640 research outputs found
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
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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
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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
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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
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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
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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
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