A 15 Mb large paracentric chromosome 21 inversion identified in Czech population through a pair of flanking duplications

Molecular Cytogenetics

Zdenek Sedlacek²  Marketa Havlovicova²  Michaela Hejtmankova¹  Drahuse Novotna²  Miroslava Hancarova²  Marie Trkova¹  Jana Drabova² 

[1] Gennet, Prague, Czech Republic;Department of Biology and Medical Genetics, Charles University 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic

关键词: Founder effect;    SNP arrays;    USP25;    Duplication;    Inversion;   

Others  :  1149851
DOI  :  10.1186/1755-8166-7-51

 received in 2014-04-09, accepted in 2014-06-20,  发布年份 2014

【 摘 要 】

Background

Inversions are balanced structural chromosome rearrangements, which can influence gene expression and the risk of unbalanced chromosome constitution in offspring. Many examples of inversion polymorphisms exist in human, affecting both heterochromatic regions and euchromatin.

Results

We describe a novel, 15 Mb long paracentric inversion, inv(21)(q21.1q22.11), affecting more than a third of human 21q. Despite of its length, the inversion cannot be detected using karyotyping due to similar band patterns on the normal and inverted chromosomes, and is therefore likely to escape attention. Its identification was aided by the repeated observation of the same pair of 150 kb long duplications present in cis on chromosome 21 in three Czech families subjected to microarray analysis. The finding prompted us to hypothesise that this co-occurrence of two remote duplications could be associated with an inversion of the intervening segment, and this speculation turned out to be right. The inversion was confirmed in a series of FISH experiments which also showed that the second copy of each of the duplications was always located at the opposite end of the inversion. The presence of the same pair of duplications in additional individuals reported in public databases indicates that the inversion may also be present in other populations. Three out of the total of about 4000 chromosomes 21 examined in our sample carried the duplications and were inverted, corresponding to carrier frequency of about 1/660. Although the breakpoints affect protein-coding genes, the occurrence of the inversion in normal parents and siblings of our patients and the occurrence of the duplications in unaffected controls in databases indicate that this rare variant is rather non-pathogenic. The inverted segment carried an identical shared haplotype in the three families studied. The haplotypes, however, diverged very rapidly in the flanking regions, possibly pointing to an ancient founder event at the origin of the inversion.

Conclusions

The identification of inv(21)(q21.1q22.11) supports the notion that paracentric inversions are the most common form of chromosomal variation and that some of them may still remain undetected.

【 授权许可】

   
2014 Drabova et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Walzer S, Breau G, Gerald PS: A chromosome survey of 2,400 normal newborn infants. J Pediatr 1969, 74:438-448.
• [2]Feuk L: Inversion variants in the human genome: role in disease and genome architecture. Genome Med 2010, 2:11. BioMed Central Full Text
• [3]Salm MP, Horswell SD, Hutchison CE, Speedy HE, Yang X, Liang L, Schadt EE, Cookson WO, Wierzbicki AS, Naoumova RP, Shoulders CC: The origin, global distribution, and functional impact of the human 8p23 inversion polymorphism. Genome Res 2012, 22:1144-1153.
• [4]Giglio S, Broman KW, Matsumoto N, Calvari V, Gimelli G, Neumann T, Ohashi H, Voullaire L, Larizza D, Giorda R, Weber JL, Ledbetter DH, Zuffardi O: Olfactory receptor-gene clusters, genomic-inversion polymorphisms, and common chromosome rearrangements. Am J Hum Genet 2001, 68:874-883.
• [5]Gilling M, Dullinger JS, Gesk S, Metzke-Heidemann S, Siebert R, Meyer T, Brondum-Nielsen K, Tommerup N, Ropers HH, Tumer Z, Kalscheuer VM, Thomas NS: Breakpoint cloning and haplotype analysis indicate a single origin of the common Inv(10)(p11.2q21.2) mutation among northern Europeans. Am J Hum Genet 2006, 78:878-883.
• [6]Fickelscher I, Liehr T, Watts K, Bryant V, Barber JC, Heidemann S, Siebert R, Hertz JM, Tumer Z, Simon Thomas N: The variant inv(2)(p11.2q13) is a genuinely recurrent rearrangement but displays some breakpoint heterogeneity. Am J Hum Genet 2007, 81:847-856.
• [7]Youings S, Ellis K, Ennis S, Barber J, Jacobs P: A study of reciprocal translocations and inversions detected by light microscopy with special reference to origin, segregation, and recurrent abnormalities. Am J Med Genet A 2004, 126A:46-60.
• [8]Martinez-Fundichely A, Casillas S, Egea R, Ramia M, Barbadilla A, Pantano L, Puig M, Caceres M: InvFEST, a database integrating information of polymorphic inversions in the human genome. Nucleic Acids Res 2014, 42:D1027-D1032.
• [9]Macdonald JR, Ziman R, Yuen RK, Feuk L, Scherer SW: The Database of Genomic Variants: a curated collection of structural variation in the human genome. Nucleic Acids Res 2014, 42:D986-D992.
• [10]Lakich D, Kazazian HH Jr, Antonarakis SE, Gitschier J: Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nat Genet 1993, 5:236-241.
• [11]Kleczkowska A, Fryns JP, Van den Berghe H: Pericentric inversions in man: personal experience and review of the literature. Hum Genet 1987, 75:333-338.
• [12]Madan K: Paracentric inversions: a review. Hum Genet 1995, 96:503-515.
• [13]Osborne LR, Li M, Pober B, Chitayat D, Bodurtha J, Mandel A, Costa T, Grebe T, Cox S, Tsui LC, Scherer SW: A 1.5 million-base pair inversion polymorphism in families with Williams-Beuren syndrome. Nat Genet 2001, 29:321-325.
• [14]Antonacci F, Kidd JM, Marques-Bonet T, Ventura M, Siswara P, Jiang Z, Eichler EE: Characterization of six human disease-associated inversion polymorphisms. Hum Mol Genet 2009, 18:2555-2566.
• [15]Thomas NS, Bryant V, Maloney V, Cockwell AE, Jacobs PA: Investigation of the origins of human autosomal inversions. Hum Genet 2008, 123:607-616.
• [16]Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C, Williams C, Stalker H, Hamid R, Hannig V, Abdel-Hamid H, Bader P, McCracken E, Niyazov D, Leppig K, Thiese H, Hummel M, Alexander N, Gorski J, Kussmann J, Shashi V, Johnson K, Rehder C, Ballif BC, Shaffer LG, Eichler EE: A copy number variation morbidity map of developmental delay. Nat Genet 2011, 43:838-846.
• [17]Vogler C, Gschwind L, Rothlisberger B, Huber A, Filges I, Miny P, Auschra B, Stetak A, Demougin P, Vukojevic V, Kolassa IT, Elbert T, de Quervain DJ, Papassotiropoulos A: Microarray-based maps of copy-number variant regions in European and sub-Saharan populations. PLoS One 2010, 5:e15246.
• [18]Morel F, Laudier B, Guerif F, Couet ML, Royere D, Roux C, Bresson JL, Amice V, De Braekeleer M, Douet-Guilbert N: Meiotic segregation analysis in spermatozoa of pericentric inversion carriers using fluorescence in-situ hybridization. Hum Reprod 2007, 22:136-141.
• [19]Jaarola M, Martin RH, Ashley T: Direct evidence for suppression of recombination within two pericentric inversions in humans: a new sperm-FISH technique. Am J Hum Genet 1998, 63:218-224.
• [20]Bhatt SS, Manvelyan M, Moradkhani K, Hunstig F, Mrasek K, Puechberty J, Lefort G, Sarda P, Weise A, Liehr T, Pellestor F: Inverted segment size and the presence of recombination hot spot clusters matter in sperm segregation analysis. Cytogenet Genome Res 2014, 142:145-149.
• [21]O'Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB, Phelps IG, Carvill G, Kumar A, Lee C, Ankenman K, Munson J, Hiatt JB, Turner EH, Levy R, O'Day DR, Krumm N, Coe BP, Martin BK, Borenstein E, Nickerson DA, Mefford HC, Doherty D, Akey JM, Bernier R, Eichler EE, Shendure J: Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 2012, 338:1619-1622.
• [22]de Jong S, Chepelev I, Janson E, Strengman E, van den Berg LH, Veldink JH, Ophoff RA: Common inversion polymorphism at 17q21.31 affects expression of multiple genes in tissue-specific manner. BMC Genomics 2012, 13:458. BioMed Central Full Text
• [23]Courtens W, Grossman D, Van Roy N, Messiaen L, Vamos E, Toppet V, Haumont D, Streydio C, Jauch A, Vermeesch JR, Speleman F: Noonan-like phenotype in monozygotic twins with a duplication-deficiency of the long arm of chromosome 18 resulting from a maternal paracentric inversion. Hum Genet 1998, 103:497-505.
• [24]Barbi G, Kennerknecht I, Wohr G, Avramopoulos D, Karadima G, Petersen MB: Mirror-symmetric duplicated chromosome 21q with minor proximal deletion, and with neocentromere in a child without the classical Down syndrome phenotype. Am J Med Genet 2000, 91:116-122.
• [25]Weise A, Rittinger O, Starke H, Ziegler M, Claussen U, Liehr T: De novo 9-break-event in one chromosome 21 combined with a microdeletion in 21q22.11 in a mentally retarded boy with short stature. Cytogenet Genome Res 2003, 103:14-16.
• [26]Mau UA, Petruch UR, Kaiser P, Eggermann T: Familial robertsonian translocation 15;21 and rare paracentric inv(21): unexpected re-inversion in a child with translocation trisomy 21. Eur J Hum Genet 2000, 8:815-819.
• [27]Entesarian M, Carlsson B, Mansouri MR, Stattin EL, Holmberg E, Golovleva I, Stefansson H, Klar J, Dahl N: A chromosome 10 variant with a 12 Mb inversion [inv(10)(q11.22q21.1)] identical by descent and frequent in the Swedish population. Am J Med Genet A 2009, 149A:380-386.
• [28]Colella S, Yau C, Taylor JM, Mirza G, Butler H, Clouston P, Bassett AS, Seller A, Holmes CC, Ragoussis J: QuantiSNP: an Objective Bayes Hidden-Markov Model to detect and accurately map copy number variation using SNP genotyping data. Nucleic Acids Res 2007, 35:2013-2025.