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. 2012 May 28:12:71.
doi: 10.1186/1471-2148-12-71.

An ancient history of gene duplications, fusions and losses in the evolution of APOBEC3 mutators in mammals

Carsten Münk  1 , Anouk Willemsen, Ignacio G Bravo
Affiliations

An ancient history of gene duplications, fusions and losses in the evolution of APOBEC3 mutators in mammals

Carsten Münk et al. BMC Evol Biol. .

Abstract

Background: The APOBEC3 (A3) genes play a key role in innate antiviral defense in mammals by introducing directed mutations in the DNA. The human genome encodes for seven A3 genes, with multiple splice alternatives. Different A3 proteins display different substrate specificity, but the very basic question on how discerning self from non-self still remains unresolved. Further, the expression of A3 activity/ies shapes the way both viral and host genomes evolve.

Results: We present here a detailed temporal analysis of the origin and expansion of the A3 repertoire in mammals. Our data support an evolutionary scenario where the genome of the mammalian ancestor encoded for at least one ancestral A3 gene, and where the genome of the ancestor of placental mammals (and possibly of the ancestor of all mammals) already encoded for an A3Z1-A3Z2-A3Z3 arrangement. Duplication events of the A3 genes have occurred independently in different lineages: humans, cats and horses. In all of them, gene duplication has resulted in changes in enzyme activity and/or substrate specificity, in a paradigmatic example of convergent adaptive evolution at the genomic level. Finally, our results show that evolutionary rates for the three A3Z1, A3Z2 and A3Z3 motifs have significantly decreased in the last 100 Mya. The analysis constitutes a textbook example of the evolution of a gene locus by duplication and sub/neofunctionalization in the context of virus-host arms race.

Conclusions: Our results provide a time framework for identifying ancestral and derived genomic arrangements in the APOBEC loci, and to date the expansion of this gene family for different lineages through time, as a response to changes in viral/retroviral/retrotransposon pressure.

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Figures

Figure 1
Figure 1
Dated Bayesian phylogenetic tree for the A3 family using A1 sequences as outgroup. Scale bar given in Mya. Values at the nodes correspond to ML bootstrap support. Error bars encompass 95% HPD for the age of the nodes. Star symbols indicate duplication events in the corresponding lineage and moment in time. Clock cartoons labels the nodes used for calibration. Mammalian clades are labelled using colours (code in the inset). No sequences from Xenarthra could be found in our searches.
Figure 2
Figure 2
Projection of the A3 phylogenetic relationships onto the human genomic locus. Exon composition and gene arrangement of the seven A3 genes are displayed. Labels indicate median age [95% HPD] of the corresponding nodes. Several milestones in the evolution of mammals are indicated.
Figure 3
Figure 3
Projection of the A3 phylogenetic relationships onto the horse (a) and cat (b) genomic loci. Exon composition and gene arrangement of the A3 genes are displayed. Labels indicate median age [95% HPD] of the corresponding nodes. Several milestones in the evolution of mammals are indicated.
Figure 4
Figure 4
Histogram showing the distribution of the percentages of Ka/Ks values for each position for the genes A1, AICDA, A3Z1, A3Z2 and A3Z3 (colour code in the inset).
Figure 5
Figure 5
Slide window analysis showing the variation of Ka/Ks along the corresponding sequence (colour code in the inset). Values have been computed using a window of five positions and a step of one.
Figure 6
Figure 6
Graph plotting the evolutionary rate against the node age for (a) A1 and AICDA sequences and (b) A3Z1, A3Z2 and A3Z3 sequences. Colour code in the inset. Values for the goodness and significance of the fit to a straight line are provided. For the A1 genes, the values with and without the indicated point ($) are given. When this value is not included in the analysis the trend is not statistically significant.
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