How HLA diversity is apportioned: influence of selection and relevance to transplantation

In his 1972 paper 'The apportionment of human diversity', Lewontin showed that, when averaged over loci, genetic diversity is predominantly attributable to differences among individuals within populations. However, selection can alter the apportionment of diversity of specific genes or genomic regions. We examine genetic diversity at the human leucocyte antigen (HLA) loci, located within the major histocompatibility complex (MHC) region. HLA genes code for proteins that are critical to adaptive immunity and are well-documented targets of balancing selection. The single-nucleotide polymorphisms (SNPs) within HLA genes show strong signatures of balancing selection on large timescales and are broadly shared among populations, displaying low F-ST values. However, when we analyse haplotypes defined by these SNPs (which define 'HLA alleles'), we find marked differences in frequencies between geographic regions. These differences are not reflected in the F-ST values because of the extreme polymorphism at HLA loci, illustrating challenges in interpreting F-ST. Differences in the frequency of HLA alleles among geographic regions are relevant to bone-marrow transplantation, which requires genetic identity at HLA loci between patient and donor. We discuss the case of Brazil's bone marrow registry, where a deficit of enrolled volunteers with African ancestry reduces the chance of finding donors for individuals with an MHC region of African ancestry.This article is part of the theme issue 'Celebrating 50 years since Lewontin's apportionment of human diversity'.

Automated summary

In his 1972 paper 'The apportionment of human diversity', Lewontin demonstrated that genetic diversity is mainly attributed to differences within populations. However, selection can affect diversity of specific genes or genomic regions. This study focuses on genetic diversity at the human leucocyte antigen (HLA) loci, which play a critical role in adaptive immunity. The findings show balancing selection on HLA genes over large timescales, as indicated by low F-ST values. However, when analyzing HLA alleles defined by single-nucleotide polymorphisms (SNPs), significant frequency differences between geographic regions are observed. These differences have implications for bone marrow transplantation, particularly in regions with a deficit of donors matching MHC region of African ancestry, as seen in Brazil's bone marrow registry.