Abstract: The present invention provides transgenic animals comprising some or all components of a human heavy and/or light chain immunoglobulin variable region locus, methods of making such animals, methods of making human antibodies using such animals, and methods of treatment using the human antibodies made in such animals, wherein the animals comprise in their genome a plurality of human heavy chain V gene segments all of which are immediately preceded by the same first leader peptide-encoding sequence, and/or a plurality of human light chain V gene segments all of which are immediately preceded by the same second leader peptide-encoding sequence, or both. The invention also provides polynucleotide constructs comprising two or more human heavy or light chain leader/V gene segments comprising identical leader peptide-encoding sequences.