Massively parallel sequencing reveals the complex structure of an irradiated human chromosome on a mouse background in the Tc1 model of Down syndrome
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Massively parallel sequencing reveals the complex structure of an irradiated human chromosome on a mouse background in the Tc1 model of Down syndrome. / Gribble, Susan M; Wiseman, Frances K; Clayton, Stephen; Prigmore, Elena; Langley, Elizabeth; Yang, Fengtang; Maguire, Sean; Fu, Beiyuan; Rajan, Diana; Sheppard, Olivia; Scott, Carol; Hauser, Heidi; Stephens, Philip J; Stebbings, Lucy A; Ng, Bee Ling; Fitzgerald, Tomas; Quail, Michael A; Banerjee, Ruby; Rothkamm, Kai; Tybulewicz, Victor L J; Fisher, Elizabeth M C; Carter, Nigel P.
In: PLOS ONE, Vol. 8, No. 4, 2013, p. e60482.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Massively parallel sequencing reveals the complex structure of an irradiated human chromosome on a mouse background in the Tc1 model of Down syndrome
AU - Gribble, Susan M
AU - Wiseman, Frances K
AU - Clayton, Stephen
AU - Prigmore, Elena
AU - Langley, Elizabeth
AU - Yang, Fengtang
AU - Maguire, Sean
AU - Fu, Beiyuan
AU - Rajan, Diana
AU - Sheppard, Olivia
AU - Scott, Carol
AU - Hauser, Heidi
AU - Stephens, Philip J
AU - Stebbings, Lucy A
AU - Ng, Bee Ling
AU - Fitzgerald, Tomas
AU - Quail, Michael A
AU - Banerjee, Ruby
AU - Rothkamm, Kai
AU - Tybulewicz, Victor L J
AU - Fisher, Elizabeth M C
AU - Carter, Nigel P
PY - 2013
Y1 - 2013
N2 - Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and presents a complex phenotype that arises from abnormal dosage of genes on this chromosome. However, the individual dosage-sensitive genes underlying each phenotype remain largely unknown. To help dissect genotype--phenotype correlations in this complex syndrome, the first fully transchromosomic mouse model, the Tc1 mouse, which carries a copy of human chromosome 21 was produced in 2005. The Tc1 strain is trisomic for the majority of genes that cause phenotypes associated with DS, and this freely available mouse strain has become used widely to study DS, the effects of gene dosage abnormalities, and the effect on the basic biology of cells when a mouse carries a freely segregating human chromosome. Tc1 mice were created by a process that included irradiation microcell-mediated chromosome transfer of Hsa21 into recipient mouse embryonic stem cells. Here, the combination of next generation sequencing, array-CGH and fluorescence in situ hybridization technologies has enabled us to identify unsuspected rearrangements of Hsa21 in this mouse model; revealing one deletion, six duplications and more than 25 de novo structural rearrangements. Our study is not only essential for informing functional studies of the Tc1 mouse but also (1) presents for the first time a detailed sequence analysis of the effects of gamma radiation on an entire human chromosome, which gives some mechanistic insight into the effects of radiation damage on DNA, and (2) overcomes specific technical difficulties of assaying a human chromosome on a mouse background where highly conserved sequences may confound the analysis. Sequence data generated in this study is deposited in the ENA database, Study Accession number: ERP000439.
AB - Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and presents a complex phenotype that arises from abnormal dosage of genes on this chromosome. However, the individual dosage-sensitive genes underlying each phenotype remain largely unknown. To help dissect genotype--phenotype correlations in this complex syndrome, the first fully transchromosomic mouse model, the Tc1 mouse, which carries a copy of human chromosome 21 was produced in 2005. The Tc1 strain is trisomic for the majority of genes that cause phenotypes associated with DS, and this freely available mouse strain has become used widely to study DS, the effects of gene dosage abnormalities, and the effect on the basic biology of cells when a mouse carries a freely segregating human chromosome. Tc1 mice were created by a process that included irradiation microcell-mediated chromosome transfer of Hsa21 into recipient mouse embryonic stem cells. Here, the combination of next generation sequencing, array-CGH and fluorescence in situ hybridization technologies has enabled us to identify unsuspected rearrangements of Hsa21 in this mouse model; revealing one deletion, six duplications and more than 25 de novo structural rearrangements. Our study is not only essential for informing functional studies of the Tc1 mouse but also (1) presents for the first time a detailed sequence analysis of the effects of gamma radiation on an entire human chromosome, which gives some mechanistic insight into the effects of radiation damage on DNA, and (2) overcomes specific technical difficulties of assaying a human chromosome on a mouse background where highly conserved sequences may confound the analysis. Sequence data generated in this study is deposited in the ENA database, Study Accession number: ERP000439.
KW - Animals
KW - Chromosomes, Human/radiation effects
KW - Chromosomes, Human, Pair 21
KW - Comparative Genomic Hybridization
KW - Disease Models, Animal
KW - Down Syndrome/genetics
KW - Gamma Rays/adverse effects
KW - Gene Dosage
KW - High-Throughput Nucleotide Sequencing
KW - Humans
KW - In Situ Hybridization, Fluorescence
KW - Male
KW - Mice
KW - Oligonucleotide Array Sequence Analysis
KW - Recombination, Genetic
KW - Trisomy
U2 - 10.1371/journal.pone.0060482
DO - 10.1371/journal.pone.0060482
M3 - SCORING: Journal article
C2 - 23596509
VL - 8
SP - e60482
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 4
ER -
