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Using HLA to Study Disease, Evolution and Human History


The classical HLA loci are the most polymorphic loci in the human genome, with more than 6400 alleles.  The extensive nature of HLA polymorphism makes for highly informative and convenient markers for studies of individual ancestry, population genetics, the peopling history of the world, and protein evolution.

HLA proteins are found on the surfaces of all nucleated cells, and  present endogenous and exogenous peptides to T-cells, permitting the distinction to be drawn between self-and non-self tissue and initiating specific immune responses.  HLA interaction with T-cells (and NK-cells) is central to understanding immune-related disease; in many cases (e.g., type-1-diabetes and ankylosing spondylitis), the HLA region is the major genetic determinant of disease.


Our aim in studying HLA is to understand the mechanisms by which HLA polymorphism results in susceptibility and resistance to cancer, and infectious and autoimmune diseases, to determine how HLA polymorphism is distributed on a global scale and understand how natural selection has acted to maintain our species’ diversity, and to make inferences about human history by relating the distribution of HLA polymorphism to global patterns of disease prevalence.

HLA and Human History

The so-called Sahul-hypothesis proposes that the indigenous  populations of Australia and the Papua New Guinea (PNG) highlands are the descendants of a single population that occupied the Sahul landmass before a rise in sea-levels 9,000 years ago separated Australia from New Guinea. Our phylogenetic analysis of the HLA profiles in 30 Pacific populations (see insert) shows that Aboriginal Australian populations are closer to PNG highland populations than coastal and lowland PNG populations (proposed to have arrived after the rise in sea levels), in clear support of this hypothesis.


Disease, HLA Genetics and Geography

Nasopharyngeal Carcinoma (NPC) is an Epstein-Barr virus (EBV) related cancer that has a low incidence throughout most of the world, but is common among Han Chinese populations in southern China and Southeast Asia.  We have shown NPC to be positively associated (odds ratio = 2.3, p-value of 0.006) with the HLA-A*0207 allele in these populations. This allele differs from the HLA-A*0201 allele by a single amino acid residue (Y99C) that influences the affinity of three distinct peptide binding pockets in the HLA molecule, reducing the ability of the A*0207 allele to present EBV peptides, so that  EBV escapes  immune detection.  The global distributions of the A*0201 and *0207 alleles (below) reveal that the *0207 allele is only found in Southeast Asia. Thus, while EBV (and other environmental prerequisites for NPC) is worldwide, the geographic restriction of NPC is explained by the corresponding range of this susceptibility allele.


Our current HLA projects include studies of the association of Rheumatoid Arthritis and Crohn’s Disease, and Ulcerative Colitis with HLA variation, and studies of the global patterns of HLA allelic diversity and the tempo and mode of the evolution of HLA allelic diversity. We are interested in developing novel analytical methods for investigating the action of natural selection at the level of individual polymorphic amino acids.


Revised: Friday, October 9, 2015 2:12 PM

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