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

Christina Ernst,Michelle C Ward,Frances Connor,Margus Lukk,Hannah K Long,Duncan T Odom,Timothy F Rayner,Claudia Kutter,Robert J Klose,Nils Eling,Lovorka Stojic,Sarah J Aitken,Jeremy Pike

doi:10.7554/elife.20235

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.

Highlights

IntroductionThe most common viable aneuploidy in humans is Down Syndrome, which is caused by an extra copy of chromosome 21 that is maternally inherited in over 90% of all cases (Hulten et al, 2010)
We demonstrate that the male mouse-transmitted human chromosome is accurately regulated and transcribed in derived somatic tissues, despite having undergone chromatin condensation and epigenetic reprogramming associated with spermatogenesis
The large-scale remodelling caused by male germline passage of the human chromosome resulted in transcription initiation indistinguishable from female germline-derived HsChr21 (Figure 4—figure supplement 1). These results strongly argue that the process of chromatin decondensation after fertilization does not distort the transcriptional deployment of the aneuploid human chromosome during mouse embryogenesis

Summary

Introduction

The most common viable aneuploidy in humans is Down Syndrome, which is caused by an extra copy of chromosome 21 that is maternally inherited in over 90% of all cases (Hulten et al, 2010). An elegant mouse model of human Down Syndrome is the aneuploid Tc1 mouse, which transmits an almost complete copy of human chromosome 21 (HsChr21) via the female germline (O’Doherty et al, 2005; Sheppard et al, 2012). Passage of aneuploid DNA via the female germline is preferred in the majority of trisomic mouse models, most of which exhibit total male sterility (Davisson et al, 2007; Hernandez and Fisher, 1999). Efficient and stable male germline transmission of foreign aneuploid DNA has only been reported in mice for comparatively small human artificial or fragmented chromosomes (Tomizuka et al, 1997; Voet et al, 2001; Weuts et al, 2012).

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