Monogenic or polygenic disease model organisms humanized with two or more genes

A non-human animal transgenic system for assessing a heterologous disease phenotype, comprising:

• a host animal comprising and expressing a first heterologous polypeptide coding sequence and a second heterologous polypeptide coding sequence, wherein the first and second heterologous polypeptide coding sequences are integrated into the host genome, wherein at least one of the first heterologous polypeptide coding sequence or the second heterologous polypeptide coding sequence comprises one or more mutations in the heterologous polypeptide coding sequence as compared to a wildtype reference sequence resulting in at least one amino acid change when the first heterologous polypeptide coding sequence or the second heterologous polypeptide coding sequence is expressed,
• and wherein expression of the first and second heterologous polypeptide coding sequence contribute to the heterologous disease phenotype.

A non-human animal humanized transgenic system for assessing a monogenic or polygenic human disease phenotype, comprising:

• a host animal comprising and expressing a first human polypeptide coding sequence and a second human polypeptide coding sequence, wherein the first and second human polypeptide coding sequences are integrated into the genome of the host animal, wherein at least one of the first human polypeptide coding sequence or the second human polypeptide coding sequence comprises one or more mutations in the human gene exon coding sequence as compared to a wildtype reference sequence resulting in at least one amino acid change when the first human gene or the second human gene is expressed in the host animal,
• and wherein expression of the first and second human polypeptide coding sequences contribute to the monogenic or polygenic human disease phenotype.