Carter JJ, Daugherty MD, Qi X et al.Identification of an overprinting gene in Merkel cell polyomavirus provides evolutionary insight into the birth of viral genes. Proc Natl Acad Sci USA 110:12744-12749

Divisions of Human Biology, Public Health Sciences, and Basic Sciences and Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center, Seattle, WA 98109.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2013; 110(31). DOI: 10.1073/pnas.1303526110
Source: PubMed


Many viruses use overprinting (alternate reading frame utilization) as a means to increase protein diversity in genomes severely constrained by size. However, the evolutionary steps that facilitate the de novo generation of a novel protein within an ancestral ORF have remained poorly characterized. Here, we describe the identification of an overprinting gene, expressed from an Alternate frame of the Large T Open reading frame (ALTO) in the early region of Merkel cell polyomavirus (MCPyV), the causative agent of most Merkel cell carcinomas. ALTO is expressed during, but not required for, replication of the MCPyV genome. Phylogenetic analysis reveals that ALTO is evolutionarily related to the middle T antigen of murine polyomavirus despite almost no sequence similarity. ALTO/MT arose de novo by overprinting of the second exon of T antigen in the common ancestor of a large clade of mammalian polyomaviruses. Taking advantage of the low evolutionary divergence and diverse sampling of polyomaviruses, we propose evolutionary transitions that likely gave birth to this protein. We suggest that two highly constrained regions of the large T antigen ORF provided a start codon and C-terminal hydrophobic motif necessary for cellular localization of ALTO. These two key features, together with stochastic erasure of intervening stop codons, resulted in a unique protein-coding capacity that has been preserved ever since its birth. Our study not only reveals a previously undefined protein encoded by several polyomaviruses including MCPyV, but also provides insight into de novo protein evolution.

Download full-text


Available from: Harmit Singh Malik, Jan 07, 2014
  • Source
    • "The ALTO-coding sequence has a similar genome position as the second exon of MT-ag and the encoded proteins display C-terminal similarity. Therefore, Carter et al. suggested that ALTO may be a compensation for the lack of MT-ag (Carter et al., 2013). On the other hand, the rodent polyomavirus genomes encoding MT-ag also encode the conserved start codon of ALTO. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Polyomaviruses have so far only been isolated from mammals and birds. Typical for all members of this family is their double-stranded genome of approximately 5,000 base-pairs which can be divided into an early region encoding at least two functional proteins, the large and small tumor antigens, and a late region encompassing genes for the capsid proteins VP1 and VP2. During the last 10 years several novel polyomaviruses have been described in non-human primates and man. This review compares the non-human primate polyomavirus genomes that have been completely sequenced with each other and with the genomes of human polyomaviruses. We predict the presence of protein- and microRNA-encoding sequences. Our analyses demonstrate that several genetically distinct groups of non-human primate polyomaviruses exist, that different polyomaviruses can infect the same non-human primate species but that most of their proteins display highly similar domains and motifs, indicating conservation of key functions.
    Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 06/2014; 26. DOI:10.1016/j.meegid.2014.05.030 · 3.02 Impact Factor
  • Source
    • "While no other polyomaviruses are known to encode this agnoprotein, murine and hamster polyomavirus encode a middle T antigen which functions as transforming protein [40]. Recently, also MCPyV was found to encode a protein phylogenetically related to this middle T antigen, called ALTO [41]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Polyomaviruses are a family of non-enveloped DNA viruses infecting several species, including humans, primates, birds, rodents, bats, horse, cattle, raccoon and sea lion. They typically cause asymptomatic infection and establish latency but can be reactivated under certain conditions causing severe diseases. MicroRNAs (miRNAs) are small non-coding RNAs that play important roles in several cellular processes by binding to and inhibiting the translation of specific mRNA transcripts. In this review, we summarize the current knowledge of microRNAs involved in polyomavirus infection. We review in detail the different viral miRNAs that have been discovered and the role they play in controlling both host and viral protein expression. We also give an overview of the current understanding on how host miRNAs may function in controlling polyomavirus replication, immune evasion and pathogenesis.
    Virology Journal 08/2013; 10(1):268. DOI:10.1186/1743-422X-10-268 · 2.18 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recently, the family Polyomaviridae was classified as 3 genera, such as Orthopolyomavirus, Wukipolyomavirus which contain mammalian polyomaviruses and Avipolyomavirus which only contain avian polyomaviruses. We have recently isolated novel polyomaviruses, including Mastomys Polyoamvirus (MasPyV) and Vervet monkey Polyoamvirus-1 (VmPyV-1) by epidemiological activities and examined functions of their encoding proteins. In addition, we have been investigating the mechanisms of replication of human polyomavirus, JC polyomavirus (JCPyV). We recently obtained the results of function of JCVPyV-encoding proteins, including early protein (Large T antigen) and late proteins (VP1 and Agno). In this review, we summarized the data of our basic research activities.
    Uirusu 01/2014; 64(1):25-34. DOI:10.2222/jsv.64.25
Show more