuron. 70 (5): 886–897. doi:10.1016/j.neuron.2011.05.015.
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  21. ↑ Johnson, Matthew E.; Viggiano, Luigi; Bailey, Jeffrey A.; Abdul-Rauf, Munah; Goodwin, Graham; Rocchi, Mariano; Eichler, Evan E. (2001). "Positive selection of a gene family during the emergence of humans and African apes". Nature. 413 (6855): 514–9. doi:10.1038/35097067. PMID 11586358.
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  25. ↑ http://genome.ucsc.edu/cgi-bin/hgTracks
  26. ↑ http://www.ncbi.nlm.nih.gov/dbvar/content/overview/
  27. ↑ Smith, Sean D; Kawash Joseph K; Grigoriev Andrey (March 2015). "GROM-RD: resolving genomic biases to improve read depth detection of copy number variants". PeerJ. 3: e836. doi:10.7717/peerj.836.
  28. ↑ Abyzov, A; Urban, AE; Snyder, M; Gerstein, M (2011). "CNVnator: an approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing". Genome Res. 21: 974–84. doi:10.1101/gr.114876.110. PMC 3106330Freely accessible. PMID 21324876.
  29. ↑ Michaelson, Jacob J; Sebat Jonathan (July 2012). "forestSV: structural variant discovery through statistical learning". Nature Methods. 9: i819–i821. doi:10.1038/nmeth.2085. PMC 3427657Freely accessible. PMID 22751202.
  30. ↑ Rausch, Tobias; Zichner Thomas; Schlattl Andreas; Stütz Adrian M; Benes Vladimir; Korbel Jan O (September 2012). "DELLY: structural variant discovery by integrated paired-end and split-read analysis". Bioinformatics. England. 28 (18): i333–i339. doi:10.1093/bioinformatics/bts378. PMC 3436805Freely accessible. PMID 22962449.
  31. ↑ Zhu, Mingfu; Need Anna C, Han Yujun, Ge Dongliang, Maia Jessica M, Zhu Qianqian, Heinzen Erin L, Cirulli Elizabeth T, Pelak Kimberly, He Min, Ruzzo Elizabeth K, Gumbs Curtis, Singh Abanish, Feng Sheng, Shianna Kevin V, Goldstein David B (September 2012). "Using ERDS to Infer Copy-Number Variants in High-Coverage Genomes". Am. J. Hum. Genet. United States. 91 (3): 408–21. doi:10.1016/j.ajhg.2012.07.004. PMC 3511991Freely accessible. PMID 22939633. Cite uses deprecated parameter |coauthors= (help)
  32. ↑ Chen, Ken; Wallis John W, McLellan Michael D, Larson David E, Kalicki Joelle M, Pohl Craig S, McGrath Sean D, Wendl Michael C, Zhang Qunyuan, Locke Devin P, Shi Xiaoqi, Fulton Robert S, Ley Timothy J, Wilson Richard K, Ding Li, Mardis Elaine R (September 2009). "BreakDancer: an algorithm for high-resolution mapping of genomic structural variation". Nat. Methods. United States. 6 (9): 677–81. doi:10.1038/nmeth.1363. PMID 19668202. Cite uses deprecated parameter |coauthors= (help)
  33. ↑ Hormozdiari, Fereydoun; Hajirasouliha Iman; Dao Phuong; Hach Faraz; Yorukoglu Deniz; Alkan Can; Eichler Evan E; Sahinalp S Cenk (June 2010). "Next-generation VariationHunter: combinatorial algorithms for transposon insertion discovery". Bioinformatics. England. 26 (12): i350–7. doi:10.1093/bioinformatics/btq216. PMC 2881400Freely accessible. PMID 20529927.
  34. ↑ Qi, Ji; Fangqing Zhao (June 2011). "inGAP-sv: a novel scheme to identify and visualize structural variation from paired end mapping data". Nucleic Acids Research. England. 39 (Web Server issue): W567–W575. doi:10.1093/nar/gkr506. PMC 3125812Freely accessible. PMID 21715388.
  35. ↑ Layer, Ryan M; Chiang, Colby; Quinlan, Aaron R; Hall, Ira M (2014). "LUMPY: a Probabilistic Framework for Structural Variant Discovery". Genome Biology. 15 (6): R84. doi:10.1186/gb-2014-15-6-r84.
  36. ↑ Iakovishina, D; Janoueix-Lerosey, I; Barillot, E; Regnier, M; Boeva, V (2016). "SV-Bay: structural variant detection in cancer genomes using a Bayesian approach with correction for GC-content and read mappability". Bioinformatics. 32 (7): 984–992. doi:10.1093/bioinformatics/btv7514.

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