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{{main|Copy-number variation}}
{{main|Copy-number variation}}
Copy-number variation (CNV) is a large category of structural variation, which includes [[Insertion (genetics)|insertions]], [[Deletion (genetics)|deletions]] and [[Gene duplication|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.<ref>{{cite journal |pages=525–8 |doi=10.1126/science.1098918 |title=Large-Scale Copy Number Polymorphism in the Human Genome |year=2004 |last1=Sebat |first1=J. |journal=Science |volume=305 |issue=5683 |pmid=15273396 |last2=Lakshmi |first2=B |last3=Troge |first3=J |last4=Alexander |first4=J |last5=Young |first5=J |last6=Lundin |first6=P |last7=Månér |first7=S |last8=Massa |first8=H |last9=Walker |first9=M}}</ref><ref>{{cite journal |pages=949–51 |doi=10.1038/ng1416 |title=Detection of large-scale variation in the human genome |year=2004 |last1=Iafrate |first1=A John |last2=Feuk |first2=Lars |last3=Rivera |first3=Miguel N |last4=Listewnik |first4=Marc L |last5=Donahoe |first5=Patricia K |last6=Qi |first6=Ying |last7=Scherer |first7=Stephen W |last8=Lee |first8=Charles |journal=Nature Genetics |volume=36 |issue=9 |pmid=15286789}}</ref> Also, CNVs in human genome affect more nucleotides than [[Single Nucleotide Polymorphism]] (SNP).
Copy-number variation (CNV) is a large category of structural variation, which includes [[Insertion (genetics)|insertions]], [[Deletion (genetics)|deletions]] and [[Gene duplication|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.<ref>{{cite journal |pages=525–8 |doi=10.1126/science.1098918 |title=Large-Scale Copy Number Polymorphism in the Human Genome |year=2004 |last1=Sebat |first1=J. |journal=Science |volume=305 |issue=5683 |pmid=15273396 |last2=Lakshmi |first2=B |last3=Troge |first3=J |last4=Alexander |first4=J |last5=Young |first5=J |last6=Lundin |first6=P |last7=Månér |first7=S |last8=Massa |first8=H |last9=Walker |first9=M}}</ref><ref>{{cite journal |pages=949–51 |doi=10.1038/ng1416 |title=Detection of large-scale variation in the human genome |year=2004 |last1=Iafrate |first1=A John |last2=Feuk |first2=Lars |last3=Rivera |first3=Miguel N |last4=Listewnik |first4=Marc L |last5=Donahoe |first5=Patricia K |last6=Qi |first6=Ying |last7=Scherer |first7=Stephen W |last8=Lee |first8=Charles |journal=Nature Genetics |volume=36 |issue=9 |pmid=15286789}}</ref> 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 crossing over|unequal recombination]], widespread similar sequences such as LINEs and SINEs may be a common mechanism of CNV creation.<ref>{{cite journal |pages=1110–2 |doi=10.1016/j.cell.2010.06.014 |title=Retrotransposition and Structural Variation in the Human Genome |year=2010 |last1=Lupski |first1=James R. |journal=Cell |volume=141 |issue=7 |pmid=20602993}}</ref><ref>{{cite journal |pages=47–55 |doi=10.1038/nbt.1600 |title=Nucleotide-resolution analysis of structural variants using BreakSeq and a breakpoint library |year=2010 |last1=Lam |first1=Hugo YK |last2=Mu |first2=Xinmeng Jasmine |last3=Stutz|first3=Adrian M |last4=Tanzer|first4=Andrea |last5=Cayting |first5=Philip D |last6=Snyder |first6=Michael|last7=Kim |first7=Philip M |last8=Korbel |first8=Jan O |last9=Gerstein |first9=Mark B |journal=Nature Biotechnology |volume=28 |issue=1 |pmid=20037582}}</ref>
It is also noteworthy that many of CNVs are not in coding regions. Because CNVs are usually caused by [[Unequal crossing over|unequal recombination]], widespread similar sequences such as [[Long_interspersed_element#LINEs|LINE]]s and [[Short_interspersed_element#SINEs|SINE]]s may be a common mechanism of CNV creation.<ref>{{cite journal |pages=1110–2 |doi=10.1016/j.cell.2010.06.014 |title=Retrotransposition and Structural Variation in the Human Genome |year=2010 |last1=Lupski |first1=James R. |journal=Cell |volume=141 |issue=7 |pmid=20602993}}</ref><ref>{{cite journal |pages=47–55 |doi=10.1038/nbt.1600 |title=Nucleotide-resolution analysis of structural variants using BreakSeq and a breakpoint library |year=2010 |last1=Lam |first1=Hugo YK |last2=Mu |first2=Xinmeng Jasmine |last3=Stutz|first3=Adrian M |last4=Tanzer|first4=Andrea |last5=Cayting |first5=Philip D |last6=Snyder |first6=Michael|last7=Kim |first7=Philip M |last8=Korbel |first8=Jan O |last9=Gerstein |first9=Mark B |journal=Nature Biotechnology |volume=28 |issue=1 |pmid=20037582}}</ref>


==Inversion==
==Inversion==

Revision as of 23:26, 5 April 2013

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 overlapping).[1] The definition of structural variation does not imply anything about frequency or phenotypical effects. Many of structural variants are associated with genetic diseases, however more are not. Recent research about SVs indicates that SVs are more difficult to detect than SNPs. SNPs always occur in two alleles, while approximately 5% of the human genome are defined as structurally variant in the normal population, involving more than 800 independent genes. 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.[2][3] 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.[4]

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.[5][6] 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.[7][8]

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,[9] and smaller inversions affecting idunorate 2-sulphatase (IDS) will cause Hunter syndrome.[10] 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.[11] One 900 kb inversion in the chromosome 17 is under positive selection and are predicted to increase its frequency in European population.[12]

Other structural variants

In addition to the most common kinds, there are also cryptic translocations and segmental uniparental disomy (UPD), among others. 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.[citation needed]

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). In 2007, one study,[13] new Copy-Number Variations are identified to play some role in Autism Spectrum Disorder and maybe other mental situations.

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.[14] There are also deletions related to resistance against malaria and AIDS.[15][16] Also, some highly variable segments are thought to be caused by balancing selection, but there are also studies against this hypothesis.[17]

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.[18] 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 [19] 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.[citation needed]

Software

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

Name Variations
types 		Method Language(s) Reference URL
Delly copy number variable deletion
tandem duplication 		short insert paired-ends
long-range mate-pairs
split-reads alignments 		C++ Rausch & al.[20] http://www.korbel.embl.de/software.html
ERDS CNV Zhu & al.[21]
BreakDancer Chen & al.[22] http://breakdancer.sourceforge.net/
VariationHunter Hormozdiari & al.[23] http://compbio.cs.sfu.ca/strvar.htm

References

  1. ^ Feuk, Lars; Carson, Andrew R.; Scherer, Stephen W. (2006). "Structural variation in the human genome". Nature Reviews Genetics. 7 (2): 85–97. doi:10.1038/nrg1767. PMID 16418744.
  2. ^ 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.
  3. ^ Gripenberg, Ulla (1964). "Size variation and orientation of the human Y chromosome". Chromosoma. 15 (5): 618–29. doi:10.1007/BF00319995. PMID 14333154.
  4. ^ Wyandt, H. E.; Tonk, V. S. (2004). Atlas of Human Chromosome Heteromorphisms. Netherlands: Kluwer Academic. ISBN 978-90-481-6296-3.[page needed]
  5. ^ Sebat, J.; Lakshmi, B; Troge, J; Alexander, J; Young, J; Lundin, P; Månér, S; Massa, H; Walker, M (2004). "Large-Scale Copy Number Polymorphism in the Human Genome". Science. 305 (5683): 525–8. doi:10.1126/science.1098918. PMID 15273396.
  6. ^ 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.
  7. ^ Lupski, James R. (2010). "Retrotransposition and Structural Variation in the Human Genome". Cell. 141 (7): 1110–2. doi:10.1016/j.cell.2010.06.014. PMID 20602993.
  8. ^ 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. PMID 20037582.
  9. ^ 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.
  10. ^ 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.
  11. ^ Tuzun, Eray; Sharp, Andrew J; Bailey, Jeffrey A; Kaul, Rajinder; Morrison, V Anne; Pertz, Lisa M; Haugen, Eric; Hayden, Hillary; Albertson, Donna (2005). "Fine-scale structural variation of the human genome". Nature Genetics. 37 (7): 727–32. doi:10.1038/ng1562. PMID 15895083.
  12. ^ Stefansson, Hreinn; Helgason, Agnar; Thorleifsson, Gudmar; Steinthorsdottir, Valgerdur; Masson, Gisli; Barnard, John; Baker, Adam; Jonasdottir, Aslaug; Ingason, Andres (2005). "A common inversion under selection in Europeans". Nature Genetics. 37 (2): 129–37. doi:10.1038/ng1508. PMID 15654335.
  13. ^ Marshall, Christian R.; Noor, Abdul; Vincent, John B.; Lionel, Anath C.; Feuk, Lars; Skaug, Jennifer; Shago, Mary; Moessner, Rainald; Pinto, Dalila (2008). "Structural Variation of Chromosomes in Autism Spectrum Disorder". The American Journal of Human Genetics. 82 (2): 477–88. doi:10.1016/j.ajhg.2007.12.009. PMID 18252227.
  14. ^ 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.
  15. ^ Redon, Richard; Ishikawa, Shumpei; Fitch, Karen R.; Feuk, Lars; Perry, George H.; Andrews, T. Daniel; Fiegler, Heike; Shapero, Michael H.; Carson, Andrew R. (2006). "Global variation in copy number in the human genome". Nature. 444 (7118): 444–54. doi:10.1038/nature05329. PMC 2669898. PMID 17122850.
  16. ^ Gonzalez, E.; Kulkarni, H; Bolivar, H; Mangano, A; Sanchez, R; Catano, G; Nibbs, RJ; Freedman, BI; Quinones, MP (2005). "The Influence of CCL3L1 Gene-Containing Segmental Duplications on HIV-1/AIDS Susceptibility". Science. 307 (5714): 1434–40. doi:10.1126/science.1101160. PMID 15637236.
  17. ^ Bubb, K. L.; Bovee, D; Buckley, D; Haugen, E; Kibukawa, M; Paddock, M; Palmieri, A; Subramanian, S; Zhou, Y (2006). "Scan of Human Genome Reveals No New Loci Under Ancient Balancing Selection". Genetics. 173 (4): 2165–77. doi:10.1534/genetics.106.055715. PMC 1569689. PMID 16751668.
  18. ^ http://genome.ucsc.edu/cgi-bin/hgTracks
  19. ^ http://www.ncbi.nlm.nih.gov/dbvar/content/overview/
  20. ^ Rausch, Tobias (2012). "DELLY: structural variant discovery by integrated paired-end and split-read analysis". Bioinformatics. 28 (18). England: i333–i339. doi:10.1093/bioinformatics/bts378. PMC 3436805. PMID 22962449. {{cite journal}}: Cite has empty unknown parameters: |laydate=, |laysource=, and |laysummary= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help); Unknown parameter |quotes= ignored (help)
  21. ^ Zhu, Mingfu (2012). "Using ERDS to Infer Copy-Number Variants in High-Coverage Genomes". Am. J. Hum. Genet. 91 (3). United States: 408–21. doi:10.1016/j.ajhg.2012.07.004. PMID 22939633. {{cite journal}}: Cite has empty unknown parameters: |laydate=, |laysource=, and |laysummary= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help); Unknown parameter |quotes= ignored (help)
  22. ^ Chen, Ken (2009). "BreakDancer: an algorithm for high-resolution mapping of genomic structural variation". Nat. Methods. 6 (9). United States: 677–81. doi:10.1038/nmeth.1363. PMID 19668202. {{cite journal}}: Cite has empty unknown parameters: |laydate=, |laysource=, and |laysummary= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help); Unknown parameter |quotes= ignored (help)
  23. ^ Hormozdiari, Fereydoun (2010). "Next-generation VariationHunter: combinatorial algorithms for transposon insertion discovery". Bioinformatics. 26 (12). England: i350-7. doi:10.1093/bioinformatics/btq216. PMC 2881400. PMID 20529927. {{cite journal}}: Cite has empty unknown parameters: |laydate=, |laysource=, and |laysummary= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help); Unknown parameter |month= ignored (help); Unknown parameter |quotes= ignored (help)
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