Evidence for Restriction of Ancient Primate Gammaretroviruses by APOBEC3 but Not TRIM5α Proteins

Because of evolutionary pressures imposed through episodic colonization by retroviruses, many mammals express factors, such as TRIM5α and APOBEC3 proteins, that directly restrict retroviral replication. TRIM5 and APOBEC restriction factors are most often studied in the context of modern primate lentiviruses, but it is likely that ancient retroviruses imposed the selective pressure that is evident in primate TRIM5 and APOBEC3 genes. Moreover, these antiretroviral factors have been shown to act against a variety of retroviruses, including gammaretroviruses. Endogenous retroviruses can provide a ‘fossil record’ of extinct retroviruses and perhaps evidence of ancient TRIM5 and APOBEC3 antiviral activity. Here, we investigate whether TRIM5 and APOBEC3 proteins restricted the replication of two groups of gammaretroviruses that were endogenized in the past few million years. These endogenous retroviruses appear quite widespread in the genomes of old world primates but failed to colonize the human germline. Our analyses suggest that TRIM5α proteins did not pose a major barrier to the cross-species transmission of these two families of gammaretroviruses, and did not contribute to their extinction. However, we uncovered extensive evidence for inactivation of ancient gammaretroviruses through the action of APOBEC3 cytidine deaminases. Interestingly, the identities of the cytidine deaminases responsible for inactivation appear to have varied in both a virus and host species–dependent manner. Overall, sequence analyses and reconstitution of ancient retroviruses from remnants that have been preserved in the genomes of modern organisms offer the opportunity to probe and potentially explain the evolutionary history of host defenses against retroviruses.     

Evidence for restriction of ancient primate gammaretroviruses by APOBEC3 but not TRIM5alpha proteins

Because of evolutionary pressures imposed through episodic colonization by retroviruses, many mammals express factors, such as TRIM5alpha and APOBEC3 proteins, that directly restrict retroviral replication. TRIM5 and APOBEC restriction factors are most often studied in the context of modern primate lentiviruses, but it is likely that ancient retroviruses imposed the selective pressure that is evident in primate TRIM5 and APOBEC3 genes. Moreover, these antiretroviral factors have been shown to act against a variety of retroviruses, including gammaretroviruses. Endogenous retroviruses can provide a 'fossil record' of extinct retroviruses and perhaps evidence of ancient TRIM5 and APOBEC3 antiviral activity. Here, we investigate whether TRIM5 and APOBEC3 proteins restricted the replication of two groups of gammaretroviruses that were endogenized in the past few million years. These endogenous retroviruses appear quite widespread in the genomes of old world primates but failed to colonize the human germline. Our analyses suggest that TRIM5alpha proteins did not pose a major barrier to the cross-species transmission of these two families of gammaretroviruses, and did not contribute to their extinction. However, we uncovered extensive evidence for inactivation of ancient gammaretroviruses through the action of APOBEC3 cytidine deaminases. Interestingly, the identities of the cytidine deaminases responsible for inactivation appear to have varied in both a virus and host species-dependent manner. Overall, sequence analyses and reconstitution of ancient retroviruses from remnants that have been preserved in the genomes of modern organisms offer the opportunity to probe and potentially explain the evolutionary history of host defenses against retroviruses.     

Nef: agent of cell subversion

Primate lentiviruses encode a small protein designated Nef that has been shown to be a major determinant of virus pathogenicity. Nef regulates multiple host factors in order to optimize the cellular environment for virus replication. The mechanisms by which this small protein modulates distinct host cell properties provide intriguing insight into the intricate interaction between virus and host.     

The host restriction factor APOBEC3G and retroviral Vif protein coevolve due to ongoing genetic conflict

APOBEC3G (A3G) is a host cytidine deaminase that inhibits retroviruses. HIV and related primate lentiviruses encode Vif, which counteracts A3G by inducing its degradation. This Vif-mediated A3G inhibition is species specific, suggesting that the A3G-Vif interaction has evolved as primate lentiviruses have adapted to their hosts. We examined the evolutionary dynamics of the A3G-Vif interaction within four African green monkey (AGM) subspecies, which are each naturally infected with a distinct simian immunodeficiency virus (SIV). We identified single amino acid changes within A3G in two AGM subspecies that render it resistant to Vif proteins, except for Vif from the viruses that naturally infect these subspecies. Moreover, experimental infection of AGMs shows that Vif can rapidly adapt to these arising Vif-resistant A3G genotypes. These data suggest that despite being generally nonpathogenic in its natural host, SIV infection selects for Vif-resistant forms of A3G in AGM populations, driving Vif counterevolution and functional divergence.     

Endogenous lentiviral elements in the weasel family (mustelidae)

Endogenous retroviruses provide molecular fossils for studying the ancient evolutionary history of retroviruses. Here, we report our independent discovery and analysis of endogenous lentiviral insertions (Mustelidae endogenous lentivirus [MELV]) within the genomes of weasel family (Mustelidae). Genome-scale screening identified MELV elements in the domestic ferret (Mustela putorius furo) genome (MELVmpf). MELVmpf exhibits a typical lentiviral genomic organization. Phylogenetic analyses position MELVmpf basal to either primate lentiviruses or feline immunodeficiency virus. Moreover, we verified the presence of MELV insertions in the genomes of several species of the Lutrinae and Mustelinae subfamilies but not the Martinae subfamily, suggesting that the invasion of MELV into the Mustelidae genomes likely took place between 8.8 and 11.8 Ma. The discovery of MELV in weasel genomes extends the host range of lentiviruses to the Caniformia (order Carnivora) and provides important insights into the prehistoric diversity of lentiviruses.     

Host gene evolution traces the evolutionary history of ancient primate lentiviruses

Simian immunodeficiency viruses (SIVs) have infected primate species long before  human immunodeficiency virus has infected humans. Dozens of species-specific lentiviruses are found in African primate species, including two strains that have repeatedly jumped into human populations within the past century. Traditional phylogenetic approaches have grossly underestimated the age of these primate lentiviruses. Instead, here we review how selective pressures imposed by these viruses have fundamentally altered the evolutionary trajectory of hosts genes and, even in cases where there now remains no trace of the viruses themselves, these evolutionary signatures can reveal the types of viruses that were once present. Examination of selection by ancient viruses on the adaptive evolution of host genes has been used to derive minimum age estimates for modern primate lentiviruses. This type of data suggests that ancestors of modern SIV existed in simian primates more than 10 Ma. Moreover, examples of host resistance and viral adaptation have implications not only for estimating the age and host range of ancient primate lentiviruses, but also the pathogenic potential of their modern counterparts.     

Spatial but not temporal co-divergence of a virus and its mammalian host

Co-divergence between host and parasites suggests that evolutionary processes act across similar spatial and temporal scales. Although there has been considerable work on the extent and correlates of co-divergence of RNA viruses and their mammalian hosts, relatively little is known about the extent to which virus evolution is determined by the phylogeographic history of host species. To test hypotheses related to co-divergence across a variety of spatial and temporal scales, we explored phylogenetic signatures in Andes virus (ANDV) sampled from Chile and its host rodent, Oligoryzomys longicaudatus. ANDV showed strong spatial subdivision, a phylogeographic pattern also recovered in the host using both spatial and genealogical approaches, and despite incomplete lineage sorting. Lineage structure in the virus seemed to be a response to current population dynamics in the host at the spatial scale of ecoregions. However, finer scale analyses revealed contrasting patterns of genetic structure across a latitudinal gradient. As predicted by their higher substitution rates, ANDV showed greater genealogical resolution than the rodent, with topological congruence influenced by the degree of lineage sorting within the host. However, despite these major differences in evolutionary dynamics, the geographic structure of host and virus converged across large spatial scales.     

Hantavirus evolution in relation to its rodent and insectivore hosts: no evidence for codivergence

Hantaviruses are considered one of the best examples of a long-termassociation between RNA viruses and their hosts. Based on theappearance of strong host specificity, it has been suggestedthat hantaviruses cospeciated with the rodents and insectivoresthey infect since these mammals last shared a common ancestor,approximately 100 million years ago. We tested this hypothesisof host–virus codivergence in two ways: 1) we used cophylogeneticreconciliation analysis to assess the fit of the virus treeonto that of the host and 2) we estimated the evolutionary ratesand divergence times for the Hantavirus genus using a BayesianMarkov Chain Monte Carlo method and similarly compared thesewith those of their hosts. Our reconciliation analysis providedno evidence for a history of codivergence between hantavirusesand their hosts. Further, the divergence times for the Hantavirusgenus were many orders of magnitude too recent to correspondwith the timescale of their hosts' speciation. We thereforepropose that apparent similarities between the phylogenies ofhantaviruses and their mammalian hosts are the result of a morerecent history of preferential host switching and local adaptation.Based on the presence of clade-defining amino acids in all genomicsegments, we propose that the patterns of amino acid replacementin these viruses are also compatible with a history of host-specificadaptation.     

An Endogenous Foamy-like Viral Element in the Coelacanth Genome

Little is known about the origin and long-term evolutionary mode of retroviruses. Retroviruses can integrate into their hosts'' genomes, providing a molecular fossil record for studying their deep history. Here we report the discovery of an endogenous foamy virus-like element, which we designate ‘coelacanth endogenous foamy-like virus’ (CoeEFV), within the genome of the coelacanth (Latimeria chalumnae). Phylogenetic analyses place CoeEFV basal to all known foamy viruses, strongly suggesting an ancient ocean origin of this major retroviral lineage, which had previously been known to infect only land mammals. The discovery of CoeEFV reveals the presence of foamy-like viruses in species outside the Mammalia. We show that foamy-like viruses have likely codiverged with their vertebrate hosts for more than 407 million years and underwent an evolutionary transition from water to land with their vertebrate hosts. These findings suggest an ancient marine origin of retroviruses and have important implications in understanding foamy virus biology.     

Origins and evolution of AIDS viruses: estimating the time-scale

The primate lentiviruses comprise SIV strains from various host species, as well as two viruses, HIV-1 and HIV-2, that cause AIDS in humans. The origins of HIV-1 and HIV-2 have been traced to cross-species transmissions from chimpanzees and sooty mangabey monkeys respectively. Two approaches have been taken to estimate the time-scale of the evolution of these viruses. Certain groups of SIV strains appear to have evolved in a host-dependent manner, implying a time-scale of many thousands or even millions of years. In stark contrast, molecular clock calculations have previously been used to estimate a time-scale of only tens or hundreds of years. Those calculations largely ignored heterogeneity of evolutionary rates across different sites within sequences. In fact, the distribution of rates at different sites seems extremely skewed in HIV-1, and so the time-depth of the primate lentivirus evolutionary tree may have been underestimated by at least a factor of ten. However, these date estimates still seem to be far too recent to be consistent with host-dependent evolution.     

Mean Protein Evolutionary Distance: A Method for Comparative Protein Evolution and Its Application

Proteins are under tight evolutionary constraints, so if a protein changes it can only do so in ways that do not compromise its function. In addition, the proteins in an organism evolve at different rates. Leveraging the history of patristic distance methods, a new method for analysing comparative protein evolution, called Mean Protein Evolutionary Distance (MeaPED), measures differential resistance to evolutionary pressure across viral proteomes and is thereby able to point to the proteins’ roles. Different species’ proteomes can also be compared because the results, consistent across virus subtypes, concisely reflect the very different lifestyles of the viruses. The MeaPED method is here applied to influenza A virus, hepatitis C virus, human immunodeficiency virus (HIV), dengue virus, rotavirus A, polyomavirus BK and measles, which span the positive and negative single-stranded, doubled-stranded and reverse transcribing RNA viruses, and double-stranded DNA viruses. From this analysis, host interaction proteins including hemagglutinin (influenza), and viroporins agnoprotein (polyomavirus), p7 (hepatitis C) and VPU (HIV) emerge as evolutionary hot-spots. By contrast, RNA-directed RNA polymerase proteins including L (measles), PB1/PB2 (influenza) and VP1 (rotavirus), and internal serine proteases such as NS3 (dengue and hepatitis C virus) emerge as evolutionary cold-spots. The hot spot influenza hemagglutinin protein is contrasted with the related cold spot H protein from measles. It is proposed that evolutionary cold-spot proteins can become significant targets for second-line anti-viral therapeutics, in cases where front-line vaccines are not available or have become ineffective due to mutations in the hot-spot, generally more antigenically exposed proteins. The MeaPED package is available from www.pam1.bcs.uwa.edu.au/~michaelw/ftp/src/meaped.tar.gz.     

慢病毒与哺乳动物宿主的协同进化

选取部分哺乳动物代表类群为例,构建病毒及宿主因子基因树并与宿主物种树进行拓扑结构比较,探讨感染哺乳动物的慢病毒与宿主的协同进化.结果表明慢病毒Pol酶基因以及部分宿主因子的进化与宿主的进化历史相同,提示慢病毒可能随哺乳动物的基因组垂直进化,或其首次感染哺乳动物是一次较古老的事件.     

Orthopoxvirus K3 orthologs show virus- and host-specific inhibition of the antiviral protein kinase PKR

The antiviral protein kinase R (PKR) is an important host restriction factor, which poxviruses must overcome to productively infect host cells. To inhibit PKR, many poxviruses encode a pseudosubstrate mimic of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2), designated K3 in vaccinia virus. Although the interaction between PKR and eIF2α is highly conserved, some K3 orthologs from host-restricted poxviruses were previously shown to inhibit PKR in a species-specific manner. To better define this host range function, we compared the sensitivity of PKR from 17 mammals to inhibition by K3 orthologs from closely related orthopoxviruses, a genus with a generally broader host range. The K3 orthologs showed species-specific inhibition of PKR and exhibited three distinct inhibition profiles. In some cases, PKR from closely related species showed dramatic differences in their sensitivity to K3 orthologs. Vaccinia virus expressing the camelpox virus K3 ortholog replicated more than three orders of magnitude better in human and sheep cells than a virus expressing vaccinia virus K3, but both viruses replicated comparably well in cow cells. Strikingly, in site-directed mutagenesis experiments between the variola virus and camelpox virus K3 orthologs, we found that different amino acid combinations were necessary to mediate improved or diminished inhibition of PKR derived from different host species. Because there is likely a limited number of possible variations in PKR that affect K3-interactions but still maintain PKR/eIF2α interactions, it is possible that by chance PKR from some potential new hosts may be susceptible to K3-mediated inhibition from a virus it has never previously encountered. We conclude that neither the sensitivity of host proteins to virus inhibition nor the effectiveness of viral immune antagonists can be inferred from their phylogenetic relatedness but must be experimentally determined.     

High-affinity laminin receptor is a receptor for Sindbis virus in mammalian cells.

Sindbis virus is an alphavirus with a very wide host range, being able to infect many birds and mammals as well as mosquitoes. We have isolated a monoclonal antibody that largely blocks virus binding to mammalian cells. This antibody was found to be directed against the C-terminal domain of the high-affinity laminin receptor, a 67-kDa protein present on the cell surface that binds with high affinity to basement membrane laminin and that is known to be important in development and in tumor invasion. This receptor is believed to be formed from a 295-amino-acid polypeptide that is modified in some unknown way after translation. The primary sequence of this 295-amino-acid protein is highly conserved among mammals. We found the hamster amino acid sequence to be identical to a mouse sequence and to differ at only two amino acids from a human sequence and at two amino acids from a bovine sequence. To verify the importance of the laminin receptor for infection by Sindbis virus, hamster cells were stably transfected with the gene encoding the 295-amino-acid protein under the control of a high-efficiency promoter. Such transfected hamster cells overexpressed the laminin receptor at the cell surface, bound severalfold more Sindbis virions than did the parental cells, and became infected by Sindbis virus with a higher efficiency. In contrast, cells transfected with the antisense gene expressed less laminin receptor on the surface and were less susceptible to the virus. Binding of the virus varied linearly with the amount of laminin receptor on the cell surface, whereas infectivity measured with a plaque assay varied with the 1.4 power of the receptor concentration, suggesting that interaction with more than one receptor aids virus penetration. By these criteria, the laminin receptor functions as the major receptor for Sindbis virus entry into mammalian cells. We also found that the anti-laminin receptor antibody partially blocked Sindbis virus binding to mosquito cells, suggesting that the laminin receptor is conserved in mosquitoes and functions as a Sindbis virus receptor in this host. The wide distribution of this highly conserved receptor may be in part responsible for the broad host range exhibited by the virus, which infects a wide range of mammals and birds as well as its mosquito vector and can infect many different tissues within these hosts.(ABSTRACT TRUNCATED AT 400 WORDS)     

Characterization of Novel Simian Immunodeficiency Viruses from Red-Capped Mangabeys from Nigeria (SIVrcmNG409 and -NG411)

Two novel simian immunodeficiency virus (SIV) strains from wild-caught red-capped mangabeys (Cercocebus torquatus torquatus) from Nigeria were characterized. Sequence analysis of the fully sequenced SIV strain rcmNG411 (SIVrcmNG411) and gag and pol sequence of SIVrcmNG409 revealed that they were genetically most closely related to the recently characterized SIVrcm from Gabon (SIVrcmGB1). Thus, red-capped mangabeys from distant geographic locations harbor a common lineage of SIV. SIVrcmNG411 carried a vpx gene in addition to vpr, suggesting a common evolutionary ancestor with SIVsm (from sooty mangabeys). However, SIVrcm was only marginally closer to SIVsm in that region than to any of the other lentiviruses. SIVrcm showed the highest similarity in pol with SIVdrl, isolated from a drill, a primate that is phylogenetically distinct from mangabey monkeys, and clustered with other primate lentiviruses (primarily SIVcpz [from chimpanzees] and SIVagmSab [from African green monkeys]) discordantly in different regions of the genome, suggesting a history of recombination. Despite the genetic relationship to SIVcpz in the pol gene, SIVrcmNG411 did not replicate in chimpanzee peripheral blood mononuclear cells (PBMC), although two other viruses unrelated to SIVcpz, SIVmndGB1 (from mandrills) and SIVlhoest (from L'Hoest monkeys), were able to grow in chimpanzee PBMC. The CCR5 24-bp deletion previously described in red-capped mangabeys from Gabon was also observed in Nigerian red-capped mangabeys, and SIVrcmNG411, like SIVrcmGB1, used CCR2B and STRL33 as coreceptors for virus entry. SIVrcm, SIVsm, SIVmndGB1, and all four SIVlhoest isolates but not SIVsun (from sun-tailed monkeys) replicated efficiently in human PBMC, suggesting that the ability to infect the human host can vary within one lineage.     

Selection of an avian retrovirus mutant with extended receptor usage.

Receptor recognition by avian retroviruses is thought to involve the interaction of two regions of the SU protein, hr1 and hr2, with the host cell surface receptor. These regions exhibit considerable variation, concordant with differences in receptor usage among the many avian leukosis virus subgroups. We hypothesize that some retroviruses have altered receptor usage in response to selective pressures imposed by receptor polymorphisms in their hosts. To test this hypothesis, we passaged td-Pr-RSV-B on cocultured permissive chicken (C/E) and nonpermissive quail (QT6/BD) cells. A variant virus with an expanded host range was identified at passage 29 and ultimately shown to be identical in sequence to td-Pr-RSV-B, except for changes at codons 155 and 156 of SU amino acid corresponding to two amino acid changes within hr1. Superinfection resistance studies suggest that the variant virus recognizes the subgroup B receptor on chicken cells and the subgroup E receptor on quail cells. These findings indicate that altered receptor usage can be conferred by small changes in env and may point to a key region for receptor interaction. Further, they demonstrate the evolutionary potential of retroviral env genes to alter receptor usage in response to appropriate selective pressure.     

Different evolutionary histories underlie congruent species richness gradients of birds and mammals

Aim The global species richness patterns of birds and mammals are strongly congruent. This could reflect similar evolutionary responses to the Earth’s history, shared responses to current climatic conditions, or both. We compare the geographical and phylogenetic structures of both richness gradients to evaluate these possibilities. Location Global. Methods Gridded bird and mammal distribution databases were used to compare their species richness gradients with the current environment. Phylogenetic trees (resolved to family for birds and to species for mammals) were used to examine underlying phylogenetic structures. Our first prediction is that both groups have responded to the same climatic gradients. Our phylogenetic predictions include: (1) that both groups have similar geographical patterns of mean root distance, a measure of the level of the evolutionary development of faunas, and, more directly, (2) that richness patterns of basal and derived clades will differ, with richness peaking in the tropics for basal clades and in the extra‐tropics for derived clades, and that this difference will hold for both birds and mammals. We also explore whether alternative taxonomic treatments for mammals can generate patterns matching those of birds. Results Both richness gradients are associated with the same current environmental gradients. In contrast, neither of our evolutionary predictions is met: the gradients have different phylogenetic structures, and the richness of birds in the lowland tropics is dominated by many basal species from many basal groups, whereas mammal richness is attributable to many species from both few basal groups and many derived groups. Phylogenetic incongruence is robust to taxonomic delineations for mammals. Main conclusions Contemporary climate can force multiple groups into similar diversity patterns even when evolutionary trajectories differ. Thus, as widely appreciated, our understanding of biodiversity must consider responses to both past and present climates, and our results are consistent with predictions that future climate change will cause major, correlated changes in patterns of diversity across multiple groups irrespective of their evolutionary histories.     

Testing parasite ‘intimacy’: the whipworm Trichuris muris in the European house mouse hybrid zone

Host‐parasite interaction studies across hybrid zones often focus on host genetic variation, treating parasites as homogeneous. ‘Intimately’ associated hosts and parasites might be expected to show similar patterns of genetic structure. In the literature, factors such as no intermediate host and no free‐living stage have been proposed as ‘intimacy’ factors likely constraining parasites to closely follow the evolutionary history of their hosts. To test whether the whipworm, Trichuris muris, is intimately associated with its house mouse host, we studied its population genetics across the European house mouse hybrid zone (HMHZ) which has a strong central barrier to gene flow between mouse taxa. T. muris has a direct life cycle and nonmobile free stage: if these traits constrain the parasite to an intimate association with its host we expect a geographic break in the parasite genetic structure across the HMHZ. We genotyped 205 worms from 56 localities across the HMHZ and additionally T. muris collected from sympatric woodmice (Apodemus spp.) and allopatric murine species, using mt‐COX1, ITS1‐5.8S‐ITS2 rDNA and 10 microsatellites. We show four haplogroups of mt‐COX1 and three clear ITS1‐5.8S‐ITS2 clades in the HMHZ suggesting a complex demographic/phylogeographic history. Microsatellites show strong structure between groups of localities. However, no marker type shows a break across the HMHZ. Whipworms from Apodemus in the HMHZ cluster, and share mitochondrial haplotypes, with those from house mice. We conclude Trichuris should not be regarded as an ‘intimate’ parasite of the house mouse: while its life history might suggest intimacy, passage through alternate hosts is sufficiently common to erase signal of genetic structure associated with any particular host taxon.     

The evolution of virulence in primate malaria parasites based on Bayesian reconstructions of ancestral states

Plasmodium parasites, the causative agents of malaria, are generally considered as harmful parasites, but many of them cause mild symptoms. Little is known about the evolutionary history and phylogenetic constraints that generate this interspecific variation in virulence due to uncertainties about the phylogenetic associations of parasites. Here, to account for such phylogenetic uncertainty, phylogenetic methods based on Bayesian statistics were followed in combination with sequence data from five genes to estimate the ancestral state of virulence in primate Plasmodium parasites. When recent parasites were categorised according to the damage caused to the host, Bayesian estimates of ancestral states indicated that the acquisition of a harmful host exploitation strategy is more likely to be a recent evolutionary event than a result of an ancient change in a character state altering virulence. On the contrary, there was more evidence for moderate host exploitation having a deep origin along the phylogenetic tree. Moreover, the evolution of host severity is determined by the phylogenetic relationships of parasites, as severity gains did not appear randomly on the evolutionary tree. Such phylogenetic constraints can be mediated by the acquisition of virulence genes. As the impact of a parasite on a host is the result of both the parasite’s investment in reproduction and host sensitivity, virulence was also estimated by calculating peak parasitemia after eliminating host effects. A directional random-walk evolutionary model showed that the ancestral primate malarias reproduced at very low parasitemia in their hosts. Consequently, the extreme variation in the outcome of malaria infection in different host species can be better understood in light of the phylogeny of parasites.     

Modular Evolution of PGC-1α in Vertebrates

In mammals, the peroxisome proliferator activated receptor (PPAR)γ coactivator-1α (PGC-1α) is a central regulator of mitochondrial gene expression, acting in concert with nuclear respiratory factor-1 (NRF-1) and the PPARs. Its role as a “master regulator” of oxidative capacity is clear in mammals, but its role in other vertebrates is ambiguous. In lower vertebrates, although PGC-1α seems to play a role in coordinating the PPARα axis as in mammals, it does not appear to be involved in NRF-1 regulation of mitochondrial content. To evaluate the evolutionary patterns of this coactivator in fish and mammals, we investigated the evolutionary trajectories of PGC-1α homologs in representative vertebrate lineages. A phylogeny of the PGC-1 paralogs suggested that the family diversified through repeated genome duplication events early in vertebrate evolution. Bayesian and maximum likelihood phylogenetic reconstructions of PGC-1α in representative vertebrate species revealed divergent evolutionary dynamics across the different functional domains of the protein. Specifically, PGC-1α exhibited strong conservation of the activation/PPAR interaction domain across vertebrates, whereas the NRF-1 and MEF2c interaction domains experienced accelerated rates of evolution in actinopterygian (fish lineages) compared to sarcopterygians (tetrapod lineages). Furthermore, analysis of the amino acid sequence of these variable domains revealed successive serine- and glutamine-rich insertions within the teleost lineages, with important ramifications for PGC-1α function in these lineages. Collectively, these results suggest modular evolution of the PGC-1α protein in vertebrates that could allow for lineage-specific divergences in the coactivating capabilities of this regulator.