Population differentiation under strong selection: a case study with HLA loci

• Grant number: 25/00828-6
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: March 01, 2025
• End date: September 30, 2028
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Diogo Meyer
• Grantee: Alfredo Antonio Reis Marin
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 21/14851-9 - Human Population Genomics: a view from admixed populations, AP.TEM

Abstract

Natural selection can result in an increase of genetic differentiation between populations, in the case where locally adapted variants differ among populations (Novembre and Di Rienzo 2009) . Natural selection can also potentially act in the opposite direction, maintaining shared diversity among populations, when selection favors similar sets of alleles in distinct populations. Finally, selection can also increase diversity within individual populations, as is the case when heterozygotes are favored. This naturally raises the question: for HLA loci, where high variability is documented, and which coevolve with pathogen diversity which is itself geographically structured (Prugnolle et al. 2005), how is genetic diversity geographically distributed?We previously showed that SNPs within HLA genes have significantly lower population pairwise FST than those from the rest of the genome (Brandt et al. 2018). However, for recently diverged populations (those from the same continental regions) FST of SNPs in HLA genes are in fact higher than genome-wide, suggesting that the mode and effect of selection vary depending on the timescale of population divergence (Nunes et al. 2021). Here, we will draw on the relatedness and structure framework of Weir and Goudet (Weir and Goudet 2017) to systematically explore the effects of selection at different geographic scales (by using different reference populations) and to address the relationship between population structure and relatedness. We are motivated by the fact that kinship at HLA loci is biologically relevant to both evolutionary dynamics (e.g., the ability of pathogens to spread throughout a population) and medical applications (e.g., the ability to find matching HLA individuals for transplantation). Our previous analyses addressed SNP-level polymorphism, but it is the combination of variants (which define "HLA alleles") that defines the repertoire of peptides that are bound and presented to the immune system. Accordingly, we will use the FST framework to compare relatedness patterns at these different biological levels.