Da Di

Immunogenetics as a tool in anthropological studies

The genes coding for the main molecules involved in the human immune system – immunoglobulins, human leucocyte antigen (HLA) molecules and killer‐cell immunoglobulin‐like receptors (KIR) – exhibit a very high level of polymorphism that reveals remarkable frequency variation in human populations. ‘Genetic marker’ (GM) allotypes located in the constant domains of IgG antibodies have been studied for over 40 years through serological typing, leading to the identification of a variety of GM haplotypes whose frequencies vary sharply from one geographic region to another. An impressive diversity of HLA alleles, which results in amino acid substitutions located in the antigen‐binding region of HLA molecules, also varies greatly among populations. The KIR differ between individuals according to both gene content and allelic variation, and also display considerable population diversity. Whereas the molecular evolution of these polymorphisms has most likely been subject to natural selection, principally driven by host–pathogen interactions, their patterns of genetic variation worldwide show significant signals of human geographic expansion, demographic history and cultural diversification. As current developments in population genetic analysis and computer simulation improve our ability to discriminate among different – either stochastic or deterministic – forces acting on the genetic evolution of human populations, the study of these systems shows great promise for investigating both the peopling history of modern humans in the time since their common origin and human adaptation to past environmental (e.g. pathogenic) changes. Therefore, in addition to mitochondrial DNA, Y‐chromosome, microsatellites, single nucleotide polymorphisms and other markers, immunogenetic polymorphisms represent essential and complementary tools for anthropological studies.

Analysis of the HLA population data (AHPD) submitted to the 15th International Histocompatibility/Immunogenetics Workshop by using the Gene[rate] computer tools accommodating ambiguous data (AHPD project report)

During the 15th International Histocompatibility and Immunogenetics Workshop (IHIWS), 14 human leukocyte antigen (HLA) laboratories participated in the Analysis of HLA Population Data (AHPD) project where 18 new population samples were analyzed statistically and compared with data available from previous workshops. To that aim, an original methodology was developed and used (i) to estimate frequencies by taking into account ambiguous genotypic data, (ii) to test for Hardy-Weinberg equilibrium (HWE) by using a nested likelihood ratio test involving a parameter accounting for HWE deviations, (iii) to test for selective neutrality by using a resampling algorithm, and (iv) to provide explicit graphical representations including allele frequencies and basic statistics for each series of data. A total of 66 data series (1-7 loci per population) were analyzed with this standard approach. Frequency estimates were compliant with HWE in all but one population of mixed stem cell donors. Neutrality testing confirmed the observation of heterozygote excess at all HLA loci, although a significant deviation was established in only a few cases. Population comparisons showed that HLA genetic patterns were mostly shaped by geographic and/or linguistic differentiations in Africa and Europe, but not in America where both genetic drift in isolated populations and gene flow in admixed populations led to a more complex genetic structure. Overall, a fruitful collaboration between HLA typing laboratories and population geneticists allowed finding useful solutions to the problem of estimating gene frequencies and testing basic population diversity statistics on highly complex HLA data (high numbers of alleles and ambiguities), with promising applications in either anthropological, epidemiological, or transplantation studies.

16(th) IHIW: analysis of HLA population data, with updated results for 1996 to 2012 workshop data (AHPD project report).

We present here the results of the Analysis of HLA Population Data (AHPD) project of the 16th International HLA and Immunogenetics Workshop (16IHIW) held in Liverpool in May–June 2012. Thanks to the collaboration of 25 laboratories from 18 different countries, HLA genotypic data for 59 new population samples (either well‐defined populations or donor registry samples) were gathered and 55 were analysed statistically following HLA‐NET recommendations. The new data included, among others, large sets of well‐defined populations from north‐east Europe and West Asia, as well as many donor registry data from European countries. The Gene[rate] computer tools were combined to create a Gene[rate] computer pipeline to automatically (i) estimate allele frequencies by an expectation‐maximization algorithm accommodating ambiguities, (ii) estimate heterozygosity, (iii) test for Hardy–Weinberg equilibrium (HWE), (iv) test for selective neutrality, (v) generate frequency graphs and summary statistics for each sample at each locus and (vi) plot multidimensional scaling (MDS) analyses comparing the new samples with previous IHIW data. Intrapopulation analyses show that HWE is rarely rejected, while neutrality tests often indicate a significant excess of heterozygotes compared with neutral expectations. The comparison of the 16IHIW AHPD data with data collected during previous workshops (12th–15th) shows that geography is an excellent predictor of HLA genetic differentiations for HLA‐A, ‐B and ‐DRB1 loci but not for HLA‐DQ, whose patterns are probably more influenced by natural selection. In Europe, HLA genetic variation clearly follows a north to south‐east axis despite a low level of differentiation between European, North African and West Asian populations. Pacific populations are genetically close to Austronesian‐speaking South‐East Asian and Taiwanese populations, in agreement with current theories on the peopling of Oceania. Thanks to this project, HLA genetic variation is more clearly defined worldwide and better interpreted in relation to human peopling history and HLA molecular evolution.

Computer simulation of human leukocyte antigen genes supports two main routes of colonization by human populations in East Asia

BackgroundRecent genetic studies have suggested that the colonization of East Asia by modern humans was more complex than a single origin from the South, and that a genetic contribution via a Northern route was probably quite substantial.ResultsHere we use a spatially-explicit computer simulation approach to investigate the human migration hypotheses of this region based on one-route or two-route models. We test the likelihood of each scenario by using Human Leukocyte Antigen (HLA) − A, −B, and − DRB1 genetic data of East Asian populations, with both selective and demographic parameters considered. The posterior distribution of each parameter is estimated by an Approximate Bayesian Computation (ABC) approach.ConclusionsOur results strongly support a model with two main routes of colonization of East Asia on both sides of the Himalayas, with distinct demographic histories in Northern and Southern populations, characterized by more isolation in the South. In East Asia, gene flow between populations originating from the two routes probably existed until a remote prehistoric period, explaining the continuous pattern of genetic variation currently observed along the latitude. A significant although dissimilar level of balancing selection acting on the three HLA loci is detected, but its effect on the local genetic patterns appears to be minor compared to those of past demographic events.

HLA variation reveals genetic continuity rather than population group structure in East Asia

Genetic differences between Northeast Asian (NEA) and Southeast Asian (SEA) populations have been observed in numerous studies. At the among-population level, despite a clear north–south differentiation observed for many genetic markers, debates were led between abrupt differences and a continuous pattern. At the within-population level, whether NEA or SEA populations have higher genetic diversity is also highly controversial. In this study, we analyzed a large set of HLA data from East Asia in order to map the genetic variation among and within populations in this continent and to clarify the distribution pattern of HLA lineages and alleles. We observed a genetic differentiation between NEA and SEA populations following a continuous pattern from north to south, and we show a significant and continuous decrease of HLA diversity by the same direction. This continuity is shaped by clinal distributions of many HLA lineages and alleles with increasing or decreasing frequencies along the latitude. These results bring new evidence in favor of the “overlapping model” proposed previously for East Asian peopling history, whereby modern humans migrated eastward from western Eurasia via two independent routes along each side of the Himalayas and, later, overlapped in East Asia across open land areas. Our study strongly suggests that intensive gene flow between NEA and SEA populations occurred and shaped the latitude-related continuous pattern of genetic variation and the peculiar HLA lineage and allele distributions observed in this continent. Probably for a very long period, the exact duration of these events remains to be estimated.

The HLA-B landscape of Africa: Signatures of pathogen-driven selection and molecular identification of candidate alleles to malaria protection

Human leukocyte antigen (HLA) genes play a key role in the immune response to infectious diseases, some of which are highly prevalent in specific environments, like malaria in sub‐Saharan Africa. Former case–control studies showed that one particular HLA‐B allele, B*53, was associated with malaria protection in Gambia, but this hypothesis was not tested so far within a population genetics framework. In this study, our objective was to assess whether pathogen‐driven selection associated with malaria contributed to shape the HLA‐B genetic landscape of Africa. To that aim, we first typed the HLA‐A and ‐B loci in 484 individuals from 11 populations living in different environments across the Sahel, and we analysed these data together with those available for 29 other populations using several approaches including linear modelling on various genetic, geographic and environmental parameters. In addition to relevant signatures of populations’ demography and migrations history in the genetic differentiation patterns of both HLA‐A and ‐B loci, we found that the frequencies of three HLA alleles, B*53, B*78 and A*74, were significantly associated with Plasmodium falciparum malaria prevalence, suggesting their increase through pathogen‐driven selection in malaria‐endemic environments. The two HLA‐B alleles were further identified, by high‐throughput sequencing, as B*53:01:01 (in putative linkage disequilibrium with one HLA‐C allele, C*04:01:01:01) and B*78:01 in all but one individuals tested, making them appropriate candidates to malaria protection. These results highlight the role of environmental factors in the evolution of the HLA polymorphism and open key perspectives for functional studies focusing on HLA peptide‐binding properties.

qKAT: a high-throughput qPCR method for KIR gene copy number and haplotype determination

Killer cell immunoglobulin-like receptors (KIRs), expressed on natural killer cells and T cells, have considerable biomedical relevance playing significant roles in immunity, pregnancy and transplantation. The KIR locus is one of the most complex and polymorphic regions of the human genome. Extensive sequence homology and copy number variation makes KIRs technically laborious and expensive to type. To aid the investigation of KIRs in human disease we developed a high-throughput, multiplex real-time polymerase chain reaction method to determine gene copy number for each KIR locus. We used reference DNA samples to validate the accuracy and a cohort of 1698 individuals to evaluate capability for precise copy number discrimination. The method provides improved information and identifies KIR haplotype alterations that were not previously visible using other approaches.

Forward-in-Time, Spatially Explicit Modeling Software to Simulate Genetic Lineages Under Selection

SELECTOR is a software package for studying the evolution of multiallelic genes under balancing or positive selection while simulating complex evolutionary scenarios that integrate demographic growth and migration in a spatially explicit population framework. Parameters can be varied both in space and time to account for geographical, environmental, and cultural heterogeneity. SELECTOR can be used within an approximate Bayesian computation estimation framework. We first describe the principles of SELECTOR and validate the algorithms by comparing its outputs for simple models with theoretical expectations. Then, we show how it can be used to investigate genetic differentiation of loci under balancing selection in interconnected demes with spatially heterogeneous gene flow. We identify situations in which balancing selection reduces genetic differentiation between population groups compared with neutrality and explain conflicting outcomes observed for human leukocyte antigen loci. These results and three previously published applications demonstrate that SELECTOR is efficient and robust for building insight into human settlement history and evolution.

Correction to: “Forward-in-Time, Spatially Explicit Modeling Software to Simulate Genetic Lineages Under Selection”

[This corrects the article DOI: 10.4137/EBO.S33488.].