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1.  Genome rearrangements and pervasive meiotic drive cause hybrid infertility in fission yeast 
eLife  2014;3:e02630.
Hybrid sterility is one of the earliest postzygotic isolating mechanisms to evolve between two recently diverged species. Here we identify causes underlying hybrid infertility of two recently diverged fission yeast species Schizosaccharomyces pombe and S. kambucha, which mate to form viable hybrid diploids that efficiently complete meiosis, but generate few viable gametes. We find that chromosomal rearrangements and related recombination defects are major but not sole causes of hybrid infertility. At least three distinct meiotic drive alleles, one on each S. kambucha chromosome, independently contribute to hybrid infertility by causing nonrandom spore death. Two of these driving loci are linked by a chromosomal translocation and thus constitute a novel type of paired meiotic drive complex. Our study reveals how quickly multiple barriers to fertility can arise. In addition, it provides further support for models in which genetic conflicts, such as those caused by meiotic drive alleles, can drive speciation.
DOI: http://dx.doi.org/10.7554/eLife.02630.001
eLife digest
It is widely thought that all of the billions of species on Earth are descended from a common ancestor. New species are created via a process called speciation, and nature employs various ‘barriers’ to keep closely related species distinct from one another. One of these barriers is called hybrid sterility. Horses and donkeys, for example, can mate to produce hybrids called mules, but mules cannot produce offspring of their own because they are infertile.
Hybrid sterility can occur for a number of reasons. Mules are infertile because they inherit 32 chromosomes from their horse parent, but only 31 chromosomes from their donkey parent—and so have an odd chromosome that they cannot pair-off when they make sperm or egg cells. However, even if a hybrid inherits the same number of chromosomes from each parent, if the chromosomes from the two parents have different structures, the hybrid may still be infertile.
Zanders et al. have now looked at two species of fission yeast—S. pombe and S. kambucha—that share 99.5% of their DNA sequence. Although hybrids of these two species inherit three chromosomes from each parent, the majority of spores (the yeast equivalent of sperm) that these hybrids produce fail to develop into new yeast cells. Zanders et al. identified two causes of this infertility: one of these was chromosomal rearrangement; the other was due to three different sites in the DNA of S. kambucha that interfere with the development of the spores that inherit S. pombe chromosomes.
Since these two yeast species are so closely related, the findings of Zanders et al. reveal how quickly multiple barriers to fertility can arise. In addition, these findings provide further support for models in which conflicts between different genes in genomes can drive the process of speciation.
DOI: http://dx.doi.org/10.7554/eLife.02630.002
doi:10.7554/eLife.02630
PMCID: PMC4066438  PMID: 24963140
speciation; meiotic drive; chromosomal rearrangements; recombination; S. pombe
2.  Mobile DNA: an evolving field 
Mobile DNA  2014;5:16.
During the Mobile Genetic Elements and Genome Evolution Keystone Symposium in March 2014, the Editors of Mobile DNA caught up with a panel of conference speakers to select key advances in the field, and hear their thoughts on where mobile DNA research is going.
doi:10.1186/1759-8753-5-16
PMCID: PMC4046146  PMID: 24904692
3.  Rapid Evolution of PARP Genes Suggests a Broad Role for ADP-Ribosylation in Host-Virus Conflicts 
PLoS Genetics  2014;10(5):e1004403.
Post-translational protein modifications such as phosphorylation and ubiquitinylation are common molecular targets of conflict between viruses and their hosts. However, the role of other post-translational modifications, such as ADP-ribosylation, in host-virus interactions is less well characterized. ADP-ribosylation is carried out by proteins encoded by the PARP (also called ARTD) gene family. The majority of the 17 human PARP genes are poorly characterized. However, one PARP protein, PARP13/ZAP, has broad antiviral activity and has evolved under positive (diversifying) selection in primates. Such evolution is typical of domains that are locked in antagonistic ‘arms races’ with viral factors. To identify additional PARP genes that may be involved in host-virus interactions, we performed evolutionary analyses on all primate PARP genes to search for signatures of rapid evolution. Contrary to expectations that most PARP genes are involved in ‘housekeeping’ functions, we found that nearly one-third of PARP genes are evolving under strong recurrent positive selection. We identified a >300 amino acid disordered region of PARP4, a component of cytoplasmic vault structures, to be rapidly evolving in several mammalian lineages, suggesting this region serves as an important host-pathogen specificity interface. We also found positive selection of PARP9, 14 and 15, the only three human genes that contain both PARP domains and macrodomains. Macrodomains uniquely recognize, and in some cases can reverse, protein mono-ADP-ribosylation, and we observed strong signatures of recurrent positive selection throughout the macro-PARP macrodomains. Furthermore, PARP14 and PARP15 have undergone repeated rounds of gene birth and loss during vertebrate evolution, consistent with recurrent gene innovation. Together with previous studies that implicated several PARPs in immunity, as well as those that demonstrated a role for virally encoded macrodomains in host immune evasion, our evolutionary analyses suggest that addition, recognition and removal of ADP-ribosylation is a critical, underappreciated currency in host-virus conflicts.
Author Summary
The outcome of viral infections is determined by the repertoire and specificity of the antiviral genes in a particular animal species. The identification of candidate immunity genes and mechanisms is a key step in describing this repertoire. Despite advances in genome sequencing, identification of antiviral genes has largely remained dependent on demonstration of their activity against candidate viruses. However, antiviral proteins that directly interact with viral targets or antagonists also bear signatures of recurrent evolutionary adaptation, which can be used to identify candidate antivirals. Here, we find that five out of seventeen genes that contain a domain that can catalyze the post-translational addition ADP-ribose to proteins bear such signatures of recurrent genetic innovation. In particular, we find that all the genes that encode both ADP-ribose addition (via PARP domains) as well as recognition and/or removal (via macro domains) activities have evolved under extremely strong diversifying selection in mammals. Furthermore, such genes have undergone multiple episodes of gene duplications and losses throughout mammalian evolution. Combined with the knowledge that some viruses also encode macro domains to counteract host immunity, our evolutionary analyses therefore implicate ADP-ribosylation as an underappreciated key step in antiviral defense in mammalian genomes.
doi:10.1371/journal.pgen.1004403
PMCID: PMC4038475  PMID: 24875882
4.  An evolutionary perspective on the broad antiviral specificity of MxA 
Current opinion in microbiology  2013;16(4):493-499.
Germ line encoded antiviral defenses in vertebrate cells tend to be either broadly acting factors that exploit general features of viral replication or effectors with strong pathogen preference by virtue of specific recognition of viral proteins. The Mx GTPases, however, are atypical since they have broad antiviral activity against a wide range of RNA and DNA viruses despite specifically targeting different proteins across virus families. This review presents recent advances in understanding the biochemical properties and evolution of the primate ortholog MxA, and discusses how this information begins to provide molecular insights into the mechanisms behind the intriguing conundrum of how MxA is able to engage a diversity of viral proteins yet elicit antiviral breadth.
doi:10.1016/j.mib.2013.04.005
PMCID: PMC3763691  PMID: 23725670
5.  An Evolutionary Screen Highlights Canonical and Noncanonical Candidate Antiviral Genes within the Primate TRIM Gene Family 
Genome Biology and Evolution  2013;5(11):2141-2154.
Recurrent viral pressure has acted on host-encoded antiviral genes during primate and mammalian evolution. This selective pressure has resulted in dramatic episodes of adaptation in host antiviral genes, often detected via positive selection. These evolutionary signatures of adaptation have the potential to highlight previously unrecognized antiviral genes (also called restriction factors). Although the TRIM multigene family is recognized for encoding several bona fide restriction factors (e.g., TRIM5alpha), most members of this expansive gene family remain uncharacterized. Here, we investigated the TRIM multigene family for signatures of positive selection to identify novel candidate antiviral genes. Our analysis reveals previously undocumented signatures of positive selection in 17 TRIM genes, 10 of which represent novel candidate restriction factors. These include the unusual TRIM52 gene, which has evolved under strong positive selection despite its encoded protein lacking a putative viral recognition (B30.2) domain. We show that TRIM52 arose via gene duplication from the TRIM41 gene. Both TRIM52 and TRIM41 have dramatically expanded RING domains compared with the rest of the TRIM multigene family, yet this domain has evolved under positive selection only in primate TRIM52, suggesting that it represents a novel host–virus interaction interface. Our evolutionary-based screen not only documents positive selection in known TRIM restriction factors but also highlights candidate novel restriction factors, providing insight into the interfaces of host–pathogen interactions mediated by the TRIM multigene family.
doi:10.1093/gbe/evt163
PMCID: PMC3845644  PMID: 24158625
TRIM5; TRIM52; positive selection; dN/dS; restriction factors
6.  Learning to protect your genome on the fly 
Cell  2011;147(7):1440-1441.
Piwi-associated RNAs (piRNAs) help defend host genomes against germline transposons. In this issue of Cell, Khurana et al. (2011) show how alterations in the piRNA-encoding loci within a single generation allow a naïve fly genome to overcome the initially insurmountable challenge imposed by a newly encountered mobile element.
doi:10.1016/j.cell.2011.12.001
PMCID: PMC3725141  PMID: 22196722
7.  Birth, Death, and Replacement of Karyopherins in Drosophila 
Molecular Biology and Evolution  2011;29(5):1429-1440.
Nucleocytoplasmic transport is a broadly conserved process across eukaryotes. Despite its essential function and conserved mechanism, components of the nuclear transport apparatus have been implicated in genetic conflicts in Drosophila, especially in the male germ line. The best understood case is represented by a truncated RanGAP gene duplication that is part of the segregation distorter system in Drosophila melanogaster. Consistent with the hypothesis that the nuclear transport pathway is at the heart of mediating genetic conflicts, both nucleoporins and directionality imposing components of nuclear transport have previously been shown to evolve under positive selection. Here, we present a comprehensive phylogenomic analysis of importins (karyopherins) in Drosophila evolution. Importins are adaptor molecules that physically mediate the transport of cargo molecules and comprise the third component of the nuclear transport apparatus. We find that importins have been repeatedly gained and lost throughout various stages of Drosophila evolution, including two intriguing examples of an apparently coincident loss and gain of nonorthologous and noncanonical importin-α. Although there are a few signatures of episodic positive selection, genetic innovation in importin evolution is more evident in patterns of recurrent gene birth and loss specifically for function in Drosophila testes, which is consistent with their role in supporting host genomes defense against segregation distortion.
doi:10.1093/molbev/msr306
PMCID: PMC3339319  PMID: 22160828
gene duplication; importins; genetic conflict; Drosophila
8.  Extensive evolutionary and functional diversity among mammalian AIM2-like receptors 
The Journal of Experimental Medicine  2012;209(11):1969-1983.
An evolutionary and functional analysis of mammalian AIM2-like receptors reveals remarkable diversity and redundancy.
Innate immune detection of nucleic acids is important for initiation of antiviral responses. Detection of intracellular DNA activates STING-dependent type I interferons (IFNs) and the ASC-dependent inflammasome. Certain members of the AIM2-like receptor (ALR) gene family contribute to each of these pathways, but most ALRs remain uncharacterized. Here, we identify five novel murine ALRs and perform a phylogenetic analysis of mammalian ALRs, revealing a remarkable diversification of these receptors among mammals. We characterize the expression, localization, and functions of the murine and human ALRs and identify novel activators of STING-dependent IFNs and the ASC-dependent inflammasome. These findings validate ALRs as key activators of the antiviral response and provide an evolutionary and functional framework for understanding their roles in innate immunity.
doi:10.1084/jem.20121960
PMCID: PMC3478938  PMID: 23045604
9.  Evolution-guided identification of antiviral specificity determinants in the broadly acting interferon-induced innate immunity factor MxA 
Cell host & microbe  2012;12(4):598-604.
Summary
MxA is an interferon-induced dynamin-like GTPase with wide-ranging antiviral activity, which hinges upon detection of unique viral structures that differ across virus families. Despite elucidation of its structure, the basis of MxA antiviral specificity remains enigmatic. We used an evolution-guided approach to identify the loop L4 of MxA as a hotspot for recurrent positive selection in primates. Further, we show that single amino acid changes in L4 are necessary and sufficient to explain dramatic differences in species-specific antiviral activity of primate MxA proteins against the orthomyxoviruses Thogoto virus and influenza A virus. Taken together, our findings identify a genetic determinant of MxA target recognition and suggest a model by which MxA achieves antiviral breadth without compromising viral specificity.
doi:10.1016/j.chom.2012.09.005
PMCID: PMC3540999  PMID: 23084925
10.  A rapidly evolving genomic toolkit for Drosophila heterochromatin 
Fly  2013;7(3):137-141.
Heterochromatin is the enigmatic eukaryotic genome compartment found mostly at telomeres and centromeres. Conventional approaches to sequence assembly and genetic manipulation fail in this highly repetitive, gene-sparse, and recombinationally silent DNA. In contrast, genetic and molecular analyses of euchromatin-encoded proteins that bind, remodel, and propagate heterochromatin have revealed its vital role in numerous cellular and evolutionary processes. Utilizing the 12 sequenced Drosophila genomes, Levine et al1 took a phylogenomic approach to discover new such protein “surrogates” of heterochromatin function and evolution. This paper reported over 20 new members of what was traditionally believed to be a small and static Heterochromatin Protein 1 (HP1) gene family. The newly identified HP1 proteins are structurally diverse, lineage-restricted, and expressed primarily in the male germline. The birth and death of HP1 genes follows a “revolving door” pattern, where new HP1s appear to replace old HP1s. Here, we address alternative evolutionary models that drive this constant innovation.
doi:10.4161/fly.24335
PMCID: PMC4049844  PMID: 23519206
Heterochromatin Protein 1; gene duplication; germline; phylogenomics; heterochromatin; chromodomain; chromoshadow domain; pseudogenization; Drosophila; HP1
11.  Poxviruses deploy genomic accordions to adapt rapidly against host antiviral defenses 
Cell  2012;150(4):831-841.
Summary
In contrast to RNA viruses, double-stranded DNA viruses have low mutation rates, yet must still adapt rapidly in response to changing host defenses. To determine mechanisms of adaptation we subjected the model poxvirus vaccinia to serial propagation in human cells, where its anti-host factor K3L is maladapted against the anti-viral Protein Kinase R (PKR). Viruses rapidly acquired higher fitness via recurrent K3L gene amplifications, incurring up to 7-10% increases in genome size. These transient gene expansions were necessary and sufficient to counteract human PKR and facilitated the gain of an adaptive amino acid substitution in K3L that also defeats PKR. Subsequent reductions in gene amplifications offset the costs associated with larger genome size while retaining adaptive substitutions. Our discovery of viral ‘gene-accordions’ explains how poxviruses can rapidly adapt to defeat different host defenses despite low mutation rates and reveals how classical Red Queen conflicts can progress through unrecognized intermediates.
doi:10.1016/j.cell.2012.05.049
PMCID: PMC3499626  PMID: 22901812
12.  The ability of primate lentiviruses to degrade the monocyte restriction factor SAMHD1 preceded the birth of the viral accessory protein Vpx 
Cell host & microbe  2012;11(2):194-204.
The human SAMHD1 protein potently restricts lentiviral infection in dendritic cells and monocyte/macrophages, but is antagonized by the primate lentiviral protein Vpx which targets SAMHD1for degradation. However, only two of eight primate lentivirus lineages encode Vpx whereas its paralog, Vpr, is conserved across all extant primate lentiviruses. We find that not only multiple Vpx but also some Vpr proteins are able to degrade SAMHD1 and such antagonism led to dramatic positive selection of SAMHD1 in the primate subfamily Cercopithecinae. Residues that have evolved under positive selection precisely determine sensitivity to Vpx/Vpr degradation and alter binding specificity. By overlaying these functional analyses on a phylogenetic framework of Vpr and Vpx evolution, we can decipher the chronology of acquisition of SAMHD1-degrading abilities in lentiviruses. We conclude that vpr neofunctionalized to degrade SAMHD1 even prior to the birth of a separate vpx gene, thereby initiating an evolutionary arms race with SAMHD1.
doi:10.1016/j.chom.2012.01.004
PMCID: PMC3288607  PMID: 22284954
13.  Paleovirology – Ghosts and gifts of viruses past 
Current opinion in virology  2011;1(4):304-309.
The emerging field of paleovirology aims to study the evolutionary age and impact of ancient viruses (paleoviruses) on host biology. Despite a historical emphasis on retroviruses, paleoviral ‘fossils’ have recently been uncovered from a broad swathe of viruses. These viral imprints have upended long-held notions of the age and mutation rate of viruses. While 'direct' paleovirology relies on the insertion of viral genes in animal genomes, examination of adaptive changes in host genes that occurred in response to paleoviral infections provides a complementary strategy for making ‘indirect’ paleovirological inferences. Finally, viruses have also impacted host biology by providing genes hosts have domesticated for their own purpose.
doi:10.1016/j.coviro.2011.06.007
PMCID: PMC3190193  PMID: 22003379
14.  The function and evolution of the restriction factor viperin in primates was not driven by lentiviruses 
Retrovirology  2012;9:55.
Background
Viperin, also known as RSAD2, is an interferon-inducible protein that potently restricts a broad range of different viruses such as influenza, hepatitis C virus, human cytomegalovirus and West Nile virus. Viperin is thought to affect virus budding by modification of the lipid environment within the cell. Since HIV-1 and other retroviruses depend on lipid domains of the host cell for budding and infectivity, we investigated the possibility that Viperin also restricts human immunodeficiency virus and other retroviruses.
Results
Like other host restriction factors that have a broad antiviral range, we find that viperin has also been evolving under positive selection in primates. The pattern of positive selection is indicative of Viperin's escape from multiple viral antagonists over the course of primate evolution. Furthermore, we find that Viperin is interferon-induced in HIV primary target cells. We show that exogenous expression of Viperin restricts the LAI strain of HIV-1 at the stage of virus release from the cell. Nonetheless, the effect of Viperin restriction is highly strain-specific and does not affect most HIV-1 strains or other retroviruses tested. Moreover, knockdown of endogenous Viperin in a lymphocytic cell line did not significantly affect the spreading infection of HIV-1.
Conclusion
Despite positive selection having acted on Viperin throughout primate evolution, our findings indicate that Viperin is not a major restriction factor against HIV-1 and other retroviruses. Therefore, other viral lineages are likely responsible for the evolutionary signatures of positive selection in viperin among primates.
doi:10.1186/1742-4690-9-55
PMCID: PMC3414838  PMID: 22734835
15.  A unified phylogeny-based nomenclature for histone variants 
Histone variants are non-allelic protein isoforms that play key roles in diversifying chromatin structure. The known number of such variants has greatly increased in recent years, but the lack of naming conventions for them has led to a variety of naming styles, multiple synonyms and misleading homographs that obscure variant relationships and complicate database searches. We propose here a unified nomenclature for variants of all five classes of histones that uses consistent but flexible naming conventions to produce names that are informative and readily searchable. The nomenclature builds on historical usage and incorporates phylogenetic relationships, which are strong predictors of structure and function. A key feature is the consistent use of punctuation to represent phylogenetic divergence, making explicit the relationships among variant subtypes that have previously been implicit or unclear. We recommend that by default new histone variants be named with organism-specific paralog-number suffixes that lack phylogenetic implication, while letter suffixes be reserved for structurally distinct clades of variants. For clarity and searchability, we encourage the use of descriptors that are separate from the phylogeny-based variant name to indicate developmental and other properties of variants that may be independent of structure.
doi:10.1186/1756-8935-5-7
PMCID: PMC3380720  PMID: 22650316
16.  Phylogenomic Analysis Reveals Dynamic Evolutionary History of the Drosophila Heterochromatin Protein 1 (HP1) Gene Family 
PLoS Genetics  2012;8(6):e1002729.
Heterochromatin is the gene-poor, satellite-rich eukaryotic genome compartment that supports many essential cellular processes. The functional diversity of proteins that bind and often epigenetically define heterochromatic DNA sequence reflects the diverse functions supported by this enigmatic genome compartment. Moreover, heterogeneous signatures of selection at chromosomal proteins often mirror the heterogeneity of evolutionary forces that act on heterochromatic DNA. To identify new such surrogates for dissecting heterochromatin function and evolution, we conducted a comprehensive phylogenomic analysis of the Heterochromatin Protein 1 gene family across 40 million years of Drosophila evolution. Our study expands this gene family from 5 genes to at least 26 genes, including several uncharacterized genes in Drosophila melanogaster. The 21 newly defined HP1s introduce unprecedented structural diversity, lineage-restriction, and germline-biased expression patterns into the HP1 family. We find little evidence of positive selection at these HP1 genes in both population genetic and molecular evolution analyses. Instead, we find that dynamic evolution occurs via prolific gene gains and losses. Despite this dynamic gene turnover, the number of HP1 genes is relatively constant across species. We propose that karyotype evolution drives at least some HP1 gene turnover. For example, the loss of the male germline-restricted HP1E in the obscura group coincides with one episode of dramatic karyotypic evolution, including the gain of a neo-Y in this lineage. This expanded compendium of ovary- and testis-restricted HP1 genes revealed by our study, together with correlated gain/loss dynamics and chromosome fission/fusion events, will guide functional analyses of novel roles supported by germline chromatin.
Author Summary
Our genome is comprised of two compartments. The euchromatin harbors abundant genes and regulatory information, while heterochromatin harbors few genes and abundant repetitive DNA. These characteristic features of heterochromatin challenge traditional methods of sequence assembly and molecular dissection. The analysis, instead, of proteins that localize to and often functionally define heterochromatic sequence has illuminated numerous heterochromatin-dependent, essential cellular processes, including chromosome segregation, telomere stability, and gene regulation. With the aim of increasing our sample of heterochromatin-localizing proteins, we performed a comprehensive search for new members of Heterochromatin Protein 1 gene family over 40 million years of Drosophila evolution. Our report expands this family from a modest five genes to 26 genes. Unlike the founding family members, the HP1s we describe are structurally diverse, largely restricted to male reproductive tissue, and highly dynamic over evolutionary time. Despite recurrent HP1 gene birth and death, gene numbers per species are relatively constant. These gene “replacements” likely support a dynamic biological process. We propose, and present evidence for, the hypothesis that recurrent chromosomal rearrangements drive at least some HP1 gene family dynamics observed. We anticipate that these HP1 genes will help define new heterochromatin-dependent processes in the male germline.
doi:10.1371/journal.pgen.1002729
PMCID: PMC3380853  PMID: 22737079
17.  The Breadth of Antiviral Activity of Apobec3DE in Chimpanzees Has Been Driven by Positive Selection ▿  
Journal of Virology  2011;85(21):11361-11371.
The Apobec3 family of cytidine deaminases can inhibit the replication of retroviruses and retrotransposons. Human and chimpanzee genomes encode seven Apobec3 paralogs; of these, Apobec3DE has the greatest sequence divergence between humans and chimpanzees. Here we show that even though human and chimpanzee Apobec3DEs are very divergent, the two orthologs similarly restrict long terminal repeat (LTR) and non-LTR retrotransposons (MusD and Alu, respectively). However, chimpanzee Apobec3DE also potently restricts two lentiviruses, human immunodeficiency virus type 1 (HIV-1) and the simian immunodeficiency virus (SIV) that infects African green monkeys (SIVagmTAN), unlike human Apobec3DE, which has poor antiviral activity against these same viruses. This difference between human and chimpanzee Apobec3DE in the ability to restrict retroviruses is not due to different levels of Apobec3DE protein incorporation into virions but rather to the ability of Apobec3DE to deaminate the viral genome in target cells. We further show that Apobec3DE rapidly evolved in chimpanzee ancestors approximately 2 to 6 million years ago and that this evolution drove the increased breadth of chimpanzee Apobec3DE antiviral activity to its current high activity against some lentiviruses. Despite a difference in target specificities between human and chimpanzee Apobec3DE, Apobec3DE is likely to currently play a role in host defense against retroelements in both species.
doi:10.1128/JVI.05046-11
PMCID: PMC3194980  PMID: 21835794
18.  Convergent Evolution of Escape from Hepaciviral Antagonism in Primates 
PLoS Biology  2012;10(3):e1001282.
Escape from antagonism by hepatitis C and related viruses has repeatedly evolved in antiviral factor MAVS via convergent evolution, revealing an ancient history of previous viral encounters in primates.
The ability to mount an interferon response on sensing viral infection is a critical component of mammalian innate immunity. Several viruses directly antagonize viral sensing pathways to block activation of the host immune response. Here, we show that recurrent viral antagonism has shaped the evolution of the host protein MAVS—a crucial component of the viral-sensing pathway in primates. From sequencing and phylogenetic analyses of MAVS from 21 simian primates, we found that MAVS has evolved under strong positive selection. We focused on how this positive selection has shaped MAVS' susceptibility to Hepatitis C virus (HCV). We functionally tested MAVS proteins from diverse primate species for their ability to resist antagonism by HCV, which uses its protease NS3/4A to cleave human MAVS. We found that MAVS from multiple primates are resistant to inhibition by the HCV protease. This resistance maps to single changes within the protease cleavage site in MAVS, which protect MAVS from getting cleaved by the HCV protease. Remarkably, most of these changes have been independently acquired at a single residue 506 that evolved under positive selection. We show that “escape” mutations lower affinity of the NS3 protease for MAVS and allow it to better restrict HCV replication. We further show that NS3 proteases from all other primate hepaciviruses, including the highly divergent GBV-A and GBV-C viruses, are functionally similar to HCV. We conclude that convergent evolution at residue 506 in multiple primates has resulted in escape from antagonism by hepaciviruses. Our study provides a model whereby insights into the ancient history of viral infections in primates can be gained using extant host and virus genes. Our analyses also provide a means by which primates might clear infections by extant hepaciviruses like HCV.
Author Summary
Hepatitis C virus (HCV) causes chronic liver disease and is estimated to infect 170 million people worldwide. HCV is able to establish a persistent infection in part by inhibiting the innate immune response. It does so by using its protease, NS3, to cleave the host's antiviral factor MAVS, which normally activates the interferon response. Using an assay that measures MAVS activity, we found that multiple primate species contain a version of MAVS that is resistant to HCV antagonism. Surprisingly, most of these primates have independently converged on changes in the same amino acid residue of MAVS to escape cleavage by the HCV protease. We found that the HCV protease has lower binding affinity for these resistant MAVS variants, which consequently are more effective at restricting HCV infection. Using a combination of phylogenetic and functional analyses of proteases from other HCV-related viruses, we infer that ancestral primates were likely exposed to and adapted to HCV-like viruses. One consequence of this adaptation is that changes that have given rise to extant MAVS variants may now provide protection from modern-day viruses.
doi:10.1371/journal.pbio.1001282
PMCID: PMC3302847  PMID: 22427742
19.  Absence of Positive Selection on Centromeric Histones in Tetrahymena Suggests Unsuppressed Centromere-Drive in Lineages Lacking Male Meiosis 
Journal of Molecular Evolution  2011;72(5-6):510-520.
Centromere-drive is a process where centromeres compete for transmission through asymmetric "female" meiosis for inclusion into the oocyte. In symmetric "male" meiosis, all meiotic products form viable germ cells. Therefore, the primary incentive for centromere-drive, a potential transmission bias, is believed to be missing from male meiosis. In this article, we consider whether male meiosis also bears the primary cost of centromere-drive. Because different taxa carry out different combinations of meiotic programs (symmetric + asymmetric, symmetric only, asymmetric only), it is possible to consider the evolutionary consequences of centromere-drive in the context of these differing systems. Groups with both types of meiosis have large, rapidly evolving centromeric regions, and their centromeric histones (CenH3s) have been shown to evolve under positive selection, suggesting roles as suppressors of centromere-drive. In contrast, taxa with only symmetric male meiosis have shown no evidence of positive selection in their centromeric histones. In this article, we present the first evolutionary analysis of centromeric histones in ciliated protozoans, a group that only undergoes asymmetric "female" meiosis. We find no evidence of positive selection acting on CNA1, the CenH3 of Tetrahymena species. Cytological observations of a panel of Tetrahymena species are consistent with dynamic karyotype evolution in this lineage. Our findings suggest that defects in male meiosis, and not mitosis or female meiosis, are the primary selective force behind centromere-drive suppression. Our study raises the possibility that taxa like ciliates, with only female meiosis, may therefore undergo unsuppressed centromere drive.
Electronic supplementary material
The online version of this article (doi:10.1007/s00239-011-9449-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s00239-011-9449-0
PMCID: PMC3144370  PMID: 21643829
Tetrahymena thermophila; Positive selection; Phylogeny; Asymmetric female meiosis; Karyotype
20.  Ancient Adaptive Evolution of Tetherin Shaped the Functions of Vpu and Nef in Human Immunodeficiency Virus and Primate Lentiviruses† ▿  
Journal of Virology  2010;84(14):7124-7134.
Tetherin/BST-2 is a host-encoded protein that restricts a wide diversity of viruses at the stage of virion release. However, viruses have evolved antagonists of Tetherin, including the Vpu and Nef proteins of primate lentiviruses. Like other host genes subject to viral antagonism, primate Tetherin genes have evolved under positive selection. We show here that viral antagonists acting at three independent sites of selection have driven the evolution of Tetherin, with the strongest selective pressure on the cytoplasmic tail domain. Human Tetherin is unique among the Tetherins of simian primates in that it has a 5-amino-acid deletion that results in the loss of the residue under the strongest positive selection. We show that this residue at amino acid 17 is the site of the functional interaction of Tetherin with Nef, since single amino acid substitutions at this single position can determine the susceptibility of Tetherin to Nef antagonism. While the simian immunodeficiency viruses SIVcpz and SIVgor are able to antagonize their hosts' Tetherin with Nef, human immunodeficiency virus type 1 (HIV-1) Vpu has evolved to counteract Tetherin in humans. We mapped the adaptations in the N-terminal transmembrane domain of Vpu that allow it to counteract human Tetherin. Our combined evolutionary and functional studies have allowed us to reconstruct the host-pathogen interactions that have shaped Tetherin and its lentivirus-encoded antagonists.
doi:10.1128/JVI.00468-10
PMCID: PMC2898239  PMID: 20444900
21.  Altered heterochromatin binding by a hybrid sterility protein in Drosophila sibling species 
Science (New York, N.Y.)  2009;326(5959):1538-1541.
Hybrid sterility of the heterogametic sex is one of the first postzygotic reproductive barriers to evolve during speciation, yet the molecular basis of hybrid sterility is poorly understood. We show that the hybrid male sterility gene Odysseussite homeobox gene (OdsH) encodes a protein that localizes to evolutionarily dynamic loci within heterochromatin and leads to their decondensation. In D. mauritiana X D. simulans male hybrids, OdsH from D. mauritiana (OdsHmau) acts as a sterilizing factor by associating with the heterochromatic Y chromosome of D. simulans, whereas D. simulans OdsH (OdsHsim) does not. Characterization of sterile hybrid testes revealed that OdsH abundance and localization in the premeiotic phases of spermatogenesis differs between species. These results reveal that rapid heterochromatin evolution affects the onset of hybrid sterility.
doi:10.1126/science.1181756
PMCID: PMC2987944  PMID: 19933102
D. mauritiana; D. simulans; Dobzhansky-Muller incompatibilities; heterochromatin; speciation
22.  A Surrogate Approach to Study the Evolution of Noncoding DNA Elements That Organize Eukaryotic Genomes 
Journal of Heredity  2009;100(5):624-636.
Comparative genomics provides a facile way to address issues of evolutionary constraint acting on different elements of the genome. However, several important DNA elements have not reaped the benefits of this new approach. Some have proved intractable to current day sequencing technology. These include centromeric and heterochromatic DNA, which are essential for chromosome segregation as well as gene regulation, but the highly repetitive nature of the DNA sequences in these regions make them difficult to assemble into longer contigs. Other sequences, like dosage compensation X chromosomal sites, origins of DNA replication, or heterochromatic sequences that encode piwi-associated RNAs, have proved difficult to study because they do not have recognizable DNA features that allow them to be described functionally or computationally. We have employed an alternate approach to the direct study of these DNA elements. By using proteins that specifically bind these noncoding DNAs as surrogates, we can indirectly assay the evolutionary constraints acting on these important DNA elements. We review the impact that such “surrogate strategies” have had on our understanding of the evolutionary constraints shaping centromeres, origins of DNA replication, and dosage compensation X chromosomal sites. These have begun to reveal that in contrast to the view that such structural DNA elements are either highly constrained (under purifying selection) or free to drift (under neutral evolution), some of them may instead be shaped by adaptive evolution and genetic conflicts (these are not mutually exclusive). These insights also help to explain why the same elements (e.g., centromeres and replication origins), which are so complex in some eukaryotic genomes, can be simple and well defined in other where similar conflicts do not exist.
doi:10.1093/jhered/esp063
PMCID: PMC2877547  PMID: 19635763
Drosophila; positive selection; protein–DNA interactions; rapid evolution
23.  Diversifying selection and functional analysis of interleukin-4 suggests antagonism-driven evolution at receptor-binding interfaces 
Background
Interleukin-4 (IL4) is a secreted immunoregulatory cytokine critically involved in host protection from parasitic helminths [1]. Reasoning that helminths may have evolved mechanisms to antagonize IL4 to maximize their dispersal, we explored mammalian IL4 evolution.
Results
This analysis revealed evidence of diversifying selection at 15 residues, clustered in epitopes responsible for IL4 binding to its Type I and Type II receptors. Such a striking signature of selective pressure suggested either recurrent episodes of pathogen antagonism or ligand/receptor co-evolution. To test the latter possibility, we performed detailed functional analysis of IL4 allotypes expressed by Mus musculus musculus and Mus musculus castaneus, which happen to differ at 5 residues (including three at positively selected sites) in and adjacent to the site 1 epitope that binds the IL4Rα subunit shared by the Type I and Type II IL4 receptors. We show that this intra-species variation affects the ability of IL4 neither to bind IL4 receptor alpha (IL4Rα) nor to signal biological responses through its Type I receptor.
Conclusions
Our results -- reminiscent of clustered positively selected sites revealing functionally important residues at host-virus interaction interfaces -- are consistent with IL4 having evolved to avoid recurrent pathogen antagonism, while maintaining the capacity to bind and signal through its cognate receptor. This work exposes what may be a general feature of evolutionary conflicts fought by pathogen antagonists at host protein-protein interaction interfaces involved in immune signaling: the emergence of receptor-binding ligand epitopes capable of buffering amino acid variation.
doi:10.1186/1471-2148-10-223
PMCID: PMC3017759  PMID: 20649995
24.  An Expanded Clade of Rodent Trim5 Genes 
Virology  2009;385(2):473-483.
Trim5α from primates (including humans), cows, and rabbits has been shown to be an active antiviral host gene that acts against a range of retroviruses. Although this suggests that Trim5α may be a common antiviral restriction factor among mammals, the status of Trim5 genes in rodents has been unclear. Using genomic and phylogenetic analyses, we describe an expanded paralogous cluster of at least eight Trim5-like genes in mice (including the previously described Trim12 and Trim30 genes), and three Trim5-like genes in rats. Our characterization of the rodent Trim5 locus, and comparison to the Trim5 locus in humans, cows, and rabbits, indicates that Trim5 has undergone independent evolutionary expansions within species. Evolutionary analysis shows that rodent Trim5 genes have evolved under positive selection, suggesting evolutionary conflicts consistent with important antiviral function. Sampling six rodent Trim5 genes failed to reveal antiviral activities against a set of eight retroviral challenges, although we predict that such activities exist.
doi:10.1016/j.virol.2008.12.018
PMCID: PMC2692226  PMID: 19147168
Retrovirus; rodent; Trim5; adaptive evolution; restriction factor; paralog
25.  Paleovirology—Modern Consequences of Ancient Viruses 
PLoS Biology  2010;8(2):e1000301.
doi:10.1371/journal.pbio.1000301
PMCID: PMC2817711  PMID: 20161719

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