Humanized Rodents that Express Heavy Chain Containing VL Domains

A genetically modified non-human animal that comprises

• (a) one or more unrearranged human Vκ gene segments and one or more unrearranged human Jκ gene segments at an endogenous immunoglobulin heavy chain locus of the non-human animal,
• (b) one or more unrearranged human Vκ gene segments and one or more unrearranged human Jκ gene segments at an endogenous immunoglobulin light chain locus of the non-human animal, wherein the non-human animal is capable of expressing an ADAM6 protein or functional fragment thereof.

A rodent comprising one or more human immunoglobulin light chain gene segments operably linked to a non-human immunoglobulin heavy chain constant region gene, wherein the rodent expresses one or more ADAM6 proteins.

A method for modifying a heavy chain immunoglobulin locus of a rodent, comprising:

• (a) making a first modification of a rodent heavy chain immunoglobulin locus that results in a reduction or elimination of endogenous ADAM6 activity in a male rodent, wherein the first modification includes insertion a gene segment selected from one or more human VL gene segments, one or more human JL gene segments, and a combination thereof;
• and,
• (b) making a second modification to add a nucleic acid sequence to the rodent that confers upon the rodent ADAM6 activity that is functional in a male rodent.

The method according to claim 36, wherein the first and the second modification are made in a single ES cell, and the single ES cell is introduced into a host embryo to make the rodent.