Skip to main content
PMC home page
Genetics logoLink to Genetics
. 2002 Apr;160(4):1273–1281. doi: 10.1093/genetics/160.4.1273

Dependence of epistasis on environment and mutation severity as revealed by in silico mutagenesis of phage t7.

Lingchong You 1, John Yin 1
PMCID: PMC1462038  PMID: 11973286

Abstract

Understanding how interactions among deleterious mutations affect fitness may shed light on a variety of fundamental biological phenomena, including the evolution of sex, the buffering of genetic variations, and the topography of fitness landscapes. It remains an open question under what conditions and to what extent such interactions may be synergistic or antagonistic. To address this question, we employed a computer model for the intracellular growth of bacteriophage T7. We created in silico 90,000 mutants of phage T7, each carrying from 1 to 30 mutations, and evaluated the fitness of each by simulating its growth cycle. The simulations sought to account for the severity of single deleterious mutations on T7 growth, as well as the effect of the resource environment on our fitness measures. We found that mildly deleterious mutations interacted synergistically in poor-resource environments but antagonistically in rich-resource environments. However, severely deleterious mutations always interacted antagonistically, irrespective of environment. These results suggest that synergistic epistasis may be difficult to experimentally distinguish from nonepistasis because its effects appear to be most pronounced when the effects of mutations on fitness are most challenging to measure. Our approach demonstrates how computer simulations of developmental processes can be used to quantitatively study genetic interactions at the population level.

Full Text

The Full Text of this article is available as a PDF (114.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Charlesworth B. Mutation-selection balance and the evolutionary advantage of sex and recombination. Genet Res. 1990 Jun;55(3):199–221. doi: 10.1017/s0016672300025532. [DOI] [PubMed] [Google Scholar]
  2. Davies E. K., Peters A. D., Keightley P. D. High frequency of cryptic deleterious mutations in Caenorhabditis elegans. Science. 1999 Sep 10;285(5434):1748–1751. doi: 10.1126/science.285.5434.1748. [DOI] [PubMed] [Google Scholar]
  3. Elena S. F., Lenski R. E. Test of synergistic interactions among deleterious mutations in bacteria. Nature. 1997 Nov 27;390(6658):395–398. doi: 10.1038/37108. [DOI] [PubMed] [Google Scholar]
  4. Endy D., Kong D., Yin J. Intracellular kinetics of a growing virus: a genetically structured simulation for bacteriophage T7. Biotechnol Bioeng. 1997 Jul 20;55(2):375–389. doi: 10.1002/(SICI)1097-0290(19970720)55:2<375::AID-BIT15>3.0.CO;2-G. [DOI] [PubMed] [Google Scholar]
  5. Endy D., You L., Yin J., Molineux I. J. Computation, prediction, and experimental tests of fitness for bacteriophage T7 mutants with permuted genomes. Proc Natl Acad Sci U S A. 2000 May 9;97(10):5375–5380. doi: 10.1073/pnas.090101397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Fry J. D., Keightley P. D., Heinsohn S. L., Nuzhdin S. V. New estimates of the rates and effects of mildly deleterious mutation in Drosophila melanogaster. Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):574–579. doi: 10.1073/pnas.96.2.574. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Haigh J. The accumulation of deleterious genes in a population--Muller's Ratchet. Theor Popul Biol. 1978 Oct;14(2):251–267. doi: 10.1016/0040-5809(78)90027-8. [DOI] [PubMed] [Google Scholar]
  8. Keightley P. D., Caballero A., García-Dorado A. Population genetics: surviving under mutation pressure. Curr Biol. 1998 Mar 26;8(7):R235–R237. doi: 10.1016/s0960-9822(98)70148-4. [DOI] [PubMed] [Google Scholar]
  9. Kimura M., Maruyama T. The mutational load with epistatic gene interactions in fitness. Genetics. 1966 Dec;54(6):1337–1351. doi: 10.1093/genetics/54.6.1337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kondrashov A. S. Classification of hypotheses on the advantage of amphimixis. J Hered. 1993 Sep-Oct;84(5):372–387. doi: 10.1093/oxfordjournals.jhered.a111358. [DOI] [PubMed] [Google Scholar]
  11. Lenski R. E., Ofria C., Collier T. C., Adami C. Genome complexity, robustness and genetic interactions in digital organisms. Nature. 1999 Aug 12;400(6745):661–664. doi: 10.1038/23245. [DOI] [PubMed] [Google Scholar]
  12. Mukai T., Chigusa S. I., Mettler L. E., Crow J. F. Mutation rate and dominance of genes affecting viability in Drosophila melanogaster. Genetics. 1972 Oct;72(2):335–355. doi: 10.1093/genetics/72.2.335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Peck J. R., Waxman D. Mutation and sex in a competitive world. Nature. 2000 Jul 27;406(6794):399–404. doi: 10.1038/35019055. [DOI] [PubMed] [Google Scholar]
  14. Peters A. D., Keightley P. D. A test for epistasis among induced mutations in Caenorhabditis elegans. Genetics. 2000 Dec;156(4):1635–1647. doi: 10.1093/genetics/156.4.1635. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Spassky B., Dobzhansky T., Anderson W. W. Genetics of natural populations. XXXVI. Epistatic interactions of the components of the genetic load in Drosophila pseudoobscura. Genetics. 1965 Sep;52(3):653–664. doi: 10.1093/genetics/52.3.653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. West S. A., Peters A. D., Barton N. H. Testing for epistasis between deleterious mutations. Genetics. 1998 May;149(1):435–444. doi: 10.1093/genetics/149.1.435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Whitlock M. C., Bourguet D. Factors affecting the genetic load in Drosophila: synergistic epistasis and correlations among fitness components. Evolution. 2000 Oct;54(5):1654–1660. doi: 10.1111/j.0014-3820.2000.tb00709.x. [DOI] [PubMed] [Google Scholar]
  18. Wilke C. O., Adami C. Interaction between directional epistasis and average mutational effects. Proc Biol Sci. 2001 Jul 22;268(1475):1469–1474. doi: 10.1098/rspb.2001.1690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. You L., Yin J. Patterns of regulation from mRNA and protein time series. Metab Eng. 2000 Jul;2(3):210–217. doi: 10.1006/mben.1999.0139. [DOI] [PubMed] [Google Scholar]
  20. You Lingchong, Suthers Patrick F., Yin John. Effects of Escherichia coli physiology on growth of phage T7 in vivo and in silico. J Bacteriol. 2002 Apr;184(7):1888–1894. doi: 10.1128/JB.184.7.1888-1894.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. de Visser J. A., Hoekstra R. F., van den Ende H. An experimental test for synergistic epistasis and its application in Chlamydomonas. Genetics. 1997 Mar;145(3):815–819. doi: 10.1093/genetics/145.3.815. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Genetics are provided here courtesy of Oxford University Press

RESOURCES