# Evolution and Function of Immunogenetic Diversity across the Eastern Hemisphere

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2022 · $794,519

## Abstract

ABSTRACT
Human leukocyte antigens (HLA) and killer cell immunoglobulin-like receptors (KIR) are critical facets of the
human immune system. Interactions of KIR, expressed by natural killer cells (NK cells), with HLA class I,
expressed by most tissue cells, modulate immune cell functions. Variations in the highly polymorphic KIR and
HLA genes are linked directly to NK cell functions and have profound impact on human health, including
associations with autoimmunity and neurological disease, severity of infectious disease, pregnancy
syndromes, and risk of cancer. Our ability to resolve the mechanisms of immune-mediated disease, to develop
personalized medicines, including immunotherapies, and to match organ donors with recipients relies on our
ability to accurately characterize KIR and HLA class I diversity. Despite this crucial importance, there is a lack
of knowledge concerning the extent and nature of KIR and HLA class I diversity worldwide. This deficit includes
the Eastern Hemisphere, which encompasses half the world's population, and multiple underrepresented
groups in the USA. During this project we will fill these gaps in this knowledge through determining the
characteristics and functional consequences of KIR and HLA class I diversity across the entire Eastern
Hemisphere.
We will examine 15,612 individuals representing 51 discrete populations, including indigenous populations
from East Asia, South Asia, multiple Pacific Islands and Oceania. To overcome difficulties in analyzing these
complex genomic regions, we developed a targeted sequencing and bioinformatics approach to analyze KIR
and HLA class I genes at high throughput and resolution. To analyze an additional 22,905 individuals, we will
develop an imputation algorithm to determine high-resolution KIR alleles from whole-genome SNP data. We
will construct imputation panels specifically for these populations who have been neglected in previous
analyses. This goal will be made possible through the extensive training data generated. We will then
characterize the distribution of KIR and HLA haplotypes across the Eastern Hemisphere.
We will examine how the geographic patterns of KIR and HLA diversity have been shaped by natural selection
and investigate the impact of adaptive introgression and admixture specifically focused to the KIR and HLA loci
in our study populations. We will determine the functional properties of those variants we have identified as
targeted by natural selection. We will pursue these aims implementing innovative laboratory and analytical
tools. These developments include CRISPR/cas9 targeting of long-read sequencing to examine KIR structural
diversity, and methods both to identify alleles subject to natural selection, and the mode of selection acting on
them. The expected outcome of this work is the genetic and functional characterization of HLA and KIR across
multiple human populations, and a comprehensive understanding of how this variation is geographically
distribu...

## Key facts

- **NIH application ID:** 10365232
- **Project number:** 1R01AI151549-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Paul John Norman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $794,519
- **Award type:** 1
- **Project period:** 2022-07-11 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10365232

## Citation

> US National Institutes of Health, RePORTER application 10365232, Evolution and Function of Immunogenetic Diversity across the Eastern Hemisphere (1R01AI151549-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10365232. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*