Functional Interpretation of Variants in Immune Genes

Genetic variants in a subset of genes are associated with lymphoma, and inherited immune defects. The James lab is developing models to study (1) whether and how novel variants of these genes cause changes in protein function, and (2) the developmental and homeostatic effects of variants in these genes.

Most genetic variants found in subjects with immune disease are of unknown functional effect. We combine saturation genome editing with functional assays to measure the effect of all possible variants in immune genes. The goal is to create look-up tables that clinicians can use to diagnose and treat immune disease.

Exome sequencing has identified variants in PIK3CD (E1021K) and CARD11 (L244P) that lead to inherited immune deficiency and/or lymphoma. We helped develop novel murine models with B-cell intrinsic expression of these variants and found that they exhibit many of the clinical features found in patients.

Lupus and type 1 diabetes are complex diseases caused by a combination of genetic risk and environmental interactions. We use gene editing and proteomics in cell lines, and in primary human B cells to model the individual and combinatorial role of genetic variants in autoimmunity and immune dysregulation.