The Pathogen Adaptation of HLA Alleles and the Correlation with Autoimmune Diseases based on the HLA Diversity Resource in the Han Chinese

ABSTRACT Human leukocyte antigen (HLA) genes play a crucial role in the adaptation of human populations to the dynamic pathogenic environment. Despite their significance, investigating the pathogen-driven evolution of HLAs and the implications for autoimmune diseases presents considerable challenges. Here, we genotyped over twenty HLA genes at 3-field resolution in 8278 individuals from diverse ethnic backgrounds, including 4013 unrelated Han Chinese. We focused on the adaptation of HLAs in the Han Chinese by analysing their binding affinity for various pathogens, and explored the potential correlations between pathogen adaptation and autoimmune diseases. Our findings reveal that specific HLA alleles like HLA-DRB1*07:01 and HLA-DQB1*06:01, confer strong pathogen adaptability at the sequence level, notably for Corynebacterium diphtheriae and Bordetella pertussis . Additionally, alleles like HLA*03:02 demonstrate adaptive selection against pathogens like Mycobacterium tuberculosis and Coronavirus at the gene expression level. Simultaneously, the aforementioned HLA alleles are closely related to some autoimmune diseases such as multiple sclerosis (MS). These exploratory discoveries shed light on the intricate coevolutionary relationships between pathogen adaptation and autoimmune diseases in the human population. These efforts led to an HLA database at http://bigdata.ibp.ac.cn/HLAtyping , aiding searches for HLA allele frequencies (AF) across populations.