Historical contingency and entrenchment in protein evolution under purifying selection

The fitness contribution of an allele at one genetic site may depend on alleles at other sites, a phenomenon known as epistasis. Epistasis can profoundly influence the process of evolution in populations under selection, and can shape the course of protein evolution across divergent species. Whereas epistasis between adaptive substitutions has been the subject of extensive study, relatively little is known about epistasis under purifying selection. Here we use mechanistic models of thermodynamic stability in a ligand-binding protein to explore the structure of epistatic interactions between substitutions that fix in protein sequences under purifying selection. We find that the selection coefficients of mutations that are nearly-neutral when they fix are highly contingent on the presence of preceding mutations. Conversely, mutations that are nearly-neutral when they fix are subsequently entrenched due to epistasis with later substitutions. Our evolutionary model includes insertions and deletions, as well as point mutations, and so it allows us to quantify epistasis within each of these classes of mutations, and also to study the evolution of protein length. We find that protein length remains largely constant over time, because indels are more deleterious than point mutations. Our results imply that, even under purifying selection, protein sequence evolution is highly contingent on history and so it cannot be predicted by the phenotypic effects of mutations assayed in the wild-type sequence.Comment: 42 pages, 13 figure

The inevitability of unconditionally deleterious substitutions during adaptation

Studies on the genetics of adaptation typically neglect the possibility that a deleterious mutation might fix. Nonetheless, here we show that, in many regimes, the first substitution is most often deleterious, even when fitness is expected to increase in the long term. In particular, we prove that this phenomenon occurs under weak mutation for any house-of-cards model with an equilibrium distribution. We find that the same qualitative results hold under Fisher's geometric model. We also provide a simple intuition for the surprising prevalence of unconditionally deleterious substitutions during early adaptation. Importantly, the phenomenon we describe occurs on fitness landscapes without any local maxima and is therefore distinct from "valley-crossing". Our results imply that the common practice of ignoring deleterious substitutions leads to qualitatively incorrect predictions in many regimes. Our results also have implications for the substitution process at equilibrium and for the response to a sudden decrease in population size.Comment: Corrected typos and minor errors in Supporting Informatio

Foreign direct investment and U.S. national security: CFIUS under the Obama Administration

The Committee on Foreign Investment in the United States review process slowed during the inaugural year of the Obama Administration. The authors examine the origins of this shift and suggest actions that parties can take to facilitate the process

外国投资与美国国家安全：奥巴马政府下的CFIUS

美国对外投资部门的审批速度，在奥巴马政府就职年中放缓。作者研究了这种转变的原因并建议各方能够采取行动来加速这一进程

Foreign direct investment and U.S. national security: CFIUS under the Obama Administration

The Committee on Foreign Investment in the United States review process slowed during the inaugural year of the Obama Administration. The authors examine the origins of this shift and suggest actions that parties can take to facilitate the process

The Revised National Security Review Process for FDI in the US

This perspective explains the new regulations governing the US government's national security review process for foreign mergers and acquisitions of US businesses which became effective December 22, 2008

经修订的有关外国在美国直接投资的国家安全审查程序

2008年12月22日，规定美国政府对外国并购美国企业进行国家安全审查程序的新规则生效。这是修改和加强美国外国投资委员会（CFIUS） 审查的漫长努力的最后一步