Adaptive Immune Variation in an admixed Guatemalan Population

Abstract (English)

Immune response genes are among the most diverse and have been key targets of natural selection, shaped by demographic history. With over 1,500 known immune genes and multiple alleles, studying each in relation to infectious disease requires vast datasets, often unfeasible in fieldwork settings. A selection mapping approach can help narrow down key loci with biological significance. To investigate this, we exome-sequenced 90 admixed Guatemalan participants from Chiquimula, Guatemala, using the IDT xGen Exome Research Panel. HLA frequencies were typed at G-group resolution using HLA-LA to identify classical HLA loci under selection. Balancing and positive selection on immune genes were determined through Tajima’s D, looking at the top 1% of both tails. To expand coverage and leverage off-target mapping, we imputed alignments with the TopMed Imputation Server. We calculated the Population Branch Statistic (PBS) and Ancestry Specific Population Branch Statistics (AS-PBS) using East Asians and Iberians from the 1000 Genomes Project as outgroups. Admixture was accounted for by using G-Nomix to determine local ancestry. Delta ancestry served as a proxy for post-admixture selection. The top 1% of overlapping results were examined through Gene Ontology and KEGG Pathways for enriched pathways, as well as GTEx and the GWAS catalog for expression and trait associations. Together, this analysis identified key immune response loci for future fieldwork studies examining infectious disease such as Dengue in admixed populations. This work was done in conjunction with Leticia Castillo-Signor (Ministerio de Salud Publica de Guatemala), Sonia Capetillo (Ministerio de Salud Publica de Guatemala), and Abigail W. Bigham (UCLA).