Absence of Heterozygosity Due to Template Switching during Replicative Rearrangements

Claudia M. B. Carvalho; Rolph Pfundt; Daniel A. King; Sarah J. Lindsay; Luciana W. Zuccherato; Merryn V. E. Macville; Pengfei Liu; Diana Johnson; Pawel Stankiewicz; Chester W. Brown; Chad A. Shaw; Matthew E. Hurles; Grzegorz Ira; P. J. Hastings; Han G. Brunner; James R. Lupski

doi:10.1016/j.ajhg.2015.01.021

Absence of Heterozygosity Due to Template Switching during Replicative Rearrangements

Claudia M. B. Carvalho
, Rolph Pfundt
, Daniel A. King
, Sarah J. Lindsay
, Luciana W. Zuccherato
, Merryn V. E. Macville
, Pengfei Liu
, Diana Johnson
, Pawel Stankiewicz
, Chester W. Brown
, Chad A. Shaw
, Matthew E. Hurles
, Grzegorz Ira
, P. J. Hastings
, Han G. Brunner
, James R. Lupski^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

We investigated complex genomic rearrangements (CGRs) consisting of triplication copy-number variants (CNVs) that were accompanied by extended regions of copy-number-neutral absence of heterozygosity (AOH) in subjects with multiple congenital abnormalities. Molecular analyses provided observational evidence that in humans, post-zygotically generated CGRs can lead to regional uniparental disomy (UPD) due to template switches between homologs versus sister chromatids by using microhomology to prime DNA replication-a prediction of the replicative repair model, MMBIR. Our findings suggest that replication-based mechanisms might underlie the formation of diverse types of genomic alterations (CGRs and AOH) implicated in constitutional disorders.

Original language	English
Pages (from-to)	555-564
Number of pages	10
Journal	American Journal of Human Genetics
Volume	96
Issue number	4
DOIs	https://doi.org/10.1016/j.ajhg.2015.01.021
Publication status	Published - 2 Apr 2015

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Carvalho, C. M. B., Pfundt, R., King, D. A., Lindsay, S. J., Zuccherato, L. W., Macville, M. V. E., Liu, P., Johnson, D., Stankiewicz, P., Brown, C. W., Shaw, C. A., Hurles, M. E., Ira, G., Hastings, P. J., Brunner, H. G., & Lupski, J. R. (2015). Absence of Heterozygosity Due to Template Switching during Replicative Rearrangements. American Journal of Human Genetics, 96(4), 555-564. https://doi.org/10.1016/j.ajhg.2015.01.021

@article{65d8e367b6ee4a3ab9df2614865f3d6b,

title = "Absence of Heterozygosity Due to Template Switching during Replicative Rearrangements",

abstract = "We investigated complex genomic rearrangements (CGRs) consisting of triplication copy-number variants (CNVs) that were accompanied by extended regions of copy-number-neutral absence of heterozygosity (AOH) in subjects with multiple congenital abnormalities. Molecular analyses provided observational evidence that in humans, post-zygotically generated CGRs can lead to regional uniparental disomy (UPD) due to template switches between homologs versus sister chromatids by using microhomology to prime DNA replication-a prediction of the replicative repair model, MMBIR. Our findings suggest that replication-based mechanisms might underlie the formation of diverse types of genomic alterations (CGRs and AOH) implicated in constitutional disorders.",

author = "Carvalho, \{Claudia M. B.\} and Rolph Pfundt and King, \{Daniel A.\} and Lindsay, \{Sarah J.\} and Zuccherato, \{Luciana W.\} and Macville, \{Merryn V. E.\} and Pengfei Liu and Diana Johnson and Pawel Stankiewicz and Brown, \{Chester W.\} and Shaw, \{Chad A.\} and Hurles, \{Matthew E.\} and Grzegorz Ira and Hastings, \{P. J.\} and Brunner, \{Han G.\} and Lupski, \{James R.\}",

year = "2015",

month = apr,

day = "2",

doi = "10.1016/j.ajhg.2015.01.021",

language = "English",

volume = "96",

pages = "555--564",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "4",

}

Carvalho, CMB, Pfundt, R, King, DA, Lindsay, SJ, Zuccherato, LW, Macville, MVE, Liu, P, Johnson, D, Stankiewicz, P, Brown, CW, Shaw, CA, Hurles, ME, Ira, G, Hastings, PJ, Brunner, HG & Lupski, JR 2015, 'Absence of Heterozygosity Due to Template Switching during Replicative Rearrangements', American Journal of Human Genetics, vol. 96, no. 4, pp. 555-564. https://doi.org/10.1016/j.ajhg.2015.01.021

TY - JOUR

T1 - Absence of Heterozygosity Due to Template Switching during Replicative Rearrangements

AU - Carvalho, Claudia M. B.

AU - Pfundt, Rolph

AU - King, Daniel A.

AU - Lindsay, Sarah J.

AU - Zuccherato, Luciana W.

AU - Macville, Merryn V. E.

AU - Liu, Pengfei

AU - Johnson, Diana

AU - Stankiewicz, Pawel

AU - Brown, Chester W.

AU - Shaw, Chad A.

AU - Hurles, Matthew E.

AU - Ira, Grzegorz

AU - Hastings, P. J.

AU - Brunner, Han G.

AU - Lupski, James R.

PY - 2015/4/2

Y1 - 2015/4/2

N2 - We investigated complex genomic rearrangements (CGRs) consisting of triplication copy-number variants (CNVs) that were accompanied by extended regions of copy-number-neutral absence of heterozygosity (AOH) in subjects with multiple congenital abnormalities. Molecular analyses provided observational evidence that in humans, post-zygotically generated CGRs can lead to regional uniparental disomy (UPD) due to template switches between homologs versus sister chromatids by using microhomology to prime DNA replication-a prediction of the replicative repair model, MMBIR. Our findings suggest that replication-based mechanisms might underlie the formation of diverse types of genomic alterations (CGRs and AOH) implicated in constitutional disorders.

AB - We investigated complex genomic rearrangements (CGRs) consisting of triplication copy-number variants (CNVs) that were accompanied by extended regions of copy-number-neutral absence of heterozygosity (AOH) in subjects with multiple congenital abnormalities. Molecular analyses provided observational evidence that in humans, post-zygotically generated CGRs can lead to regional uniparental disomy (UPD) due to template switches between homologs versus sister chromatids by using microhomology to prime DNA replication-a prediction of the replicative repair model, MMBIR. Our findings suggest that replication-based mechanisms might underlie the formation of diverse types of genomic alterations (CGRs and AOH) implicated in constitutional disorders.

U2 - 10.1016/j.ajhg.2015.01.021

DO - 10.1016/j.ajhg.2015.01.021

M3 - Article

C2 - 25799105

SN - 0002-9297

VL - 96

SP - 555

EP - 564

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 4

ER -

Absence of Heterozygosity Due to Template Switching during Replicative Rearrangements

Abstract

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