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2017 ; 28
(7-8
): 302-314
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From engineering to editing the rat genome
#MMPMID28752194
Meek S
; Mashimo T
; Burdon T
Mamm Genome
2017[Aug]; 28
(7-8
): 302-314
PMID28752194
show ga
Since its domestication over 100 years ago, the laboratory rat has been the
preferred experimental animal in many areas of biomedical research (Lindsey and
Baker The laboratory rat. Academic, New York, pp 1-52, 2006). Its physiology,
size, genetics, reproductive cycle, cognitive and behavioural characteristics
have made it a particularly useful animal model for studying many human disorders
and diseases. Indeed, through selective breeding programmes numerous strains have
been derived that are now the mainstay of research on hypertension, obesity and
neurobiology (Okamoto and Aoki Jpn Circ J 27:282-293, 1963; Zucker and Zucker J
Hered 52(6):275-278, 1961). Despite this wealth of genetic and phenotypic
diversity, the ability to manipulate and interrogate the genetic basis of
existing phenotypes in rat strains and the methodology to generate new rat models
has lagged significantly behind the advances made with its close cousin, the
laboratory mouse. However, recent technical developments in stem cell biology and
genetic engineering have again brought the rat to the forefront of biomedical
studies and enabled researchers to exploit the increasingly accessible wealth of
genome sequence information. In this review, we will describe how a breakthrough
in understanding the molecular basis of self-renewal of the pluripotent founder
cells of the mammalian embryo, embryonic stem (ES) cells, enabled the derivation
of rat ES cells and their application in transgenesis. We will also describe the
remarkable progress that has been made in the development of gene editing enzymes
that enable the generation of transgenic rats directly through targeted genetic
modifications in the genomes of zygotes. The simplicity, efficiency and
cost-effectiveness of the CRISPR/Cas gene editing system, in particular, mean
that the ability to engineer the rat genome is no longer a limiting factor. The
selection of suitable targets and gene modifications will now become a priority:
a challenge where ES culture and gene editing technologies can play complementary
roles in generating accurate bespoke rat models for studying biological processes
and modelling human disease.
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