Controlled Somatic and Germline Copy Number Variation in the Mouse Model

Yann Herault,Arnaud Duchon,Matthieu Raveau,Damien Marechal,Patricia Pereira,Emilie Dalloneau,Veronique Brault

doi:10.2174/138920210793176038

Abstract

Changes in the number of chromosomes, but also variations in the copy number of chromosomal regions have been described in various pathological conditions, such as cancer and aneuploidy, but also in normal physiological condition. Our classical view of DNA replication and mitotic preservation of the chromosomal integrity is now challenged as new technologies allow us to observe such mosaic somatic changes in copy number affecting regions of chromosomes with various sizes. In order to go further in the understanding of copy number influence in normal condition we could take advantage of the novel strategy called Targeted Asymmetric Sister Chromatin Event of Recombination (TASCER) to induce recombination during the G2 phase so that we can generate deletions and duplications of regions of interest prior to mitosis. Using this approach in the mouse we could address the effects of copy number variation and segmental aneuploidy in daughter cells and allow us to explore somatic mosaics for large region of interest in the mouse.

Highlights

Our knowledge about human genetic variation has considerably evolved in the past few years with the development of genome-wide technologies unrevealing structural variations such as oligonucleotide microarray technologies and the next-generation sequencing with “paired-end” methods [1] that enable to screen the genome at a submicroscopic level
The identification of frequent copy number variants (CNVs) between individuals, including deletions and duplications of DNA sequences has definitely changed our view of genome integrity
In addition of being a major source of genetic diversity in the human population, CNVs are responsible for various pathological conditions such as cancer, aneuploidies and contiguous gene syndromes (CGS)

Summary

INTRODUCTION

Our knowledge about human genetic variation has considerably evolved in the past few years with the development of genome-wide technologies unrevealing structural variations such as oligonucleotide microarray technologies and the next-generation sequencing with “paired-end” methods [1] that enable to screen the genome at a submicroscopic level. The technology based on the Cre-loxP system is used to generate new chromosomes carrying deletions, duplications, inversions and translocations in targeted regions of interest and to study contiguous gene syndromes as well as normal developmental processes associated with CN V. Modelling chromosomal rearrangements such as deletions, duplications, inversions or translocations in the mouse genome has been made possible by combining gene targeting in embryonic stem (ES) cells [60,61,62,63] with site-specific recombinase (SSR) systems such as the Cre-loxP [64]. Nakatani and collaborators (2009) generated a 6.3 Mb duplication of the conserved linkage group on Mmu and showed that the mouse model generated recapitulated aspects of human autism such as social abnormalities and increased anxiety and fear, providing a new tool to decipher the physiological and molecular mechanism underlying this pathology

IN VIVO GERMLINE CRE-LOXP RECOMBINATION

Findings

SOMATIC GENETIC ENGINEERING