Epistasis among deleterious mutations in the HIV-1 protease

Epistasis among deleterious mutations in the HIV-1 protease

Fecha de publicación online: 14/07/2009


A central goal in molecular evolution is to understand how genetic
interactions between protein mutations shape protein function and fitness.
While intergenic epistasis has been extensively explored in eukaryotes,
bacteria, and viruses, intragenic epistatic interactions have been insufficiently
studied. Here, we employ a model system in which lambda phage
fitness correlates with the enzymatic activity of human immunodeficiency
virus type 1 (HIV-1) protease to systematically determine the epistatic
interactions between intragenic pairs of deleterious protein substitutions.
We generated 114 genotypes of the HIV-1 protease, each carrying pairs of
nucleotide substitution mutations whose separated and combined deleterious
effects on fitness were then determined. A high proportion (39%) of
pairs displayed lethality. Several pairs exhibited significant interactions for
fitness, including positive and negative epistasis. Significant negative
epistatic interactions predominated (15%) over positive interactions (2%).
However, the average±SD epistatic effect, ē=0.0025±0.1334, was not
significantly different from zero (p=0.8368). Notably, epistatic interactions,
regardless of epistatic direction, tend to be more frequent in the context of
less deleterious mutations. In the present study, the high frequencies of
lethality and negative epistasis indicate that the HIV-1 protease is highly
sensitive to the effects of deleterious mutations. Therefore, proteins may not
be as robust to mutational change as is usually expected.

Autores: Parera, M., Perez-Alvarez, N., Clotet, B., and Martinez, M. A.
  • Código Doi: J Mol Biol 392, 243-250

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