Balancing selection and heterogeneity across the classical human leukocyte antigen loci: a meta-analytic review of 497 population studies.

Molecular differences between HLA alleles vary up to 57 nucleotides within the peptide binding coding region of human Major Histocompatibility Complex (MHC) genes, but it is still unclear whether this variation results from a stochastic process or from selective constraints related to functional differences among HLA molecules. Although HLA alleles are generally treated as equidistant molecular units in population genetic studies, DNA sequence diversity among populations is also crucial to interpret the observed HLA polymorphism. In this study, we used a large dataset of 2,062 DNA sequences defined for the different HLA alleles to analyze nucleotide diversity of seven HLA genes in 23,500 individuals of about 200 populations spread worldwide. We first analyzed the HLA molecular structure and diversity of these populations in relation to geographic variation and we further investigated possible departures from selective neutrality through Tajima's tests and mismatch distributions. All results were compared to those obtained by classical approaches applied to HLA allele frequencies.Our study shows that the global patterns of HLA nucleotide diversity among populations are significantly correlated to geography, although in some specific cases the molecular information reveals unexpected genetic relationships. At all loci except HLA-DPB1, populations have accumulated a high proportion of very divergent alleles, suggesting an advantage of heterozygotes expressing molecularly distant HLA molecules (asymmetric overdominant selection model). However, both different intensities of selection and unequal levels of gene conversion may explain the heterogeneous mismatch distributions observed among the loci. Also, distinctive patterns of sequence divergence observed at the HLA-DPB1 locus suggest current neutrality but old selective pressures on this gene. We conclude that HLA DNA sequences advantageously complement HLA allele frequencies as a source of data used to explore the genetic history of human populations, and that their analysis allows a more thorough investigation of human MHC molecular evolution.

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HLA DNA sequence variation among human populations: molecular signatures of demographic and selective events.

The invention discloses methods for the generation of chimaeric human-non-human antibodies and chimaeric antibody chains, antibodies and antibody chains so produced, and derivatives thereof including fully humanised antibodies; compositions comprising said antibodies, antibody chains and derivatives, as well as cells, non-human mammals and vectors, suitable for use in said methods.

Animal Models and Therapeutic Molecules

Human immunoglobulin allotypes are antigenic determinants (or "markers") determined serologically, classically by hemagglutination inhibition, on the human immunoglobulin (IG) heavy and light chains. The allotypes have been identified on the gamma1, gamma2, gamma3, and alpha2 heavy chains (they are designated as G1m, G2m, G3m, and A2m allotypes, respectively), and on the kappa light chain (Km allotypes). Gm-Am allotypes are inherited in fixed combinations, or Gm-Am haplotypes, owing to the linkage of the human IGHC genes (IGHG3, IGHG1, IGHA1, IGHG2, IGHG4, IGHE, and IGHA2 from 5' to 3' in the IGH locus on chromosome 14). Gm and Am allotypes have been one of the most powerful tools in population genetics and very instrumental in molecular characterization of the human IGHC genes (gene conversion, copy number variation, gene order). They represent a major system for understanding immunogenicity of the polymorphic IG chains, in relation with amino acid and conformational changes. The correlation between G3m allotypes and amino acid changes has been possible with the sequencing of many alleles of the IGHG3 gene, from individuals from different populations and with known allotypes. In this chapter, we integrate genetics and sequence data and provide an updated overview of the Gm-Am haplotypes and Km allotypes. We propose, for the first time, a complete elucidation of the G3m allotypes, illustrated by the "IMGT G3m allele butterfly" concept that allows a graphical representation of the G3m alleles (variants of a gene expressing a given set of allotypes). Knowledge of allotypes is important in antibody engineering and humanization of monoclonal antibodies to improve immunotherapy.

Human Gm, Km, and Am allotypes and their molecular characterization: a remarkable demonstration of polymorphism.

The Strait of Gibraltar is a crucial area in the settlement history of modern humans because it represents a possible connection between Africa and Europe. So far, genetic data were inconclusive about the fact that this strait constitutes a barrier to gene flow, as previous results were highly variable depending on the genetic locus studied. The present study evaluates the impact of the Gibraltar region in reducing gene flow between populations from North-Western Africa and South-Western Europe, by comparing formally various genetic loci. First, we compute several statistics of population differentiation. Then, we use an original simulation approach in order to infer the most probable evolutionary scenario for the settlement of the area, taking into account the effects of both demography and natural selection at some loci. We show that the genetic patterns observed today in the region of the Strait of Gibraltar may reflect an ancient population genetic structure which has not been completely erased by more recent events such as Neolithic migrations. Moreover, the differences observed among the loci (i.e. a strong genetic boundary revealed by the Y-chromosome polymorphism and, at the other extreme, no genetic differentiation revealed by HLA-DRB1 variation) across the strait suggest specific evolutionary histories like sex-mediated migration and natural selection. By considering a model of balancing selection for HLA-DRB1, we here estimate a coefficient of selection of 2.2% for this locus (although weaker in Europe than in Africa), which is in line with what was estimated from synonymous versus non-synonymous substitution rates. Selection at this marker thus appears strong enough to leave a signature not only at the DNA level, but also at the population level where drift and migration processes were certainly relevant. Our multi-loci approach using both descriptive analyses and Bayesian inferences lead to better characterize the role of the Strait of Gibraltar in the evolution of modern humans. We show that gene flow across the Strait of Gibraltar occurred at relatively high rates since pre-Neolithic times and that natural selection and sex-bias migrations distorted the demographic signal at some specific loci of our genome.

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Human genetic differentiation across the Strait of Gibraltar.

North Africa is populated by many Arab- and Berber-speaking populations whose genetic history is still poorly understood. In this study, we analyse the HLA-DRB1 and DQB1 molecular diversity in three populations from the south of Tunisia--Berbers from Jerba, Berbers from Matmata and Arabs from Gabes--and we compare them to a large set of populations from the whole Mediterranean region. Among the three populations studied, the Berbers from Jerba are the most peculiar, as they diverge significantly from other North Africans while being genetically highly diversified and close to populations from the Near East. Thus, Jerba may have been a crossing point, in historical times, where colonization from the eastern Mediterranean area left significant genetic traces. By contrast, the populations from Matmata and Gabes are genetically similar to other Arab and Berber-speaking populations from different areas of the Maghrib, despite some peculiar allele and haplotype frequencies. At a larger scale, northwest Africa and southwest Europe are closely related according to these polymorphisms, while the populations from the eastern Mediterranean area are much more differentiated. The close genetic relatedness found for HLA among populations of the western Mediterranean region challenges previous results based on Y chromosome analyses, where the Gibraltar Strait appeared to constitute a main genetic barrier.

HLA class II genetic diversity in southern Tunisia and the Mediterranean area.

The Gm polymorphism of human IgG immunoglobulins was investigated in three different ethnic groups--Arabs, Berbers and 'dark-skinned people'--on Jerba Island, Tunisia. The genetic relationships among these groups and several populations from North Africa, sub-Saharan Africa, west Asia and Europe were analysed by principal coordinate analysis, Fst significance testing, and analysis of molecular variance based on haplotype frequencies. The results revealed a non-significant genetic differentiation between Arabs and Berbers from Jerba. However, the Jerbian population of sub-Saharan African origin was close to Ethiopians. Gene flow among the three Jerbian populations, as well as an East African origin of the dark-skinned individuals, is proposed to account for the observed genetic pattern. However, the genetic diversity observed among the different Tunisian populations did not show any significant correlation with either geographic or linguistic differentiation. A preliminary analysis of the restriction fragment length polymorphism of the IGHG genes in Arabs and Berbers from Jerba confirmed the close genetic relationship between the two populations. However, it also indicated a lower level of genetic diversity in the Berbers, which may be explained by more rapid genetic drift due to longer isolation on the island.

A. Ben Ammar Elgaaied

Papers

HLA class II genetic diversity in southern Tunisia and the Mediterranean area.

A study of Gm allotypes and immunoglobulin heavy gamma IGHG genes in Berbers, Arabs and sub-Saharan Africans from Jerba Island, Tunisia