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
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",

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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",

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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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