TRANSGENIC ANIMALS AND USES THEREOF
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.