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Immune-driven positive and balancing selection in human populations
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
Genomic analyses inform on migration events during the peopling of Eurasia
High-coverage whole-genome sequence studies have so far focused\ud
on a limited number1 of geographically restricted populations2â5,\ud
or been targeted at specific diseases, such as cancer6. Nevertheless,\ud
the availability of high-resolution genomic data has led to the\ud
development of new methodologies for inferring population\ud
history7â9 and refuelled the debate on the mutation rate in humans10.\ud
Here we present the Estonian Biocentre Human Genome Diversity\ud
Panel (EGDP), a dataset of 483 high-coverage human genomes\ud
from 148 populations worldwide, including 379 new genomes from\ud
125 populations, which we group into diversity and selection\ud
sets. We analyse this dataset to refine estimates of continent-wide\ud
patterns of heterozygosity, long- and short-distance gene flow, archaic\ud
admixture, and changes in effective population size through time as\ud
well as for signals of positive or balancing selection. We find a genetic\ud
signature in present-day Papuans that suggests that at least 2% of\ud
their genome originates from an early and largely extinct expansion\ud
of anatomically modern humans (AMHs) out of Africa. Together\ud
with evidence from the western Asian fossil record11, and admixture\ud
between AMHs and Neanderthals predating the main Eurasian\ud
expansion12, our results contribute to the mounting evidence for\ud
the presence of AMHs out of Africa earlier than 75,000 years ago
Genomic analyses inform on migration events during the peopling of Eurasia.
High-coverage whole-genome sequence studies have so far focused on a limited number of geographically restricted populations, or been targeted at specific diseases, such as cancer. Nevertheless, the availability of high-resolution genomic data has led to the development of new methodologies for inferring population history and refuelled the debate on the mutation rate in humans. Here we present the Estonian Biocentre Human Genome Diversity Panel (EGDP), a dataset of 483 high-coverage human genomes from 148 populations worldwide, including 379 new genomes from 125 populations, which we group into diversity and selection sets. We analyse this dataset to refine estimates of continent-wide patterns of heterozygosity, long- and short-distance gene flow, archaic admixture, and changes in effective population size through time as well as for signals of positive or balancing selection. We find a genetic signature in present-day Papuans that suggests that at least 2% of their genome originates from an early and largely extinct expansion of anatomically modern humans (AMHs) out of Africa. Together with evidence from the western Asian fossil record, and admixture between AMHs and Neanderthals predating the main Eurasian expansion, our results contribute to the mounting evidence for the presence of AMHs out of Africa earlier than 75,000 years ago.Support was provided by: Estonian Research Infrastructure Roadmap grant no 3.2.0304.11-0312; Australian Research Council Discovery grants (DP110102635 and DP140101405) (D.M.L., M.W. and E.W.); Danish National Research Foundation; the Lundbeck Foundation and KU2016 (E.W.); ERC Starting Investigator grant (FP7 - 261213) (T.K.); Estonian Research Council grant PUT766 (G.C. and M.K.); EU European Regional Development Fund through the Centre of Excellence in Genomics to Estonian Biocentre (R.V.; M.Me. and A.Me.), and Centre of Excellence for Genomics and Translational Medicine Project No. 2014-2020.4.01.15-0012 to EGC of UT (A.Me.) and EBC (M.Me.); Estonian Institutional Research grant IUT24-1 (L.S., M.J., A.K., B.Y., K.T., C.B.M., Le.S., H.Sa., S.L., D.M.B., E.M., R.V., G.H., M.K., G.C., T.K. and M.Me.) and IUT20-60 (A.Me.); French Ministry of Foreign and European Affairs and French ANR grant number ANR-14-CE31-0013-01 (F.-X.R.); Gates Cambridge Trust Funding (E.J.); ICG SB RAS (No. VI.58.1.1) (D.V.L.); Leverhulme Programme grant no. RP2011-R-045 (A.B.M., P.G. and M.G.T.); Ministry of Education and Science of Russia; Project 6.656.2014/K (S.A.F.); NEFREX grant funded by the European Union (People Marie Curie Actions; International Research Staff Exchange Scheme; call FP7-PEOPLE-2012-IRSES-number 318979) (M.Me., G.H. and M.K.); NIH grants 5DP1ES022577 05, 1R01DK104339-01, and 1R01GM113657-01 (S.Tis.); Russian Foundation for Basic Research (grant N 14-06-00180a) (M.G.); Russian Foundation for Basic Research; grant 16-04-00890 (O.B. and E.B); Russian Science Foundation grant 14-14-00827 (O.B.); The Russian Foundation for Basic Research (14-04-00725-a), The Russian Humanitarian Scientific Foundation (13-11-02014) and the Program of the Basic Research of the RAS Presidium âBiological diversityâ (E.K.K.); Wellcome Trust and Royal Society grant WT104125AIA & the Bristol Advanced Computing Research Centre (http://www.bris.ac.uk/acrc/) (D.J.L.); Wellcome Trust grant 098051 (Q.A.; C.T.-S. and Y.X.); Wellcome Trust Senior Research Fellowship grant 100719/Z/12/Z (M.G.T.); Young Explorers Grant from the National Geographic Society (8900-11) (C.A.E.); ERC Consolidator Grant 647787 âLocalAdaptatioâ (A.Ma.); Program of the RAS Presidium âBasic research for the development of the Russian Arcticâ (B.M.); Russian Foundation for Basic Research grant 16-06-00303 (E.B.); a Rutherford Fellowship (RDF-10-MAU-001) from the Royal Society of New Zealand (M.P.C.)