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Compensatory mutations cause excess of antagonistic epistasis in RNA secondary structure folding.

Wilke CO, Lenski RE, Adami C - BMC Evol. Biol. (2003)

Bottom Line: However, in a number of recent studies, a prevalence of antagonistic epistasis (the tendency of multiple mutations to have a mitigating rather than reinforcing effect) has been observed.We found a clear prevalence of antagonistic epistasis in RNA secondary structure folding.Our findings imply that the average direction of epistasis in simple fitness landscapes is directly related to the density with which fitness peaks are distributed in these landscapes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Digital Life Laboratory 136-93, California Institute of Technology, Pasadena, CA 91125, USA. wilke@caltech.edu

ABSTRACT

Background: The rate at which fitness declines as an organism's genome accumulates random mutations is an important variable in several evolutionary theories. At an intuitive level, it might seem natural that random mutations should tend to interact synergistically, such that the rate of mean fitness decline accelerates as the number of random mutations is increased. However, in a number of recent studies, a prevalence of antagonistic epistasis (the tendency of multiple mutations to have a mitigating rather than reinforcing effect) has been observed.

Results: We studied in silico the net amount and form of epistatic interactions in RNA secondary structure folding by measuring the fraction of neutral mutants as a function of mutational distance d. We found a clear prevalence of antagonistic epistasis in RNA secondary structure folding. By relating the fraction of neutral mutants at distance d to the average neutrality at distance d, we showed that this prevalence derives from the existence of many compensatory mutations at larger mutational distances.

Conclusions: Our findings imply that the average direction of epistasis in simple fitness landscapes is directly related to the density with which fitness peaks are distributed in these landscapes.

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Functions w(d) (■), wneut(d) (□), and wcomp(d) (*), calculated using method M2, for a representative sequence. The lines merely connect the points to guide the eye.
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Figure 5: Functions w(d) (■), wneut(d) (□), and wcomp(d) (*), calculated using method M2, for a representative sequence. The lines merely connect the points to guide the eye.

Mentions: If compensatory mutations were responsible for the shift of β to values below one, then by adjusting the function w(d) to remove their contribution we should find a distribution of β symmetrical around one. As described in the Methods section, it is possible to separate the contribution to w(d) of neutral mutations that lie on the same network wneut(d) from the contribution wcomp(d) that reflects compensatory mutations from neighboring neutral networks onto the reference network. Figure 5 shows w(d), wneut(d) and wcomp(d), estimated using method M2, for a typical example. The contribution of wneut(d) to w(d) dwindles as the mutational distance d increases, while wcomp(d) becomes increasingly dominant. In other words, at large distances d, most of the viable sequences arise through compensatory mutations.


Compensatory mutations cause excess of antagonistic epistasis in RNA secondary structure folding.

Wilke CO, Lenski RE, Adami C - BMC Evol. Biol. (2003)

Functions w(d) (■), wneut(d) (□), and wcomp(d) (*), calculated using method M2, for a representative sequence. The lines merely connect the points to guide the eye.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC149451&req=5

Figure 5: Functions w(d) (■), wneut(d) (□), and wcomp(d) (*), calculated using method M2, for a representative sequence. The lines merely connect the points to guide the eye.
Mentions: If compensatory mutations were responsible for the shift of β to values below one, then by adjusting the function w(d) to remove their contribution we should find a distribution of β symmetrical around one. As described in the Methods section, it is possible to separate the contribution to w(d) of neutral mutations that lie on the same network wneut(d) from the contribution wcomp(d) that reflects compensatory mutations from neighboring neutral networks onto the reference network. Figure 5 shows w(d), wneut(d) and wcomp(d), estimated using method M2, for a typical example. The contribution of wneut(d) to w(d) dwindles as the mutational distance d increases, while wcomp(d) becomes increasingly dominant. In other words, at large distances d, most of the viable sequences arise through compensatory mutations.

Bottom Line: However, in a number of recent studies, a prevalence of antagonistic epistasis (the tendency of multiple mutations to have a mitigating rather than reinforcing effect) has been observed.We found a clear prevalence of antagonistic epistasis in RNA secondary structure folding.Our findings imply that the average direction of epistasis in simple fitness landscapes is directly related to the density with which fitness peaks are distributed in these landscapes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Digital Life Laboratory 136-93, California Institute of Technology, Pasadena, CA 91125, USA. wilke@caltech.edu

ABSTRACT

Background: The rate at which fitness declines as an organism's genome accumulates random mutations is an important variable in several evolutionary theories. At an intuitive level, it might seem natural that random mutations should tend to interact synergistically, such that the rate of mean fitness decline accelerates as the number of random mutations is increased. However, in a number of recent studies, a prevalence of antagonistic epistasis (the tendency of multiple mutations to have a mitigating rather than reinforcing effect) has been observed.

Results: We studied in silico the net amount and form of epistatic interactions in RNA secondary structure folding by measuring the fraction of neutral mutants as a function of mutational distance d. We found a clear prevalence of antagonistic epistasis in RNA secondary structure folding. By relating the fraction of neutral mutants at distance d to the average neutrality at distance d, we showed that this prevalence derives from the existence of many compensatory mutations at larger mutational distances.

Conclusions: Our findings imply that the average direction of epistasis in simple fitness landscapes is directly related to the density with which fitness peaks are distributed in these landscapes.

Show MeSH