Abstract
One of the challenges of genomic research after the completion of the human genome project is to assign a function to all the genes and to understand their interactions and organizations. Among the various techniques, the emergence of chromosome engineering tools with the aim to manipulate large genomic regions in the mouse model offers a powerful way to accelerate the discovery of gene functions and provides more mouse models to study normal and pathological developmental processes associated with aneuploidy. The combination of gene targeting in ES cells, recombinase technology, and other techniques makes it possible to generate new chromosomes carrying specific and defined deletions, duplications, inversions, and translocations that are accelerating functional analysis. This review presents the current status of chromosome engineering techniques and discusses the different applications as well as the implication of these new techniques in future research to better understand the function of chromosomal organization and structures.
Highlights
Recent strategies to produce mouse lines that contain large genomic rearrangements represent a major advance to accelerate functional genomics and to provide animal models for developmental processes and human diseases such as contiguous gene and gene dosage effect syndromes
The possibility of manipulating large chromosome fragments or whole chromosomes using microcell-mediated chromosome transfer (MMCT) offers the opportunity to study the function of large genes or clusters of genes and provides more and more mouse models to study human pathologies such as contiguous gene syndromes
Chromosome engineering combined with the transchromosomic approach is widely used for dissecting the function, the regulation, and the contribution of genes to genetic disorders, such as contiguous gene and aneuploidy syndromes
Summary
Recent strategies to produce mouse lines that contain large genomic rearrangements represent a major advance to accelerate functional genomics and to provide animal models for developmental processes and human diseases such as contiguous gene and gene dosage effect syndromes. Homologous recombination in ES cells using replacement vectors has generated deletion of genomic fragments up to 30 kb [7,8], but inducing large defined chromosomal rearrangements was only achieved in the mid-1990s by taking advantages of the Cre/loxP recombinase system [9,10,11,12] and defining the chromosomal engineering strategy This technology led to the creation of new genetic tools for functional analysis of the mouse genome. Several groups succeeded in generating in vivo large deletions, duplications, inversions, and translocations (Table 1) This can be carried out between two loxP sites in cis either inserted in ES cells [22,74,75,76] or selected after classical crossing-over between two original founder lines by the sequential targeted recombination induced genomic rearrangement (STRING) (Figure 3), [24,77,78]. Duboule and collaborators to analyze the molecular mechanisms that modulate expression of Hox genes encoding transcription
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