Fu M et al. (2023), Divergent allele advantage in the MHC and amphi...

XB-ART-59939

Infect Genet Evol 2023 Jul 01;111:105429. doi: 10.1016/j.meegid.2023.105429.

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Divergent allele advantage in the MHC and amphibian emerging infectious disease.

Fu M , Eimes JA , Waldman B .

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Genetic variation in the major histocompatibility complex (MHC) may be associated with resistance to the amphibian chytrid fungus Batrachochytrium dendrobatidis (Bd). The pathogen originated in Asia, then spread worldwide, causing amphibian population declines and species extinctions. We compared the expressed MHC IIβ1 alleles of a Bd-resistant species, Bufo gargarizans, from South Korea with those of a Bd-susceptible Australasian species, Litoria caerulea. We found at least six expressed MHC IIβ1 loci in each of the two species. Amino acid diversity encoded by these MHC alleles was similar between species, but the genetic distance of those alleles known for potential broader pathogen-derived peptide binding was greater in the Bd-resistant species. In addition, we found a potentially rare allele in one resistant individual from the Bd-susceptible species. Deep next-generation sequencing recovered approximately triple the genetic resolution accessible from traditional cloning-based genotyping. Targeting the full MHC IIβ1 enables us to better understand how host MHC may adapt to emerging infectious diseases.

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Genes referenced: myh6
GO keywords: MHC class II protein binding [+]

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	Fig. 1. Identification of multiple expressed MHC IIß1 loci in Bd-susceptible and resistant species. Distribution of the individual number of MHC IIß1 alleles in Litoria caerulea and Bufo gargarizans. Frog images, left, L. caerulea; right, B. gargarizans.
	Fig. 2. Maximum likelihood phylogenetic tree of nucleotide MHC IIß1 alleles in L. caerulea. Branch lengths were measured in the number of substitutions per site. One thousand bootstrap replicates were conducted. The values next to branches represent bootstrap values. Note: MHC IIB1 is synonymous with MHC IIß1.
	Fig. 3. Maximum likelihood phylogenetic tree of nucleotide MHC IIß1 alleles in B. gargarizans. Branch lengths were measured in the number of substitutions per site. One thousand bootstrap replicates were conducted. The values next to branches represent bootstrap values. Note: MHC IIB1 is synonymous with MHC IIß1.
	Fig. 4. Wu-Kabat plot of amino acid sequences of MHC IIß1 chain from liver of B. gargarizans and L. caerulea. Asterisks represent annotated peptide binding sites (PBSs) based on the human genome, and WuKa sites of each species correspondingly. PBSs: 9, 11, 13, 28, 30, 32, 37, 38, 47, 56, 60, 61, 65, 68, 70, 71, 74, 78, 81, 82, 85, 86, 88, 89. The red line indicates the threshold over double the average Wu-Kabat variability in L. caerulea, which is 5.059. The blue line indicates the threshold over double the average Wu-Kabat variability in B. gargarizans, which is 4.261. When Wu-Kabat variability exceeds the threshold, the site is annotated as a WuKa site. Therefore, the WuKa sites in L. caerulea (WuKa_L) are at positions 2, 12, 13, 37, 48, 49, 51, 57, 67, 71, 74, 81, 86, 88, 89; while, the WuKa sites in B. gargarizans (WuKa_B) are at positions 11, 28, 37, 43, 59, 71, 74, 77, 85, 86, 88. The number in brackets after WuKa_L and Wuka_B represents the number of MHC IIß1 sequences used for this analysis. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
	Fig. 5. Different genetic divergences between Bd-resistant and susceptible species. Non-metric multidimensional scaling (NMDS) plots of MHC alleles' Grantham distances between Bd-resistant (BG) and -susceptible species (LC). BG, Bufo gargarizans. LC, Litoria caerulea. The circles indicate 95% confidence intervals for each group.
	Fig. 6. Hypothesis for the roles of rare allele advantage (RAA) and divergent allele advantage (DAA) on MHC selection when adapting to an emerging pathogen. (A) In the early adaptation to an emerging infectious disease when the pathogen-driven force is high (HPF), rare allele advantage may strenthen. Once alleles conferring resistance to, or tolerance of, the disease become common, the pathogen-driven force lessens (LPF), which may favor divergent alleles. Should another pathogen emerge, RAA may again rise in importance. (B) When the selection pressure driven by pathogens is high, RAA is more likely to occur for the susceptible population. When the pressure becomes low, DAA is more likely to be detected for maintaining MHC diversity in the adapted population after long-term coevolution with pathogens.