Inverted duplications on acentric markers

Mechanism of formation

Andrea E. Murmann, Don Conrad, Heather Mashek, Chris A. Curtis, Raluca I. Nicolae, Carole Ober, Stuart Schwartz

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Acentric inverted duplication (inv dup) markers, the largest group of chromosomal abnormalities with neocentromere formation, are found in patients both with idiopathic mental retardation and with cancer. The mechanism of their formation has been investigated by analyzing the breakpoints and the genotypes of 12 inv dup marker cases (three trisomic, six tetrasomic, two polysomic and one X chromosome derived marker) using a combination of fluorescence in situ hybridization, quantitative SNP array and microsatellite analysis. Inv dup markers were found to form either symmetrically with one breakpoint or asymmetrically with two distinct breakpoints. Genotype analyses revealed that all inv dup markers formed from one single chromatid end. This observation is incompatible with the previously suggested model by which the acentric inv dup markers form through inter-chromosomal U-type exchange. On the basis of the identification of DNA sequence motifs with inverted homologies within all observed breakpoint regions, a new general mechanism is proposed for the acentric inv dup marker formation: following a double-strand break an acentric fragment forms, during either meiosis or mitosis. The open DNA end of the acentric fragment is stabilized by the formation of an intra-chromosomal loop promoted by the presence of sequences with inverted homologies. Likely coinciding with the neocentromere formation, this stabilized fragment is duplicated during an early mitotic event, insuring the marker's survival during cell division and its presence in all cells.

Original languageEnglish (US)
Pages (from-to)2241-2256
Number of pages16
JournalHuman molecular genetics
Volume18
Issue number12
DOIs
StatePublished - Jun 5 2009
Externally publishedYes

Fingerprint

Genotype
Sequence Inversion
Nucleotide Motifs
Chromatids
Meiosis
X Chromosome
Fluorescence In Situ Hybridization
Genetic Markers
Mitosis
Chromosome Aberrations
Intellectual Disability
Cell Division
Microsatellite Repeats
Single Nucleotide Polymorphism
Survival
DNA
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Murmann, A. E., Conrad, D., Mashek, H., Curtis, C. A., Nicolae, R. I., Ober, C., & Schwartz, S. (2009). Inverted duplications on acentric markers: Mechanism of formation. Human molecular genetics, 18(12), 2241-2256. https://doi.org/10.1093/hmg/ddp160

Inverted duplications on acentric markers : Mechanism of formation. / Murmann, Andrea E.; Conrad, Don; Mashek, Heather; Curtis, Chris A.; Nicolae, Raluca I.; Ober, Carole; Schwartz, Stuart.

In: Human molecular genetics, Vol. 18, No. 12, 05.06.2009, p. 2241-2256.

Research output: Contribution to journalArticle

Murmann, AE, Conrad, D, Mashek, H, Curtis, CA, Nicolae, RI, Ober, C & Schwartz, S 2009, 'Inverted duplications on acentric markers: Mechanism of formation', Human molecular genetics, vol. 18, no. 12, pp. 2241-2256. https://doi.org/10.1093/hmg/ddp160
Murmann AE, Conrad D, Mashek H, Curtis CA, Nicolae RI, Ober C et al. Inverted duplications on acentric markers: Mechanism of formation. Human molecular genetics. 2009 Jun 5;18(12):2241-2256. https://doi.org/10.1093/hmg/ddp160
Murmann, Andrea E. ; Conrad, Don ; Mashek, Heather ; Curtis, Chris A. ; Nicolae, Raluca I. ; Ober, Carole ; Schwartz, Stuart. / Inverted duplications on acentric markers : Mechanism of formation. In: Human molecular genetics. 2009 ; Vol. 18, No. 12. pp. 2241-2256.
@article{bc5427c4edb0478c87c9d895f4329eef,
title = "Inverted duplications on acentric markers: Mechanism of formation",
abstract = "Acentric inverted duplication (inv dup) markers, the largest group of chromosomal abnormalities with neocentromere formation, are found in patients both with idiopathic mental retardation and with cancer. The mechanism of their formation has been investigated by analyzing the breakpoints and the genotypes of 12 inv dup marker cases (three trisomic, six tetrasomic, two polysomic and one X chromosome derived marker) using a combination of fluorescence in situ hybridization, quantitative SNP array and microsatellite analysis. Inv dup markers were found to form either symmetrically with one breakpoint or asymmetrically with two distinct breakpoints. Genotype analyses revealed that all inv dup markers formed from one single chromatid end. This observation is incompatible with the previously suggested model by which the acentric inv dup markers form through inter-chromosomal U-type exchange. On the basis of the identification of DNA sequence motifs with inverted homologies within all observed breakpoint regions, a new general mechanism is proposed for the acentric inv dup marker formation: following a double-strand break an acentric fragment forms, during either meiosis or mitosis. The open DNA end of the acentric fragment is stabilized by the formation of an intra-chromosomal loop promoted by the presence of sequences with inverted homologies. Likely coinciding with the neocentromere formation, this stabilized fragment is duplicated during an early mitotic event, insuring the marker's survival during cell division and its presence in all cells.",
author = "Murmann, {Andrea E.} and Don Conrad and Heather Mashek and Curtis, {Chris A.} and Nicolae, {Raluca I.} and Carole Ober and Stuart Schwartz",
year = "2009",
month = "6",
day = "5",
doi = "10.1093/hmg/ddp160",
language = "English (US)",
volume = "18",
pages = "2241--2256",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "12",

}

TY - JOUR

T1 - Inverted duplications on acentric markers

T2 - Mechanism of formation

AU - Murmann, Andrea E.

AU - Conrad, Don

AU - Mashek, Heather

AU - Curtis, Chris A.

AU - Nicolae, Raluca I.

AU - Ober, Carole

AU - Schwartz, Stuart

PY - 2009/6/5

Y1 - 2009/6/5

N2 - Acentric inverted duplication (inv dup) markers, the largest group of chromosomal abnormalities with neocentromere formation, are found in patients both with idiopathic mental retardation and with cancer. The mechanism of their formation has been investigated by analyzing the breakpoints and the genotypes of 12 inv dup marker cases (three trisomic, six tetrasomic, two polysomic and one X chromosome derived marker) using a combination of fluorescence in situ hybridization, quantitative SNP array and microsatellite analysis. Inv dup markers were found to form either symmetrically with one breakpoint or asymmetrically with two distinct breakpoints. Genotype analyses revealed that all inv dup markers formed from one single chromatid end. This observation is incompatible with the previously suggested model by which the acentric inv dup markers form through inter-chromosomal U-type exchange. On the basis of the identification of DNA sequence motifs with inverted homologies within all observed breakpoint regions, a new general mechanism is proposed for the acentric inv dup marker formation: following a double-strand break an acentric fragment forms, during either meiosis or mitosis. The open DNA end of the acentric fragment is stabilized by the formation of an intra-chromosomal loop promoted by the presence of sequences with inverted homologies. Likely coinciding with the neocentromere formation, this stabilized fragment is duplicated during an early mitotic event, insuring the marker's survival during cell division and its presence in all cells.

AB - Acentric inverted duplication (inv dup) markers, the largest group of chromosomal abnormalities with neocentromere formation, are found in patients both with idiopathic mental retardation and with cancer. The mechanism of their formation has been investigated by analyzing the breakpoints and the genotypes of 12 inv dup marker cases (three trisomic, six tetrasomic, two polysomic and one X chromosome derived marker) using a combination of fluorescence in situ hybridization, quantitative SNP array and microsatellite analysis. Inv dup markers were found to form either symmetrically with one breakpoint or asymmetrically with two distinct breakpoints. Genotype analyses revealed that all inv dup markers formed from one single chromatid end. This observation is incompatible with the previously suggested model by which the acentric inv dup markers form through inter-chromosomal U-type exchange. On the basis of the identification of DNA sequence motifs with inverted homologies within all observed breakpoint regions, a new general mechanism is proposed for the acentric inv dup marker formation: following a double-strand break an acentric fragment forms, during either meiosis or mitosis. The open DNA end of the acentric fragment is stabilized by the formation of an intra-chromosomal loop promoted by the presence of sequences with inverted homologies. Likely coinciding with the neocentromere formation, this stabilized fragment is duplicated during an early mitotic event, insuring the marker's survival during cell division and its presence in all cells.

UR - http://www.scopus.com/inward/record.url?scp=66149168915&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=66149168915&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddp160

DO - 10.1093/hmg/ddp160

M3 - Article

VL - 18

SP - 2241

EP - 2256

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 12

ER -