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Link to original content: https://pubmed.ncbi.nlm.nih.gov/20382832
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. 2010 Jun;185(2):603-9.
doi: 10.1534/genetics.110.115162. Epub 2010 Apr 9.

Distribution of fitness effects caused by single-nucleotide substitutions in bacteriophage f1

Joan B Peris  1 , Paulina Davis, José M Cuevas, Miguel R Nebot, Rafael Sanjuán
Affiliations

Distribution of fitness effects caused by single-nucleotide substitutions in bacteriophage f1

Joan B Peris et al. Genetics. 2010 Jun.

Abstract

Empirical knowledge of the fitness effects of mutations is important for understanding many evolutionary processes, yet this knowledge is often hampered by several sources of measurement error and bias. Most of these problems can be solved using site-directed mutagenesis to engineer single mutations, an approach particularly suited for viruses due to their small genomes. Here, we used this technique to measure the fitness effect of 100 single-nucleotide substitutions in the bacteriophage f1, a filamentous single-strand DNA virus. We found that approximately one-fifth of all mutations are lethal. Viable ones reduced fitness by 11% on average and were accurately described by a log-normal distribution. More than 90% of synonymous substitutions were selectively neutral, while those affecting intergenic regions reduced fitness by 14% on average. Mutations leading to amino acid substitutions had an overall mean deleterious effect of 37%, which increased to 45% for those changing the amino acid polarity. Interestingly, mutations affecting early steps of the infection cycle tended to be more deleterious than those affecting late steps. Finally, we observed at least two beneficial mutations. Our results confirm that high mutational sensitivity is a general property of viruses with small genomes, including RNA and single-strand DNA viruses infecting animals, plants, and bacteria.

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Figures

F<sc>igure</sc> 1.—
Figure 1.—
Diagram of the f1 genome showing the 100 single-nucleotide substitutions created by site-directed mutagenesis. Gene names (roman numbers) and genome positions are indicated. Colors indicate broad functional categories (blue, replication; green, particle maturation; yellow, capsid; red, extrusion). Additional details about the function of each gene can be found elsewhere (Calendar 2006). Briefly, protein II nicks the viral DNA to allow replication priming, protein X results from in-frame translation of gene II and is required for single-strand DNA accumulation, protein V binds to DNA and collapses the circular genome into a flexible rod, proteins VII and IX are small coat proteins located at the tip of the virion, protein VIII forms the cylinder containing the viral DNA, proteins III and VI are located at the tail of the virion and are involved in termination of virion assembly, protein I is an inner membrane protein that hydrolyzes ATP and promotes capsid morphogenesis, and protein IV forms a channel in the outer membrane to allow virion extrusion. Thinner, noncolored, areas denote intergenic regions, which constitute 9% of the genome. Mutations falling at coding regions are shown in three concentric rings according to whether they are synonymous (outer), missense (central), or nonsense (inner). Open, shaded, and solid circles represent neutral, significantly deleterious, and lethal mutations, respectively. Two significantly beneficial mutations are shown with asterisks. Significance levels were adjusted to 0.05 for multiple tests.
F<sc>igure</sc> 2.—
Figure 2.—
Distribution of fitness effects caused by single-nucleotide substitutions in bacteriophage f1. The frequency histogram of the 100 mutations is shown. Note that the fitness effect of lethal mutations is s = −1. The effect of each individual mutation is provided in Table S1. Shown superimposed is the best-fitting probability density function for viable, nonbeneficial mutations (a log-normal distribution with the parameter values shown in Table 3).
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