Successful transmission and transcriptional deployment of a human chromosome via mouse male meiosis

Abstract
Data availability
Article and author information
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Abstract

Most human aneuploidies originate maternally, due in part to the presence of highly stringent checkpoints during male meiosis. Indeed, male sterility is common among aneuploid mice used to study chromosomal abnormalities, and male germline transmission of exogenous DNA has been rarely reported. Here we show that despite aberrant testis architecture, males of the aneuploid Tc1 mouse strain produce viable sperm and transmit human chromosome 21 to create aneuploid offspring. In these offspring, we mapped transcription, transcriptional initiation, enhancer activity, non-methylated DNA and transcription factor binding in adult tissues. Remarkably, when compared with mice derived from female passage of human chromosome 21, the chromatin condensation during spermatogenesis and the extensive epigenetic reprogramming specific to male germline transmission resulted in almost indistinguishable patterns of transcriptional deployment. Our results reveal an unexpected tolerance of aneuploidy during mammalian spermatogenesis, and the surprisingly robust ability of mouse developmental machinery to accurately deploy an exogenous chromosome, regardless of germline transmission.

Data availability

The following data sets were generated

1. Ernst C
2. Odom DT
(2016) Chip-Seq analysis of human chromosome 21 after its passage through either the female or male mouse germline
Publicly available at the EBI European Nucleotide Archive (accession no: E-MTAB-4913).

http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-4913
1. Ernst C
2. Odom DT
(2016) BioCAP-Seq analysis of human chromosome 21 after its passage through either the mouse male germline
Publicly available at the EBI European Nucleotide Archive (accession no: E-MTAB-4930).

http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-4930
1. Ernst C
2. Odom DT
(2016) RNA-Seq in liver of Tc1 mice carrying human chromosome 21 passaged through either the female or male germline
Publicly available at the EBI European Nucleotide Archive (accession no: E-MTAB-4912).

http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-4912

The following previously published data sets were used

1. Ward MC
2. Wilson MD
3. Barbosa-Morais NL
4. Schmidt D
5. Stark R
6. Pan Q
7. Schwalie PC
8. Menon S
9. Lukk M
10. Watt S
11. Thybert D
12. Kutter C
13. Kirschner K
14. Flicek P
15. Blencowe BJ
16. Odom DT
(2014) E-MTAB-1104 - ChIP-seq of human and transgenic mouse adult liver, testes & kidney tissue to investigate epigenetic comparison
Publicly available at the EBI European Nucleotide Archive (accession no: E-MTAB-1104).

http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-1104/
1. Villar D
2. Berthelot C
3. Flicek P
4. Odom DT
(2015) E-MTAB-2633 - ChIP-Seq analysis of regulatory evolution in 20 mammals
Publicly available at the EBI European Nucleotide Archive (accession no: E-MTAB-2633).

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-2633/
1. Schmidt D
2. Wilson MD
3. Ballester B
4. Schwalie PC
5. Brown GD
6. Marshall A
7. Kutter C
8. Watt S
9. Martinez-Jimenes CP
10. Mackay S
11. Talianidis I
12. Flicek P
13. Odom DT
(2010) E-TABM-722 - ChIP-seq of Canis familiaris, Gallus gallus, Mus musculus, Homo sapiens, Monodelphis domestica to investigate CEBPA and HNF4a binding in five vertebrates
Publicly available at the EBI European Nucleotide Archive (accession no: E-TABM-722).

https://www.ebi.ac.uk/arrayexpress/experiments/E-TABM-722/
1. Long HK
2. Klose RJ
(2016) An evolutionarily conserved DNA-encoded logic shapes CpG island formation
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE72208).

http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE72208

Article and author information

Author details

Christina Ernst

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-3569-2209
Jeremy Pike

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom

Competing interests
No competing interests declared.
Sarah J Aitken

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom

Competing interests
No competing interests declared.
Hannah K Long

Department of Biochemistry, University of Oxford, Oxford, United Kingdom

Competing interests
No competing interests declared.
Nils Eling

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom

Competing interests
No competing interests declared.
Lovorka Stojic

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom

Competing interests
No competing interests declared.
Frances Connor

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom

Competing interests
No competing interests declared.
Tim F Rayner

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom

Competing interests
No competing interests declared.
Margus Lukk

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom

Competing interests
No competing interests declared.
Robert J Klose

Department of Biochemistry, University of Oxford, Oxford, United Kingdom

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-8726-7888
Claudia Kutter

Science for Life Laboratory, Stockholm, Sweden

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-8047-0058
Duncan T Odom

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom

For correspondence
Duncan.Odom@cruk.cam.ac.uk

Competing interests
Duncan T Odom, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0001-6201-5599

Funding

Cancer Research UK (A20412)

Christina Ernst
Sarah J Aitken
Nils Eling
Frances Connor
Tim F Rayner
Margus Lukk
Claudia Kutter
Duncan T Odom

European Research Council (615584)

Duncan T Odom

Wellcome (098024/Z/11/Z)

Robert J Klose

Wellcome (106563/Z/14/A)

Sarah J Aitken

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This investigation was approved by the Animal Welfare and Ethics Review Board and followed the Cambridge Institute guidelines for the use of animals in experimental studies under Home Office license PPL 70/7535.

Human subjects: Previously published human data from Ward et al. 2013 were used for comparisons in this study.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.