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Adaptive evolution of a stress response protein.

Little TJ, Nelson L, Hupp T - PLoS ONE (2007)

Bottom Line: The SEP53 gene appears to have been subject to adaptive evolution of a type that is commonly (though not exclusively) associated with coevolutionary arms races.Our data thus raises the possibility that SEP53 is a component of the mucosal/epithelial innate immune response engaged in an ongoing interaction with a pathogen.Although the pathogenic stress mediating adaptive evolution of SEP53 is not known, there are a number of well-known candidates, in particular viruses with established links to carcinoma.

View Article: PubMed Central - PubMed

Affiliation: Institute of Evolutionary Biology, School of Biology, University of Edinburgh, Edinburgh, United Kingdom. tlittle1@staffmail.ed.ac.uk

ABSTRACT

Background: Some cancers are mediated by an interplay between tissue damage, pathogens and localised innate immune responses, but the mechanisms that underlie these linkages are only beginning to be unravelled.

Methods and principal findings: Here we identify a strong signature of adaptive evolution on the DNA sequence of the mammalian stress response gene SEP53, a member of the epidermal differentiation complex fused-gene family known for its role in suppressing cancers. The SEP53 gene appears to have been subject to adaptive evolution of a type that is commonly (though not exclusively) associated with coevolutionary arms races. A similar pattern of molecular evolution was not evident in the p53 cancer-suppressing gene.

Conclusions: Our data thus raises the possibility that SEP53 is a component of the mucosal/epithelial innate immune response engaged in an ongoing interaction with a pathogen. Although the pathogenic stress mediating adaptive evolution of SEP53 is not known, there are a number of well-known candidates, in particular viruses with established links to carcinoma.

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KA/KS (solid line, left y-axis) varies greatly along the length of the SEP53 coding region based on a sliding window analysis.KS (dotted line, right y-axis) is also shown. Data are from primates only and is the mean of all pairwise comparisons involving humans. The window size was 100 bp, the step size 20 bp; varying these parameters has some effect on the output, but all combinations of window and step size consistently indicated a KA/KS trough in the N-terminal Ca+ binding domain (bp 0 to 270) and prominent peaks in the C-terminal domain (bp 271 onwards) around bp 500, 900, and 1100. The location of two repeats common to all primates are indicated as R1 and R2/R4 (see figure 2).
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pone-0001003-g001: KA/KS (solid line, left y-axis) varies greatly along the length of the SEP53 coding region based on a sliding window analysis.KS (dotted line, right y-axis) is also shown. Data are from primates only and is the mean of all pairwise comparisons involving humans. The window size was 100 bp, the step size 20 bp; varying these parameters has some effect on the output, but all combinations of window and step size consistently indicated a KA/KS trough in the N-terminal Ca+ binding domain (bp 0 to 270) and prominent peaks in the C-terminal domain (bp 271 onwards) around bp 500, 900, and 1100. The location of two repeats common to all primates are indicated as R1 and R2/R4 (see figure 2).

Mentions: Whilst KA:KS ratios >>1.0 are evidence of positive selection (see also [21]), a simple KA/KS calculation is thought to be conservative because it represents the average ratio across all codons, and does not account for the possibility that some codons are highly conserved while others evolve rapidly. Indeed, sliding window analysis along the length of SEP53 showed depressed KA/KS in the highly conserved N-terminal Ca+ binding domain and a series of peaks in the C-terminal domain (Figure 1; full alignment of SEP53 is presented in supplementary information). We therefore used an approach that allows KA/KS to vary among codons to compare the likelihood of a model that permits a proportion of codons to be under selection to the likelihood of a model that assumes neutrality at all sites [22], [23], [24]. These comparisons of neutral and selection models indicated that SEP53 was subject to adaptive evolution (Table 2), with as many as 8 percent of codons showing KA/KS substantially above 1.0. For the same analysis on the p53 gene, KA/KS was low and neutral models were as likely as selection models (Tables 1, 2). Analysis of variation within the human population did not provide additional evidence of selection at SEP53 (or p53) (Table S1), however there was little power to do so as polymorphism at both loci was extremely low.


Adaptive evolution of a stress response protein.

Little TJ, Nelson L, Hupp T - PLoS ONE (2007)

KA/KS (solid line, left y-axis) varies greatly along the length of the SEP53 coding region based on a sliding window analysis.KS (dotted line, right y-axis) is also shown. Data are from primates only and is the mean of all pairwise comparisons involving humans. The window size was 100 bp, the step size 20 bp; varying these parameters has some effect on the output, but all combinations of window and step size consistently indicated a KA/KS trough in the N-terminal Ca+ binding domain (bp 0 to 270) and prominent peaks in the C-terminal domain (bp 271 onwards) around bp 500, 900, and 1100. The location of two repeats common to all primates are indicated as R1 and R2/R4 (see figure 2).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1994589&req=5

pone-0001003-g001: KA/KS (solid line, left y-axis) varies greatly along the length of the SEP53 coding region based on a sliding window analysis.KS (dotted line, right y-axis) is also shown. Data are from primates only and is the mean of all pairwise comparisons involving humans. The window size was 100 bp, the step size 20 bp; varying these parameters has some effect on the output, but all combinations of window and step size consistently indicated a KA/KS trough in the N-terminal Ca+ binding domain (bp 0 to 270) and prominent peaks in the C-terminal domain (bp 271 onwards) around bp 500, 900, and 1100. The location of two repeats common to all primates are indicated as R1 and R2/R4 (see figure 2).
Mentions: Whilst KA:KS ratios >>1.0 are evidence of positive selection (see also [21]), a simple KA/KS calculation is thought to be conservative because it represents the average ratio across all codons, and does not account for the possibility that some codons are highly conserved while others evolve rapidly. Indeed, sliding window analysis along the length of SEP53 showed depressed KA/KS in the highly conserved N-terminal Ca+ binding domain and a series of peaks in the C-terminal domain (Figure 1; full alignment of SEP53 is presented in supplementary information). We therefore used an approach that allows KA/KS to vary among codons to compare the likelihood of a model that permits a proportion of codons to be under selection to the likelihood of a model that assumes neutrality at all sites [22], [23], [24]. These comparisons of neutral and selection models indicated that SEP53 was subject to adaptive evolution (Table 2), with as many as 8 percent of codons showing KA/KS substantially above 1.0. For the same analysis on the p53 gene, KA/KS was low and neutral models were as likely as selection models (Tables 1, 2). Analysis of variation within the human population did not provide additional evidence of selection at SEP53 (or p53) (Table S1), however there was little power to do so as polymorphism at both loci was extremely low.

Bottom Line: The SEP53 gene appears to have been subject to adaptive evolution of a type that is commonly (though not exclusively) associated with coevolutionary arms races.Our data thus raises the possibility that SEP53 is a component of the mucosal/epithelial innate immune response engaged in an ongoing interaction with a pathogen.Although the pathogenic stress mediating adaptive evolution of SEP53 is not known, there are a number of well-known candidates, in particular viruses with established links to carcinoma.

View Article: PubMed Central - PubMed

Affiliation: Institute of Evolutionary Biology, School of Biology, University of Edinburgh, Edinburgh, United Kingdom. tlittle1@staffmail.ed.ac.uk

ABSTRACT

Background: Some cancers are mediated by an interplay between tissue damage, pathogens and localised innate immune responses, but the mechanisms that underlie these linkages are only beginning to be unravelled.

Methods and principal findings: Here we identify a strong signature of adaptive evolution on the DNA sequence of the mammalian stress response gene SEP53, a member of the epidermal differentiation complex fused-gene family known for its role in suppressing cancers. The SEP53 gene appears to have been subject to adaptive evolution of a type that is commonly (though not exclusively) associated with coevolutionary arms races. A similar pattern of molecular evolution was not evident in the p53 cancer-suppressing gene.

Conclusions: Our data thus raises the possibility that SEP53 is a component of the mucosal/epithelial innate immune response engaged in an ongoing interaction with a pathogen. Although the pathogenic stress mediating adaptive evolution of SEP53 is not known, there are a number of well-known candidates, in particular viruses with established links to carcinoma.

Show MeSH
Related in: MedlinePlus