This duck and not that duck – what determines the susceptibility to infections?

Seasonal flu is just around the corner here in Sweden, with cases starting to rise week by week. And although the infection dynamic is fairly predictable at the population level, driven by both environmental factors and behavioral changes in the human population, it is not always easy to predict who will be infected or not, and whether an infection will result in mild or severe disease. Ultimately, this will depend on the exposure risk, the underlying condition of the individual, variation in specific genes in both the virus and the host and whether he/she has experienced previous infections, and in such case, how similar the current virus is to previous viruses. In short: complex interactions between the microorganism, the host, and the environment. These are things disease ecologists are interested in!

Unfortunately, for wildlife we know essentially nothing for most pathogens and hosts in terms of disease dynamics. And we know particularly little regarding the immune system and how variation in immune genes translates into protection against pathogens. If you read the literature, most studies look at the adaptive branch of the immune system, especially antibody mediated immunity and the diversity in the genes that make up the MHC loci. The MHC – or Major Histocompatability Complex – are among the most variable genes we know of, responsible for binding and presenting antigens to B- and T-cells and triggering immune processes. Although extremely interesting, they are but a part of the vast array of cells, proteins, and genes involved in immune processes.

In a recent paper, we dived straight into another set of genes: the beta-defensins. This is the first of several papers we will prepare on the subject. β-defensins are cool little proteins, actually kind of bad ass. Their main function is to interact with bacterial cell walls, where they create little pores and thereby interfere with cell homeostasis (think of Swiss cheese). β-defensins are part of the innate immune system and are ancient, present throughout the animal kingdom – and although some have evolved into new functions, such as toxins, the vast majority are involved in the fight against pathogens. Apart from directly killing invading bugs, they are involved in immune signaling and can also target some viral infections.

Our main study species is the Mallard, an important game bird species and the ancestor to domestic ducks – and the main reservoir host for influenza A virus in the Northern Hemisphere. Having studied disease dynamics in this host for a long time, we are now very curious about how variation in immune genes among Mallards translates into susceptibility to different diseases. Fortunately, the time is right for pursuing such questions, as the genome of the Mallard is available, making it easier to develop molecular tools to target specific genes. In a studied published a few weeks ago, we amplified and sequenced five β-defensin genes in a large number of individuals. First we studied these genes in a local population from Sweden, then we expanded it to cover specimens from all over the species’ range – from Europe, North America and Asia – and finally we sequenced the same genes in other species across the waterfowl phylogeny. This allowed as to ask how evolution has shaped β-defensin genes over different time scales. The results are summarized in the abstract, below:

All five genes showed remarkably low diversity at the individual-, population-, and species-level. Furthermore, there was widespread sharing of identical alleles across species divides. Thus, specific β-defensin alleles were maintained not only spatially but also over long temporal scales, with many amino acid residues being fixed across all species investigated. Purifying selection to maintain individual, highly efficacious alleles was the primary evolutionary driver of these genes in waterfowl. However, we also found evidence for balancing selection acting on the most recently duplicated β-defensin gene (AvBD3b). For this gene, we found that amino acid replacements were more likely to be radical changes, suggesting that duplication of β-defensin genes allows exploration of wider functional space. Structural conservation to maintain function appears to be crucial for avian β-defensin effector molecules, resulting in low tolerance for new allelic variants. This contrasts with other types of innate immune genes, such as receptor and signalling molecules, where balancing selection to maintain allelic diversity has been shown to be a strong evolutionary force.

Distribution of AvBD10 alleles across species, whereby coloured shading denotes mallard alleles and black shading denotes alleles found only in non-mallard waterfowl. Species with shading in the same vertical column share the allele denoted by that column. For more info see the original paper here.

To break this down into a more layman text, it means that most alleles are very old, dating back from before the different species split – evidenced by the same allele present in different waterfowl species separated by millions of years’ evolution. It also means that there is strong selection for maintaining function, that is, that mutations that change the amino acid composition largely are purged from the population. However, for one of the genes we saw evidence of balancing selection, where gene diversity in the population is favoured.

We hope this paper will be of interest for the evolutionary biology crowd, but we also see it as a first stepping stone into investigating how genetic variation translates into function. We are continuing with several lines of research, both in the lab and in experimental infections to measure how effective different allelic variants are against different pathogens, and where and how these genes are upregulated upon infection. This is very exciting research, but also a bit of a leap from what we have done in our lab before. It is a certain thrill to charter the unknown, and there’s tons of stuff to learn in order to do it well.

This paper was a collaborative effort involving four labs (Linnaeus University, University of Konstanze, University of Lund, and Wildfowl & Wetlands Trust):

Chapman, J.R., Hellgren, O., Helin, A.S., Kraus, R.H.S., Cromie, R.L. & Waldenström, J. 2016. The Evolution of Innate Immune Genes: Purifying and Balancing Selection on β-Defensins in Waterfowl. Molecular Biology and Evolution 33(12): 3075-3087.

 

 

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