Fig. 3.

Outline of the Whole-gene Humanization in Animal Model (WHAM) approach in C. elegans. A native (WT) animal is CRISPR-edited to make a gene KO animal. A whole gene substitution is made with a human coding sequence in the native locus. Next, additional CRISPR edits are made to insert clinical variants (eg “R39X”) into the humanized locus which recreates a set of Patient Avatars that represent the genetic variation of a human. Phenotypic activity of the transgenic lines is measured to enable detection of variant deficiencies.