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Thus, IFIT gene duplication may be the host's response to the evolutionary arms race where viruses are continually masking their RNAs with 'self' features.
Both IFIT1 and IFIT1B genes form distinct monophyletic clades that diverge according to mammalian species evolution, similar to other IFIT genes.
These data also reveal that all three mouse IFIT1 paralogs (previously named mouse IFIT1, IFIT1b and IFIT1c) and both rat paralogs (previously named rat IFIT1 and IFIT1b) unambiguously group within the IFIT1B gene family.
These seemingly contradictory results regarding the antiviral specificities of mouse IFIT1 and human IFIT1 have led to a conundrum in the field regarding the molecular functions and antiviral specificity of IFIT proteins in general.
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In this way, IFITs appeared to function similarly to another critical mediator of the innate immune system, Protein Kinase R (PKR), by globally inhibiting mRNA translation.
IFIT is either not expressed (Glucose) or expressed (Galactose).
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IFIT and IFITM proteins.
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Construction of yeast strains.
IFIT antiviral genes is still incompletely understood.
IFIT1 or IFIT1B genes (Figure 6A), circumventing the need to stimulate IFIT expression with interferon and allowing us to evaluate different IFIT1 or IFIT1B gene functions in an isogenic background.
In contrast, the IFIT locus in mice and rats is arranged quite differently than other mammalian genomes.
IFIT gene that restricts those viruses may be pseudogenized or lost permanently.
In carnivores such as cats and ferrets, the IFIT locus is split with IFIT5 in one chromosomal location and the remainder of the IFITs in another.
The complex evolutionary history of the IFIT family of antiviral genes has been shaped by continuous interactions between mammalian hosts and their many viruses.
For the species indicated in Figure 1, we used this information to include only IFIT sequences that were found on a single uninterrupted region of DNA in either NCBI or UCSC genome databases.
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IFIT gene repertoire even within this limited number of mammalian species.
For example, human chromosome 10 contains a single locus that encodes all five intact IFIT genes: IFIT1, IFIT1B, IFIT2, IFIT3 and IFIT5 (Figure 1A).
The functional consequences of IFIT family evolution are unknown, in part because the antiviral functions and specificities of IFITs are incompletely characterized.
Based on our new understanding of the divergent functions of IFIT1 and IFIT1B, we hypothesize that duplication or loss of different IFIT genes might directly influence the ability of a particular host species to defend against specific viral pathogens.
We find unambiguous evidence that, although they were initially assumed to be orthologs, mouse IFIT1B (previously mouse IFIT1) and human IFIT1 represent paralogous genes that diverged close to the origin of placental mammals.
We therefore asked whether expression of IFIT genes in yeast would also arrest growth.
We further showed that the IFIT gene family, especially IFIT1 and IFIT1B genes, have undergone recurrent bouts of gene duplication, gene loss, and gene conversion.
IFN induction and active repression, a second messenger, synergy with other IFIT proteins, or some other mechanism not present in yeast, IFIT1 may act globally under conditions when a cell has been breeched by a virus.
Extending our surveys across all 51 sampled vertebrate species, we found numerous instances of IFIT gene birth, gene loss and gene recombination (Figure 3).
Colored boxes indicate the presence of a given IFIT gene sequence, with multiple copies indicated as a number to the right of the colored box.
When a virus is detected in the body, hundreds of different proteins in the immune system are rapidly produced as a first line of defense to limit the ability of the virus to multiply and spread.
The resulting plasmids were used as templates to amplify the entire region spanning the Gal promoter to the Leu2 gene using primers described in Supplementary file 2 with 70 bp homology to the genomic regions flanking the His3 gene.
IFIT genes as well.
RNA recognition by human IFIT proteins.
Alignment of the IFIT gene locus from several mammalian genomes.
IFIT gene sequences across these divergent mammalian species to determine how mouse IFIT1 genes are related to those found in other species (Figure 1B).
Although gene conversion and gene turnover initially confounded IFIT phylogenetic analysis, it may now present a significant opportunity to understand the biochemical basis of the different antiviral specificities of IFIT1 and IFIT1B.
IFIT gene family: An insight into coevolution with IFN gene family.
IFIT proteins, and it has been challenging to determine how IFITs discriminate viral from host RNAs to repress viral replication specifically.
Using detailed phylogenetic analyses of IFIT genes in vertebrates, made possible by deconvolving the confounding effects of recurrent gene conversion, we show that human IFIT1 and mouse IFIT1 are two distinct paralogous genes that diverged early in mammalian evolution.
However, such an explanation would require recurrent duplication of IFIT genes in many lineages into the same genetic location and orientation, and is thus unlikely.
Note that the nomenclature for the IFIT genes marked with asterisks is as previously proposed; we suggest a revised nomenclature scheme for those genes in this report from Figure 2 onwards.
Such changes in IFIT gene composition might be expected to affect the range of viruses that can be inhibited by IFITs in different mammalian genomes.
IFIT gene repertoire in mammals.
This IFIT gene turnover might profoundly impact the spectrum of viruses that different mammalian species are capable of restricting.
However, the number and identity of IFIT genes can vary substantially between species.
These processes have resulted in a wide diversity of IFIT genes across mammalian species.
Discordant signatures of synteny and phylogeny for mammalian IFIT genes.
Similarly, in the first paragraph of the discussion, it would be nice to cite other published examples of innate immune gene families that have similarly complex evolutionary histories (in addition to citing the single review article written by the authors).
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For expression of methyltransferases and IFITs, human methyltransferases were integrated into strain BY4741 to replace the His3 gene and then transformed with p413 plasmids expressing IFITs.
IFITs may restrict viral replication through recognition of distinct viral RNA patterns.
Overall, this paper is very clearly written, the experimental and computational analyses are convincing, a clever new yeast assay for restriction activity is presented (as are complementary viral restriction data), and the field has been clarified.
We found the IFIT locus organization is similar in many other mammalian genomes including African green monkeys, rabbits, cats, ferrets, and armadillos (Figure 1A).
IFIT1 and IFIT1B genes in the absence of gene conversion, we created a maximum likelihood phylogenetic tree of the same IFIT sequences shown in Figure 1B, but with just the nucleotide sequences 3' of the observed recombination breakpoint(s) (Figure 2C).
Maximum likelihood phylogenetic tree generated using an alignment of the entire gene sequence of the indicated IFITs.
Further experiments show that the human and mouse IFIT proteins likely discriminate between host and viral RNA using different cues, leading to their action against different sets of viruses.
The authors describe the evolutionary history of the IFIT genes, and convincingly demonstrate that they fall into two separate families, IFIT1 and IFIT1B.