Homologous recombination in mammalian cells

Chemistry: molecular biology and microbiology – Treatment of micro-organisms or enzymes with electrical or... – Modification of viruses

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935 55, C12N 1500

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056122055

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BRIEF SUMMARY
TECHNICAL FIELD OF THE INVENTION

The invention relates to methods for making transgenic mammalian cells and transgenic non-human mammals by intracellularly producing DNA segments by homologous recombination of smaller DNA fragments; as well as transgenic mammalian cells and transgenic non-human mammals produced by such methods.


BACKGROUND OF THE INVENTION

A transgenic cell or animal contains one or more transgenes within its genome. A transgene is a DNA sequence integrated at a locus of a genome, wherein the transgenic DNA sequence is not otherwise normally found at that locus in that genome. Transgenes may be made up of heterologous DNA sequences (sequences normally found in the genome of other species) or homologous DNA sequences (sequences derived from the genome of the same species). Transgenic animals have been reported. For example, U.S. Pat. No. 4,736,866 discloses a transgenic mouse containing a c-myc oncogene. Other reports of transgenic animals include PTC Publication No. W082/04443 (rabbit .beta.-globin gene DNA fragment injected into the pronucleus of a mouse zygote); EPO Publication No. 0 264 166 (Hepatitis B surface antigen and Tissue Plasminogen Activator genes under control of the whey acid protein promoter for mammary tissue specific expression); EPO Publication No. 0 247 494 (transgenic mice containing heterologous DNA encoding various forms of insulin); PTC Publication No. W088/00239 (tissue specific expression of DNA encoding factor IX under control of a whey protein promoter); PTC Publication No. W088/01648 (transgenic mammal having mammary secretory cells incorporating a recombinant expression system comprising a mammary lactogen-inducible regulatory region and a structural region encoding a heterologous protein); and EPO Publication No. 0 279 582 (tissue specific expression of chloramphenicol acetyltransferase under control of rat .beta.-casein promoter in transgenic mice).
Transgenic plants have also been produced. For example, U.S. Pat. No. 4,801,540 to Hiatt, et al., discloses the transformation of plant cells with a plant expression vector containing DNA encoding tomato polygalacturonase (PG) oriented in the opposite orientation for expression. The anti-sense RNA expressed from this gene is reportedly capable of hybridizing with the endogenous PG mRNA to suppress translation.
The transgenes introduced into animals and plants so far have been of relatively short length (generally less than about 50 kb). Many eukaryotic genes, however, cover large regions of genomic DNA with many and often very large intervening sequences (introns) between those sequence portions (exons) encoding mRNA. Further, many eukaryotic genes are bounded by regulatory sequences, e.g. enhancers, tissue-specific regulators, cis-acting elements and other physically linked regulatory elements sometimes located many thousands of nucleotides away from the structural gene. The manipulation of such eukaryotic genes has been impeded by their size and complexity. Obstacles include difficulty in the construction, stability, packaging and physical manipulation of large DNA molecules.
Vehicles for cloning DNA have inherent limitations on the size of the DNA they are able to accommodate. Traditional viral vectors such as lambda phage and SV40 have limits of packaging foreign DNA of approximately 50 and 5 kb, respectively. More recently the use of F and P1-based cloning systems, and the cloning of yeast artificial chromosomes have made it possible to propagate larger, contiguous pieces of DNA.
A yeast artificial chromosome or YAC vector, is generated by ligating sequences from a yeast chromosome onto the ends of a piece of DNA. Such sequences include a centromere, two telomeres (one on each end), an origin of replication, and a selectable marker. A telomere is located on each end of the particular piece of DNA to be cloned with a centromere interposed between one of the telomeres and the DNA to be cloned. Several groups have reportedly constructed yeast libraries containing 50-200 kb of human DNA in such YAC vectors (B

REFERENCES:
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