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Heterogeneity of dN/dS ratios at the classical HLA class I genes over divergence time and across the allelic phylogeny

View ORCID ProfileBárbara Domingues Bitarello, View ORCID ProfileRodrigo dos Santos Francisco, View ORCID ProfileDiogo Meyer
doi: https://doi.org/10.1101/008342
Bárbara Domingues Bitarello
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  • For correspondence: bdbitarello@gmail.com
Rodrigo dos Santos Francisco
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Diogo Meyer
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Abstract

The classical class I HLA loci of humans show an excess of nonsynonymous with respect to synonymous substitutions at codons of the antigen recognition site (ARS), a hallmark of adaptive evolution. Additionally, high polymporphism, linkage disequilibrium and disease associations suggest that one or more balancing selection regimes have acted upon these genes. However, several questions about these selective regimes remain open. First, it is unclear if stronger evidence for selection on deep timescales is due to changes in the intensity of selection over time or to a lack of power of most methods to detect selection on recent timescales. Another question concerns the functional entities which define the selected phenotype. While most analysis focus on selection acting on individual alleles, it is also plausible that phylogenetically defined groups of alleles (“lineages”) are targets of selection. To address these questions we analyzed how dN/dS (ω) varies with respect to divergence times between alleles and phylogenetic placement (position of branches). We find that ω for ARS codons of class I HLA genes increases with divergence time and is higher for inter-lineage branches. Throughout our analyses, we used non-selected codons to control for possible effects of inflation of ω associated to intra-specific analysis, and showed that our results are not artifactual. Our findings indicate the importance of considering the timescale effect when analysing ω over a wide spectrum of divergences. Finally, our results support the divergent allele advantage model, whereby heterozygotes with more divergent alleles have higher fitness than those carrying similar alleles.

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Posted October 30, 2015.
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Heterogeneity of dN/dS ratios at the classical HLA class I genes over divergence time and across the allelic phylogeny
Bárbara Domingues Bitarello, Rodrigo dos Santos Francisco, Diogo Meyer
bioRxiv 008342; doi: https://doi.org/10.1101/008342
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Heterogeneity of dN/dS ratios at the classical HLA class I genes over divergence time and across the allelic phylogeny
Bárbara Domingues Bitarello, Rodrigo dos Santos Francisco, Diogo Meyer
bioRxiv 008342; doi: https://doi.org/10.1101/008342

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