Project

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Evolutionary significance of exceptionally long MHC haplotypes and their role in disease genetics

Applicant Gaigher Arnaud
Number 187659
Funding scheme Early Postdoc.Mobility
Research institution Max-Planck-Institut für Evolutionsbiologie Abteilung Evolutionsgenetik
Institution of higher education Institution abroad - IACH
Main discipline Genetics
Start/End 01.09.2020 - 31.08.2022
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All Disciplines (2)

Discipline
Genetics
Ecology

Keywords (5)

Evolutionary experiments; Sequence divergence; MHC/HLA haplotypes; Human evolution; Pathogen-mediated selection

Lay Summary (French)

Lead
Bien qu’il soit largement admis que la diversité génétique immunitaire joue un rôle crucial dans la résistance aux maladies, la contribution relative des mécanismes évolutifs à l’origine de cette diversité reste encore mal comprise. Ce projet vise à mieux comprendre les mécanismes génétiques impliqués dans la résistance aux agents pathogènes.
Lay summary

Chaque individu est confronté à un large éventail d’agents pathogènes, mais la capacité à résister à ses agents peut considérablement différer entre les individus. Dans ce contexte, la diversité génétique dans des régions impliquées dans l’immunité, tel que le CMH, joue un rôle primordial pour une réponse immunitaire efficace contre les agents pathogènes. Cependant, malgré une connaissance croissante du système CMH, des aspects importants de sa diversité n'ont pas été encore testés pour mieux comprendre pourquoi certains individus, populations ou espèces luttent plus efficacement contre les maladies que d’autres. En utilisant deux espèces modèles complémentaires (poisson et humain), le projet actuel vise à tester si des niveaux élevés de diversité au niveau du CMH sont liés à une résistance accrue contre des agents pathogènes. Les résultats de ce projet apporteront de nouvelles preuves empiriques du lien entre la diversité du CMH et la résistance aux agents pathogènes. En outre, cela aidera également à comprendre pourquoi des personnes d'origines ethniques différentes réagissent différemment aux maladies, ce qui aura des implications majeures dans la gestion des maladies humaines.

Direct link to Lay Summary Last update: 26.02.2020

Responsible applicant and co-applicants

Abstract

Genes of the major histocompatibility complex (MHC), with their direct involvement in pathogen resistance and link to individual fitness, have a prominent role in the study of the genetic basis of adaptation. Despite extensive efforts to understand the evolutionary processes involved in the origin and maintenance of MHC diversity, the persistence of long-range (typically millions of base-pairs long) MHC haplotypes over generations in humans and many other species remains largely elusive. Given that such haplotypes should not exist because of continuous recombination, these structures are highly intriguing, and may result from selection imposed by pathogens to favor and maintain beneficial combinations of specific MHC alleles. Specifically, haplotypes including MHC alleles that combine high levels of sequence divergence are expected to allow recognizing and fighting a wider range of pathogens than haplotypes combining a low divergence, thus increasing individual fitness. Even though this “divergent allele advantage” hypothesis is well conceptualized and biologically relevant, it has not yet been thoroughly tested to explain the maintenance of long-range MHC haplotypes observed in nature.In the present project, I therefore aim to formally test this hypothesis by investigating whether the level of sequence divergence at the haplotype level is linked to enhanced pathogen resistance and may be at the origin and maintenance of long-range MHC haplotypes in nature. I have designed the SNF project to surpass what, to my knowledge, has been limiting such research in the past, by using study organisms for which (i) the MHC system has been intensively studied and where MHC structure and haplotype organization is well characterized; (ii) experiments can be designed to access causal relationships; (iii) extensive amounts of haplotype data can be efficiently collected; and (iv) pathogen communities are well known. Sticklebacks and humans offer these opportunities, and will thus be two complementary systems on which I will focus my research. In the stickleback system, I will combine an experimental approach with computational analyses to investigate whether haplotypes with high level of sequence divergence (i) confer enhanced resistance to the natural parasite community, and (ii) occur at higher frequencies in natural habitats. In a second line of research, using an extensive dataset available from the human MHC, I will conduct a simulation study to investigate to what extent the evolution of haplotypes under selection, favoring high divergence, explains the observed MHC haplotype distribution in human populations. I will particularly focus on specific, well-known haplotypes, such as the common 8.1 ancestral haplotype, for which alleles at different MHC loci recognize a unique set of pathogens. Given this, I will investigate whether these combinations of alleles gather a specific level of sequence divergence enabling binding complementary pathogen-peptides. Finally, I will investigate whether a high level of sequence divergence (or complementary peptide binding) provides the basis for resistance against specific human diseases, using information about epidemiology and pathogen communities of human populations.By combining appropriate model species, semi-natural experiments, massive amounts of molecular data (at the genomic level) and state of the art computational approaches, this research project is highly innovative and competitive. This project promises novel insights into the evolutionary processes involved in the maintenance of long MHC haplotypes in nature, interfacing the fields of evolutionary immunology, human genetics and medicine.
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