Diversity Supplement: Defining Variation in the Natural Killer Cell Receptome in Human Populations

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ABSTRACT The overall goal of this project is to develop a comprehensive map of sequence and structural variation of the NK (natural killer) cell receptome in ancestrally diverse human populations. The two genomic regions encoding NK cell receptors, leukocyte receptor complex (LRC) and natural killer complex (NKC), house more than 90 genes with an essential role in NK cell cytotoxicity against infected and cancer cells. The complex structural variation and the high degree of sequence identity among genes within these regions have served as barriers to a comprehensive analysis in former genome-wide association and sequencing studies. With our expertise and experience in studying complex genomic variation, we will develop the most comprehensive map of sequence and structural variation of the LRC and NKC in human populations. In Specific Aim 1, we will conduct a high- throughput study entailing the complete sequencing of these two complexes using our novel and validated next- generation sequencing approach. DNA samples from 2150 samples from 18 populations, including Native Americans and admixed populations from South America, Africans, European Americans, and African Americans. Sequence data will be analyzed with our custom-designed bioinformatics pipelines. We will focus not only on gene families with a known structural variation of copy number, such as KIR (killer-cell immunoglobulin-like receptor) and LILR (leukocyte immunoglobulin-like receptors) but will analyze all common variants in all 90 NKC and LRC genes to characterize the full extent of their variation. Synergized with this approach, in Specific Aim 2, we will perform a powerful single-cell expression quantitative trait loci (eQTL) mapping of LRC and NKC by sequencing the single-cell transcriptomes of NK cells from peripheral blood mononuclear cells of 40 healthy individuals. We will identify variants associated with differential expression levels in NK cells for the initial assessment of emerging functional hypotheses. We will identify any common variants within the LRC and NKC that are associated with eQTL effects, resulting in the most comprehensive study of the NK receptome genetic variation in populations to date. This exploratory project will lay the basis for further functional studies and may ultimately lead to discovering new targets for NK cell immunotherapies.