Abstract
The protein family of Lipocalins is ubiquitously present throughout the tree of life, with the exception of the phylum Archaea. Phylogenetic relationships of chordate Lipocalins have been proposed in the past based on protein sequence similarities, but their highly divergent primary structures and a shortage of experimental annotations in genome projects have precluded a well-supported hypothesis for their evolution. In this work we propose a novel topology for the phylogenetic tree of chordate Lipocalins, inferred from multiple amino acid sequence alignments. Sixteen jawed vertebrates with fair coverage by genomic sequencing were compared. The selected species span an evolutionary range of ∼400 million years, allowing for a balanced representation of all major vertebrate clades. A consensus phylogenetic tree is proposed following a comparison of sequence-based maximum-likelihood trees and protein structure dendrograms. This new phylogeny suggests an APOD-like common ancestor in early chordates, which gave rise, via whole-genome or tandem duplications, to the six Lipocalins currently present in fish (APOD, RBP4, PTGDS, AMBP, C8G, and APOM). Further gene duplications of APOM and PTGDS resulted in the altogether 15 Lipocalins found in contemporary mammals. Insights into the functional impact of relevant amino acid residues in early diverging Lipocalins are also discussed. These results should foster the experimental exploration of novel functions alongside the identification of new members of the Lipocalin family.
Highlights
Lipocalins form an ancestral protein family so far found in all kingdoms of life except for Archaea
Previous reports aimed at maximizing the number of protein sequences to be included, which might bias phylogenetic relationships in tree nodes overrepresented in databases due to the preferential sequencing of model organisms or to genome projects that have been prioritized
The phylogenetic relationship and evolutionary timescale of the sixteen jawed vertebrates used in our study were estimated with TimeTree (Kumar et al, 2017; Figure 1A)
Summary
The evolutionary paths followed by the Lipocalins have been explored using standard in silico molecular evolution methodologies based on protein sequence alignments, exon-intron architecture and protein tertiary structure comparisons (Ganfornina et al, 2000; Gutierrez et al, 2000; Sanchez et al, 2003, 2006; Lakshmi et al, 2015). We identified particular residues accounting for both the divergence and the specificities of the main Lipocalin clades that appeared early in chordate evolution Marking such residues as important will be useful to reveal protein regions relevant for known or novel functions that can be further experimentally tested. With these results we propose an evolutionary history for Lipocalins in chordates
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