A structure-based in silico analysis of the Kell blood group system

Kell is one of the most complex blood group systems, with a highly polymorphic genetic background. Extensive allelic variations in the <i>KEL</i> gene affect the encoded erythrocyte surface protein Kell. Genetic variants causing aberrant splicing, premature termination of protein translation, or specific amino acid exchanges lead to a variety of different phenotypes with altered Kell expression levels or changes in the antigenic properties of the Kell protein. Using an <i>in silico</i> structural model of the Kell protein, we analyzed the biophysical and structural context of all full-length Kell variants of known phenotype. The results provided insights regarding the 3D co-localization of antigenic Kell variants and led us to suggest several conformational epitopes on the Kell protein surface. We found a number of correlations between the properties of individual genetic variants in the Kell protein and their respective serological phenotypes, which we used as a search filter to predict potentially new immunogenic Kell variants from an in-house whole exome sequencing dataset of 19,772 exomes. Our analysis workflow and results aid blood group serologists in predicting whether a newly identified Kell genetic variant may result in a specific phenotype.