Early human settlements in contrasting environments: HLA molecular variation and its link to population expansions and immune adaptation

Project scope

• Do the patterns of HLA diversity differ significantly among populations living in contrasting environments?
• Are the allelic repertoires observed in populations living in contrasting environments functionally relevant to explain HLA diversity?
• Does natural selection acting on HLA vary significantly in type and intensity in contrasting environments?
• Are the patterns of HLA diversity partly explained by adaptive introgression of functionally relevant HLA alleles from archaic humans?

These and other questions related to human settlement history are addressed through the molecular and bio-statistical analysis of several genes involved in our immunity: the HLA genes.

To achieve this project, we are generating a large amount of new HLA genetic data by using next generation sequencing (NGS) technology in about 5,000 individuals from 50 human populations living in different continents and environments.

We are also developing new resampling proceduresfor the estimation of haplotype frequencies, linkage disequilibrium and other statistics useful to analyze complex multi-locus HLA data, and new simulation algorithms including variable types and intensities of natural selection (i.e. positive, balancing) to simulate specific scenarios of human population expansions. We are also exploring the functional variability of HLA molecules by analyzing the allelic repertoires of populations adapted to distinct environments in relation to MHC peptide-binding motifs and environmental variables.

Project innovations

A large dataset of new population samples…

…representing more than 50 populations (about 5,000 individuals), many of them living in pathogen-rich environments (e.g. malaria endemic areas in Africa).

NGS data for multiple HLA genes…

…representing huge sets of unambiguous HLA molecular data allowing a much finer detection of polymorphism than former technologies.

Original methods in population and evolutionary genetics…

…including new implementations in Gene[rate], now integrated into the HLA-net platform and allowing users to compare directly their own data to the Gene[VA] database;
…including new implementations in Selector allowing to account for diverse kinds and intensities of selection.

An inter-disciplinary approach…

…using functional, epidemiologic and environmental data to understand better HLA molecular variation throughout the world.