Global Characterization of Germline Immune Variation

Genetic variation in immune-related genes, including HLA, Fc receptors, and T/B cell receptors, significantly influences vaccine response and susceptibility to infectious diseases. For example, HIV vaccine efficacy has been linked to immunoglobulin genotypes and B cell profiles. Similarly, T cell vaccine design depends on accurate knowledge of HLA allele distribution, yet global data remain incomplete, particularly for non-European populations. To address this, Variant Bio, with Gates Foundation support, is conducting a study to map global immune gene diversity. These genes are underrepresented in current datasets due to both limited sequencing in diverse populations and the technical complexity of these highly variable, repetitive regions.
We are benchmarking bioinformatic methods for detecting germline variation in immune genes using WGS data, comparing short-read results to targeted and long-read datasets, including fully phased genomes. We aim to analyze WGS data from diverse global cohorts, including the LASI-DAD study and other public and internal Variant Bio datasets. Population-level allele frequencies will be shared via peer-reviewed publication and databases such as The Allele Frequency Net Database, supporting broader immunogenomics research and vaccine development.

Specific Aims
1) Benchmark methods for detecting variation in HLA, Fc receptor, and T/B cell receptor genes.
2) Develop a global map of germline immune variation by geography and ancestry.
3) Publicly share allele frequencies and methods to enable downstream application.

Study Design
This retrospective analysis will use existing WGS datasets. No new sample collection is planned and no phenotypic data is being requested.

Bioinformatic Plan
WGS data will be processed using the GATK Best Practices pipeline and imputed/phased using Beagle. Targeted immune loci will be analyzed with specialized software. Methods will be validated against long-read and haplotype-resolved genome references. Emphasis will be placed on characterizing accuracy across ancestries, particularly underrepresented groups.

Variation in immune genes, including HLA, T cell receptors, B cell receptors, and Fc receptors plays a key role in how people respond to infections and vaccines. Yet most existing genetic data comes from individuals of European ancestry, limiting our understanding of global immune diversity.

This Gates Foundation–funded project aims to characterize immune gene variation in underrepresented populations. Using whole genome sequencing data – including from the LASI-DAD study we will analyze variation in key immune genes to build a broader map of global diversity.

Advanced computational methods will identify variants in these complex regions, benchmarked against newer sequencing technologies and complete genomes. Findings, including population-level allele frequencies, will be shared via publications and public databases. This will support more equitable vaccine development, especially for T cell–based vaccines that rely on accurate HLA allele data.