Exploiting the Drosophila phylogeny

The Drosophila 12 genomes project provided unprecedented opportunities for developing comparative genomic approaches, to examine features of sequence evolution across a moderately divergent insect phylogeny (Clark et al., 2007; Stark et al., 2007; Lin et al, 2008). The high levels of sequence divergence that were observed previously, in more distant insect genome comparisons, prevented examination of molecular evolution for evidence of selective constraints. However, the limited divergence among six closely-related species of the melanogaster group facilitated robust estimation of rates of synonymous and non-synonymous substitutions in protein-coding genes. Substitution analysis of single-copy orthologues from this group with respect to gene ontology classifications found that most functional categories are strongly constrained, whereas the defence response class is a rare category that exhibits an elevated ratio of non-synonymous to synonymous divergence, suggesting positive selection, or reduction of selective constraints (Clark et al., 2007). This result directly supports our previous observations that immune-related genes show elevated divergence in terms of pairwise Drosophila-Anopheles sequence identities (Zdobnov et al, 2002) and three-way fruit fly-mosquito phylogenetic distances (Waterhouse et al, 2007). Indeed, maximum likelihood analysis of gene family expansions and contractions across the 12 Drosophila species identified the defence response category as one of the most common annotations in gene families with elevated rates of gene gain or loss. These genomes represent a rich dataset for exploring the evolutionary processes (including selection and non-adaptive drift) which shape important phenotypes such as defence and immunity, metabolism and detoxification, sex and reproduction, or chemoreception.

Comprehensive annotation of the immune repertoire identified over 2500 candidate immune-related genes across the 12 Drosophila species, facilitating the investigation of evolutionary patterns in fruit fly immunity gene families and their sequence divergence (Sackton et al., 2007). Orthology analysis identified single-copy orthologues, conserved paralogues, and lineage-restricted genes from various functional categories of such families across the 12 species. Maximum likelihood modelling of gene birth/death events provided an estimate of the rates of gene turnover (duplications and losses) over the entire phylogeny of each family. These estimates showed a deficit of single-copy ortho-logues among effector families, contrasting with high prevalence of orthologues among signalling proteins. The latter class also exhibited reduced levels of gene turnover compared to both effectors and recognition proteins. Lineage-restricted genes, identified through multi-species comparisons, represent evolutionary novelties potentially generated from rearrangements and/or truncated copies of existing genes. Examples of such novelties are examined in more detail below. The gene encoding the antifungal peptide drosomycin is used as an indicator of Toll-pathway activation in D. mela-nogaster, but is restricted to the melanogaster group. Thus, even within the Drosophila genus, there is considerable variation in the repertoires of recognition and effector families, while the core signalling components show much more stable prevalence.

Sequence analysis of all single-copy ortho-logues from the melanogaster group found that the immune repertoire exhibits a significantly high proportion of adaptively selected genes. The class of recognition proteins, particularly those implicated in phagocytosis, was largely responsible for this trend, whereas effectors showed little evidence of adaptive evolution. Codon-based selection analysis along the recognition proteins located significantly more sites of possible positive selection, within regions experimentally identified as putative pathogen-interaction domains. Assessment with lineage-specific codon models identified several Imd pathway genes, indicating accelerated evolution in D. melanogaster compared with Drosophila yakuba and Drosophila erecta. The positively selected sites among these proteins showed significant clustering within regions thought to interact physically during signal transduction. These observations are in agreement with, and provide further evolutionary insight into, findings from the earlier fruit fly-mosquito comparative immunogenomic analyses (Waterhouse et al., 2007). Uncovering patterns of sequence variation which point towards adaptive evolutionary processes, can identify key components of the innate immune repertoire which may shape host-pathogen co-evolutionary dynamics.

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