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Immune-driven positive and balancing selection in human populations



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Kaewert, Sarah 


This thesis examines the evidence for positive and balancing selection on immune genes in 388 individuals grouped into thirteen geographically diverse populations. The data are high coverage whole genome sequences, many from populations that have been sparsely represented in global genetic diversity studies in the past.

Two main analyses were performed for both positive and balancing selection: enrichment tests for each population and class of immune genes, and filtering for top variants or genes driving selection signals. Four different measures of positive selection and three measures of balancing selection were used to scan the whole genome data for evidence of selection. Further filters, including functional importance predictors, were used to filter results for potential driver variants.

Positive selection results show significant enrichment for genes associated with bacteria or virus interaction, the innate immune system, and antigen processing and presentation. Results also include variants potentially driving signals of selection. One of these is a missense variant in the Northeast Siberian population in the gene IL27, which is involved in modulation of immune response to infection.

Balancing selection enrichment tests show that genes associated with T cell function and antigen processing and presentation are significantly enriched in every population. The HLA region features heavily in these enrichments. One top gene result is GNLY, a gene that produces the antimicrobial protein granulysin, in the West Siberian and Island Southeast Asian populations. Another is PGLYRP4, which is a top gene in seven populations and is involved in recognition and defense against Gram-negative and -positive bacteria.

In conclusion, as a general trend there is more enrichment in genes that interact with bacteria and viruses in the positive selection results, and more enrichment in genes involved with antigen processing and presentation and T cell function in the balancing selection results. The combined results show the different immune-driven selection histories of each population, as well as highlight a number of variants and genes that are potential drivers of selection and promising candidates for further study.





Kivisild, Toomas


selection, immunity, genetics


Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge