Coupling high-throughput genetics with phylogenetic information reveals an epistatic interaction on the influenza A virus M segment

BMC Genomics

Methodology Article

Arthur P. Young¹  Ting-Ting Wu¹  Yushen Du¹  Ren Sun¹  Tian-Hao Zhang¹  Yuanyuan Wang¹  Shuai Le²  Nicholas C. Wu³  Jian Zhou⁴  Janice M. Yoshizawa⁴  Ling Dong⁴  Xinmin Li⁴ 

[1] Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, 90095, Los Angeles, CA, USA;Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, 90095, Los Angeles, CA, USA;Department of Microbiology, Third Military Medical University, 400038, Chongqing, China;Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, 90095, Los Angeles, CA, USA;Molecular Biology InstituteUniversity of California, 90095, Los Angeles, CA, USA;Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 92037, La Jolla, CA, USA;Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, 90095, Los Angeles, CA, USA;

关键词: Mutagenesis;    Fitness profiling;    Natural sequence variation;    Coevolution analysis;    Compensatory mutation;   

DOI  :  10.1186/s12864-015-2358-7

 received in 2015-07-17, accepted in 2015-12-28,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundEpistasis is one of the central themes in viral evolution due to its importance in drug resistance, immune escape, and interspecies transmission. However, there is a lack of experimental approach to systematically probe for epistatic residues.ResultsBy utilizing the information from natural occurring sequences and high-throughput genetics, this study established a novel strategy to identify epistatic residues. The rationale is that a substitution that is deleterious in one strain may be prevalent in nature due to the presence of a naturally occurring compensatory substitution. Here, high-throughput genetics was applied to influenza A virus M segment to systematically identify deleterious substitutions. Comparison with natural sequence variation showed that a deleterious substitution M1 Q214H was prevalent in circulating strains. A coevolution analysis was then performed and indicated that M1 residues 121, 207, 209, and 214 naturally coevolved as a group. Subsequently, we experimentally validated that M1 A209T was a compensatory substitution for M1 Q214H.ConclusionsThis work provided a proof-of-concept to identify epistatic residues by coupling high-throughput genetics with phylogenetic information. In particular, we were able to identify an epistatic interaction between M1 substitutions A209T and Q214H. This analytic strategy can potentially be adapted to study any protein of interest, provided that the information on natural sequence variants is available.

【 授权许可】

CC BY   
© Wu et al. 2016