Genetic diversity of the major cat allergen, Fel d 1

Cat allergy affects ∼15% of the US population and can cause severe symptoms, including asthma. The major cat allergen, Fel d 1, drives IgE antibody responses. We conducted a comparative analysis of Fel d 1 genes, CH1 and CH2, and investigated structural features of Fel d 1 homologs across the family Felidae. The CH1 and CH2 domestic cat DNA references were used to identify homologous sequences in domestic and exotic cat genomes. Variability of these sequences within or across cat species was analyzed. Comprehensive alignments of Fel d 1 sequences and homologs from 276 domestic or exotic cats identified >100 unique, dissimilar substitutions in the protein sequences across Felidae. Selective pressure analyses of 37 exotic cat species revealed that Fel d 1 experienced positive selection, or greater variability over time, in CH1 and CH2. Linear regression of the mean pairwise identities of Fel d 1 DNA or protein sequences indicated that the genes largely reflected the evolution of Felidae. The Fel d 1 genes are highly variable (41 and 58% of the amino acid residues encoded by CH1 and CH2, respectively), suggesting that the biological function of Fel d 1, which is currently unknown, may vary among cat species and/or that Fel d 1 may be nonessential for cats. This is supported by Fel d 1 homology to nonessential proteins and recent evidence of healthy cats with CRISPR-edited CH2 genes. Fel d 1 variability could confer an evolutionary advantage for cats by allowing the allergen to bind different physiological ligands.