Manipulating the Mouse Genome to Engineer Precise Functional Syntenic Replacements with Human Sequence

Helen A C Wallace, Fatima Marques-Kranc, Melville Richardson, Francisco Luna-Crespo, Jackie A. Sharpe, Jim Hughes, William G. Wood, Douglas R. Higgs, Andrew J H Smith*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

We have devised a strategy (called recombinase-mediated genomic replacement, RMGR) to allow the replacement of large segments (>100 kb) of the mouse genome with the equivalent human syntenic region. The technique involves modifying a mouse ES cell chromosome and a human BAC by inserting heterotypic lox sites to flank the proposed exchange interval and then using Cre recombinase to achieve segmental exchange. We have demonstrated the feasibility of this approach by replacing the mouse α globin regulatory domain with the human syntenic region and generating homozygous mice that produce only human α globin chains. Furthermore, modified ES cells can be used iteratively for functional studies, and here, as an example, we have used RMGR to produce an accurate mouse model of human α thalassemia. RMGR has general applicability and will overcome limitations inherent in current transgenic technology when studying the expression of human genes and modeling human genetic diseases.

Original languageEnglish
Pages (from-to)197-209
Number of pages13
JournalCell
Volume128
Issue number1
DOIs
Publication statusPublished - 12 Jan 2007

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