Transgenic animals and uses thereof

Abstract

In general, the invention features genetically modified non-human mammals (e.g., bovines and other ungulates), and methods of making these mammals. In particular, the invention features transgenic ungulates having reduced levels of endogenous IgM heavy chain and/or prion protein.

1 . A transgenic ungulate whose genome comprises a homozygous mutation of both alleles of two different unrearranged IgM heavy chain loci, said mutations disrupting IgM heavy chain production and said transgenic ungulate producing less than 10% of endogenous IgM heavy chain relative to a control ungulate lacking the mutations, wherein said ungulate further comprises a nucleic acid encoding all or part of a xenogenous immunoglobulin locus that undergoes rearrangement and expresses a xenogenous immunoglobulin. 
     
     
         2 . The transgenic ungulate of  claim 1 , wherein said ungulate lacks functional IgM heavy chain. 
     
     
         3 . The transgenic ungulate of  claim 1 , wherein at least one mutation is by the insertion of an exogenous sequence, stop codon, or both. 
     
     
         4 . The transgenic ungulate of  claim 1 , wherein one of said loci is IgμU or IgμAY. 
     
     
         5 . The transgenic ungulate of  claim 1 , wherein one of said loci is IgμU and one of said loci is IgμAY. 
     
     
         6 . The transgenic ungulate of  claim 1 , wherein said homozygous mutations occur at different positions in said loci. 
     
     
         7 . The transgenic ungulate of  claim 1 , wherein said homozygous mutations result from different insertions. 
     
     
         8 . The transgenic ungulate of  claim 1 , wherein said homozygous mutations result from insertion of different exogenous sequences, or stop codons, or both. 
     
     
         9 . The transgenic ungulate of  claim 1 , wherein said ungulate is a bovine, ovine, porcine, or caprine. 
     
     
         10 . The transgenic ungulate of  claim 1 , wherein said ungulate is an adult bovine, a fetal bovine, or a bovine embryo. 
     
     
         11 . The transgenic ungulate of  claim 1 , wherein said xenogenous immunoglobulin is a human immunoglobulin. 
     
     
         12 . The transgenic ungulate of  claim 1 , wherein said nucleic acid is contained within a chromosome fragment. 
     
     
         13 . The transgenic ungulate of  claim 12 , wherein said chromosome fragment is a ΔHAC, ΔΔHAC, or κHAC.