Why Time Matters: Codon Evolution and the Temporal Dynamics of dN/dS

Mugal, Carina F.; Wolf, Jochen B. W.; Kaj, Ingemar

doi:10.1093/molbev/mst192

Cited by 121 publications

(137 citation statements)

References 38 publications

(72 reference statements)

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“…Because statistical measures of metapopulation structure can be affected by selection as well as migration dynamics, an unrestricted branch site random-effects model, referred to as BUSTED (Branch-Site Unrestricted Statistical Test for Episodic Diversification; implemented in the datamonkey webserver http://datamonkey.org), was used to test for gene-wide episodic diversifying selection (47). The analysis was restricted to only internal branches, which are assumed to capture at least one round of virus replication, to mitigate the biasing effects of transient deleterious mutations on the ratio of nonsynonymous to synonymous substitution rates estimates along terminal branches, where selection has not had time to fully filter such population level variation (48,49).…”

Section: Methodsmentioning

confidence: 99%

Evolution of Neuroadaptation in the Periphery and Purifying Selection in the Brain Contribute to Compartmentalization of Simian Immunodeficiency Virus (SIV) in the Brains of Rhesus Macaques with SIV-Associated Encephalitis

Rife

Nolan

Lamers³

et al. 2016

J Virol

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The emergence of a distinct subpopulation of human or simian immunodeficiency virus (HIV/SIV) sequences within the brain (compartmentalization) during infection is hypothesized to be linked to AIDS-related central nervous system (CNS) neuropathology. However, the exact evolutionary mechanism responsible for HIV/SIV brain compartmentalization has not been thoroughly investigated. Using extensive viral sampling from several different peripheral tissues and cell types and from three distinct regions within the brain from two well-characterized rhesus macaque models of the neurological complications of HIV infection (neuroAIDS), we have been able to perform in-depth evolutionary analyses that have been unattainable in HIV-infected subjects. The results indicate that, despite multiple introductions of virus into the brain over the course of infection, brain sequence compartmentalization in macaques with SIV-associated CNS neuropathology likely results from late viral entry of virus that has acquired through evolution in the periphery sufficient adaptation for the distinct microenvironment of the CNS. IMPORTANCEHIV-associated neurocognitive disorders remain prevalent among HIV type 1-infected individuals, whereas our understanding of the critical components of disease pathogenesis, such as virus evolution and adaptation, remains limited. Building upon earlier findings of specific viral subpopulations in the brain, we present novel yet fundamental results concerning the evolutionary patterns driving this phenomenon in two well-characterized animal models of neuroAIDS and provide insight into the timing of entry of virus into the brain and selective pressure associated with viral adaptation to this particular microenvironment. Such knowledge is invaluable for therapeutic strategies designed to slow or even prevent neurocognitive impairment associated with AIDS. Human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders (HAND) remain a persistent complication despite the success of highly active antiretroviral therapy (HAART) in prolonging the progression to AIDS in HIV-1-infected patients (1). Although the post-HAART era has witnessed a decrease in the prevalence of the most severe form of HAND, HIV-associated dementia (HAD), an increase in prevalence has been observed for the milder forms, referred to as asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND) (2, 3). Moreover, these assessments have been reported to be an underestimation of the true prevalence, based on a study in which approximately 64% of HIV-1-infected patients classified as "noncomplainers," self-reporting no symptoms of cognitive impairment, tested positive for HAND using comprehensive neurocognitive testing criteria (4). Furthermore, with the life expectancy for patients receiving HAART now projected to be greater than 70 years (5, 6), the reported prevalence estimations can only be expected to increase, whereas our understanding of the critical components of disease pathogenesis, such as t...

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Section: Methodsmentioning

confidence: 99%

Evolution of Neuroadaptation in the Periphery and Purifying Selection in the Brain Contribute to Compartmentalization of Simian Immunodeficiency Virus (SIV) in the Brains of Rhesus Macaques with SIV-Associated Encephalitis

Rife

Nolan

Lamers³

et al. 2016

J Virol

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“…In summary, the combination of high diversity in a structured population and a close outgroup has allowed us to study evolution on a variety of timescales spanning distances from 0.1 to 10% and revealed a consistent decreasing trend in the ratio of nonsynonymous to synonymous mutations (Rocha et al 2006;Mugal et al 2014). This trend implies an abundance of weakly deleterious mutations-at least when their effect is averaged over larger and larger timescales.…”

Section: Discussionmentioning

confidence: 88%

“…Note that as we go from comparisons of strains within one clade to interclade comparisons and eventually to interspecies comparisons, the interpretation of d ns /d si gradually changes from p N /p S to d N / d S . For a more in-depth discussion of time-dependent d N /d S , see Rocha et al (2006) and Mugal et al (2014).…”

Section: Deleterious Variants At High Frequenciesmentioning

confidence: 99%

Characterization of Genetic Diversity in the Nematode Pristionchus pacificus from Population-Scale Resequencing Data

et al. 2014

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The hermaphroditic nematode Pristionchus pacificus is an established model system for comparative studies with Caenorhabditis elegans in developmental biology, ecology, and population genetics. In this study, we present whole-genome sequencing data of 104 P. pacificus strains and the draft assembly of the obligate outcrossing sister species P. exspectatus. We characterize genetic diversity within P. pacificus and investigate the population genetic processes shaping this diversity. P. pacificus is 10 times more diverse than C. elegans and exhibits substantial population structure that allows us to probe its evolution on multiple timescales. Consistent with reduced effective recombination in this self-fertilizing species, we find haplotype blocks that span several megabases. Using the P. exspectatus genome as an outgroup, we polarized variation in P. pacificus and found a site frequency spectrum (SFS) that decays more rapidly than expected in neutral models. The SFS at putatively neutral sites is U shaped, which is a characteristic feature of pervasive linked selection. Based on the additional findings (i) that the majority of nonsynonymous variation is eliminated over timescales on the order of the separation between clades, (ii) that diversity is reduced in gene-rich regions, and (iii) that highly differentiated clades show very similar patterns of diversity, we conclude that purifying selection on many mutations with weak effects is a major force shaping genetic diversity in P. pacificus.

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“…We tested whether differences in the selection constraints during the divergence of testisexclusive genes could explain their increased number of deleterious mutations. dN/dS analysis is a well-established measure of protein divergence, specifically between distant lineages with high dN/dS ratios (41) indicating fast protein divergence, likely due to positive or relaxed selection constraints 32,33 . Thus, significant differences in dN/dS ratios of genes might indicate differences in their selection constraints.…”

Section: Resultsmentioning

confidence: 99%

Reduced selection and accumulation of deleterious mutations in genes exclusively expressed in men

Gershoni

Pietrokovski

2014

Nat Commun

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Sex-limited selection can moderate the elimination of deleterious mutations from the population and contribute to the high prevalence of common human diseases. Accordingly, deleterious mutations in autosomal genes that are exclusively expressed in only one of the sexes undergo sex-limited selection and can reach higher frequencies than mutations similarly selected in both sexes. Here we show that the number of deleterious SNPs in genes exclusively expressed in men is twofold higher than in genes that are selected in both sexes. Additional analyses suggest that the increased number of damaging mutations we found in male-specific genes is due to reduced selection in females. These results are noteworthy since many of these male-specific genes are known to be crucial for male reproduction, and are thus likely to be under strong purifying selection. We suggest that inheritance of male-infertility-causative mutations through unaffected female lineages contributes to the high incidence of male infertility.

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Why Time Matters: Codon Evolution and the Temporal Dynamics of dN/dS

Cited by 121 publications

References 38 publications

Evolution of Neuroadaptation in the Periphery and Purifying Selection in the Brain Contribute to Compartmentalization of Simian Immunodeficiency Virus (SIV) in the Brains of Rhesus Macaques with SIV-Associated Encephalitis

Evolution of Neuroadaptation in the Periphery and Purifying Selection in the Brain Contribute to Compartmentalization of Simian Immunodeficiency Virus (SIV) in the Brains of Rhesus Macaques with SIV-Associated Encephalitis

Characterization of Genetic Diversity in the Nematode Pristionchus pacificus from Population-Scale Resequencing Data

Reduced selection and accumulation of deleterious mutations in genes exclusively expressed in men

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