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Case Reports
. 2022 Jun 6;377(1852):20200420.
doi: 10.1098/rstb.2020.0420. Epub 2022 Apr 18.

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

André Silva Maróstica  1 , Kelly Nunes  1 , Erick C Castelli  2   3 , Nayane S B Silva  3 , Bruce S Weir  4 , Jérôme Goudet  5   6 , Diogo Meyer  1
Affiliations
Case Reports

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

André Silva Maróstica et al. Philos Trans R Soc Lond B Biol Sci. .

Abstract

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 FST 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 FST values because of the extreme polymorphism at HLA loci, illustrating challenges in interpreting FST. 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'.

Keywords: HLA genes; MHC; population structure; population-specific FST; transplantation.

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Conflict of interest statement

We declare we have no competing interests.

Figures

Figure 1.
Figure 1.
Schematic representation of chromosome 6, the MHC region, location of HLA loci and variation within a specific locus (HLA-B). Top: Chromosome 6, showing approximately 4 Mb region comprising the MHC, within which HLA genes are located. Middle: MHC region, with classical HLA class I and HLA class II loci. Bottom: Representation of six sequences of the HLA-B coding region, with SNPs represented as circles, with the colour indicating the allele at that position. Analyses of diversity can be carried out over SNPs (with one SNP represented by the vertical rectangle) or over HLA alleles (in this figure, there are five distinct HLA-B alleles which are named, among the six chromosomes sampled).
Figure 2.
Figure 2.
Population-specific FST across chromosome 6, in overlapping windows of 5 Mb, with a step-size of 1 Mb. The FST values were estimated for each population relative to all other populations available (i.e. each population relative to the entire world, with no geographic grouping used). Each coloured line represents a specific population; the black line represents the overall FST for each window; the black dashed line is the average overall FST for the entire chromosome. The vertical lines delimit the MHC region, within which HLA genes are contained. See electronic supplementary material, table S1, for 1000 Genomes abbreviations of population and region names.
Figure 3.
Figure 3.
Distribution of overall FST for 168 windows along chromosome 6. The FST values for windows that have at least 2 Mb contained within the MHC are shown in green, while the remaining windows on chromosome 6 are shown in red. The arrow indicates the overall FST for the SNPs contained within the three HLA loci we studied (HLA-A, -B, -C), and the vertical line is the average FST over all windows. (a) Overall FST among populations, where the kinship within each population is compared to that among populations, regardless of the continent the population belongs to. (b) Overall FST among continents, where all populations within a continent were merged and treated as a single group, and FST compares kinship within continents to that among continents.
Figure 4.
Figure 4.
The population-specific FST values for African (in blue) and European (in yellow) populations in the 1000 Genomes data, estimated for diversity at the level of HLA alleles for HLA-A, -B and -C. The horizontal line is the average population-specific FST, with a value of 0.03. Each population-specific FST was estimated by comparing the allele sharing within each population to that for the entire dataset, comprising the five African and five European populations.
Figure 5.
Figure 5.
Frequencies of a subset of HLA alleles for African and European populations (1000 Genomes data). To visualize the differences in allele frequencies between regions, we selected alleles that were either exclusive to Africa or found at frequencies that were at least threefold greater in Africa than Europe. We identify each allele by a distinct colour. ‘Others’ (in grey) refers to the cumulative frequency of all alleles that are either exclusively found in Europe, or that do not occur threefold more frequently in Africa than Europe, or that are shared between them.
Figure 6.
Figure 6.
Ancestry and donor availability in the Brazilian bone-marrow registry (REDOME, Registro Nacional de Doadores Voluntários de Medula Óssea) for matching at both alleles at five loci (10/10 matching). (a) Admixed individuals were classified following three possible criteria: self-assigned ‘IBGE category’ (defined by the Instituto Brasileiro de Geografia e Estatística, the Brazilian Institute of Geography and Statistics); genomewide African ancestry, divided into quartiles; number of FST chromosomes for which the MHC is African (0, 1 or 2). The y-axis represents the proportion of individuals with at least one compatible donor. (b) The self-assigned identifier (a proxy coarsely related to ancestry) of potential donors, with respect to the genetic ancestry in the MHC region of individuals seeking donors. Notice that for individuals seeking donors and who carry two African chromosomes in the MHC region, ‘Black’ and ‘Mixed’ make up the largest fraction of potential donors (adapted from Nunes et al. [47]).
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