In finite populations, an allele disappears or reaches fixation due to two main forces, selection and drift. Selection is generally thought to accelerate the process: a selected mutation will reach ...fixation faster than a neutral one, and a disadvantageous one will quickly disappear from the population. We show that even in simple diploid populations, this is often not true. Dominance and recessivity unexpectedly slow down the evolutionary process for weakly selected alleles. In particular, slightly advantageous dominant and mildly deleterious recessive mutations reach fixation slightly more slowly than neutral ones (at most 5%). This phenomenon determines genetic signatures opposite to those expected under strong selection, such as increased instead of decreased genetic diversity around the selected site. Furthermore, we characterize a new phenomenon: mildly deleterious recessive alleles, thought to represent a wide fraction of newly arising mutations, on average survive in a population slightly longer than neutral ones, before getting lost. Consequently, these mutations are on average slightly older than neutral ones, in contrast with previous expectations. Furthermore, they slightly increase the amount of weakly deleterious polymorphisms, as a consequence of the longer unconditional sojourn times compared to neutral mutations.
Changes in gene expression levels determine differentiation of tissues involved in development and are associated with functional decline in aging. Although development is tightly regulated, the ...transition between development and aging, as well as regulation of post-developmental changes, are not well understood. Here, we measured messenger RNA (mRNA), microRNA (miRNA), and protein expression in the prefrontal cortex of humans and rhesus macaques over the species' life spans. We find that few gene expression changes are unique to aging. Instead, the vast majority of miRNA and gene expression changes that occur in aging represent reversals or extensions of developmental patterns. Surprisingly, many gene expression changes previously attributed to aging, such as down-regulation of neural genes, initiate in early childhood. Our results indicate that miRNA and transcription factors regulate not only developmental but also post-developmental expression changes, with a number of regulatory processes continuing throughout the entire life span. Differential evolutionary conservation of the corresponding genomic regions implies that these regulatory processes, although beneficial in development, might be detrimental in aging. These results suggest a direct link between developmental regulation and expression changes taking place in aging.
High-throughput direct sequencing techniques have recently opened the possibility to sequence genomes from Pleistocene organisms. Here we analyze DNA sequences determined from a Neandertal, a ...mammoth, and a cave bear. We show that purines are overrepresented at positions adjacent to the breaks in the ancient DNA, suggesting that depurination has contributed to its degradation. We furthermore show that substitutions resulting from miscoding cytosine residues are vastly overrepresented in the DNA sequences and drastically clustered in the ends of the molecules, whereas other substitutions are rare. We present a model where the observed substitution patterns are used to estimate the rate of deamination of cytosine residues in single- and double-stranded portions of the DNA, the length of single-stranded ends, and the frequency of nicks. The results suggest that reliable genome sequences can be obtained from Pleistocene organisms.
To mitigate the COVID-19 pandemic, countries worldwide have enacted unprecedented movement restrictions, physical distancing measures, and face mask requirements. Until safe and efficacious vaccines ...or antiviral drugs become widely available, viral testing remains the primary mitigation measure for rapid identification and isolation of infected individuals. We aimed to assess the economic trade-offs of expanding and accelerating testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) across the USA in different transmission scenarios.
We used a multiscale model that incorporates SARS-CoV-2 transmission at the population level and daily viral load dynamics at the individual level to assess eight surveillance testing strategies that varied by testing frequency (from daily to monthly testing) and isolation period (1 or 2 weeks), compared with the status-quo strategy of symptom-based testing and isolation. For each testing strategy, we first estimated the costs (incorporating costs of diagnostic testing and admissions to hospital, and salary lost while in isolation) and years of life lost (YLLs) prevented under rapid and low transmission scenarios. We then assessed the testing strategies across a range of scenarios, each defined by effective reproduction number (Re), willingness to pay per YLL averted, and cost of a test, to estimate the probability that a particular strategy had the greatest net benefit. Additionally, for a range of transmission scenarios (Re from 1·1 to 3), we estimated a threshold test price at which the status-quo strategy outperforms all testing strategies considered.
Our modelling showed that daily testing combined with a 2-week isolation period was the most costly strategy considered, reflecting increased costs with greater test frequency and length of isolation period. Assuming a societal willingness to pay of US$100 000 per YLL averted and a price of $5 per test, the strategy most likely to be cost-effective under a rapid transmission scenario (Re of 2·2) is weekly testing followed by a 2-week isolation period subsequent to a positive test result. Under low transmission scenarios (Re of 1·2), monthly testing of the population followed by 1-week isolation rather than 2-week isolation is likely to be most cost-effective. Expanded surveillance testing is more likely to be cost-effective than the status-quo testing strategy if the price per test is less than $75 across all transmission rates considered.
Extensive expansion of SARS-CoV-2 testing programmes with more frequent and rapid tests across communities coupled with isolation of individuals with confirmed infection is essential for mitigating the COVID-19 pandemic. Furthermore, resources recouped from shortened isolation duration could be cost-effectively allocated to more frequent testing.
US National Institutes of Health, US Centers for Disease Control and Prevention, and Love, Tito's.
During rollout of coronavirus disease vaccination, policymakers have faced critical trade-offs. Using a mathematical model of transmission, we found that timing of vaccination rollout would be ...expected to have a substantially greater effect on mortality rate than risk-based prioritization and uptake and that prioritizing first doses over second doses may be lifesaving.
The determination of the chimpanzee genome sequence provides a means to study both structural and functional aspects of the evolution of the human genome. Here we compare humans and chimpanzees with ...respect to differences in expression levels and protein-coding sequences for genes active in brain, heart, liver, kidney, and testis. We find that the patterns of differences in gene expression and gene sequences are markedly similar. In particular, there is a gradation of selective constraints among the tissues so that the brain shows the least differences between the species whereas liver shows the most. Furthermore, expression levels as well as amino acid sequences of genes active in more tissues have diverged less between the species than have genes active in fewer tissues. In general, these patterns are consistent with a model of neutral evolution with negative selection. However, for X-chromosomal genes expressed in testis, patterns suggestive of positive selection on sequence changes as well as expression changes are seen. Furthermore, although genes expressed in the brain have changed less than have genes expressed in other tissues, in agreement with previous work we find that genes active in brain have accumulated more changes on the human than on the chimpanzee lineage.
Transcriptional neoteny in the human brain Somel, Mehmet; Franz, Henriette; Yan, Zheng ...
Proceedings of the National Academy of Sciences - PNAS,
04/2009, Volume:
106, Issue:
14
Journal Article
Peer reviewed
Open access
In development, timing is of the utmost importance, and the timing of developmental processes often changes as organisms evolve. In human evolution, developmental retardation, or neoteny, has been ...proposed as a possible mechanism that contributed to the rise of many human-specific features, including an increase in brain size and the emergence of human-specific cognitive traits. We analyzed mRNA expression in the prefrontal cortex of humans, chimpanzees, and rhesus macaques to determine whether human-specific neotenic changes are present at the gene expression level. We show that the brain transcriptome is dramatically remodeled during postnatal development and that developmental changes in the human brain are indeed delayed relative to other primates. This delay is not uniform across the human transcriptome but affects a specific subset of genes that play a potential role in neural development.
Colleges and universities in the US struggled to provide safe in-person education throughout the COVID-19 pandemic. Testing coupled with isolation is a nimble intervention strategy that can be ...tailored to mitigate the changing health and economic risks associated with SARS-CoV-2. We developed a decision-support tool to aid in the design of university-based screening strategies using a mathematical model of SARS-CoV-2 transmission. Applying this framework to a large public university reopening in the fall of 2021 with a 60% student vaccination rate, we find that the optimal strategy, in terms of health and economic costs, is twice weekly antigen testing of all students. This strategy provides a 95% guarantee that, throughout the fall semester, case counts would not exceed twice the CDC's original high transmission threshold of 100 cases per 100k persons over 7 days. As the virus and our medical armament continue to evolve, testing will remain a flexible tool for managing risks and keeping campuses open. We have implemented this model as an online tool to facilitate the design of testing strategies that adjust for COVID-19 conditions as well as campus-specific populations, resources, and priorities.
The fitness value of information Donaldson-Matasci, Matina C.; Bergstrom, Carl T.; Lachmann, Michael
Oikos,
02/2010, Volume:
119, Issue:
2
Journal Article
Peer reviewed
Open access
Communication and information are central concepts in evolutionary biology. In fact, it is hard to find an area of biology where these concepts are not used. However, quantifying the information ...transferred in biological interactions has been difficult. How much information is transferred when the first spring rainfall hits a dormant seed, or when a chick begs for food from its parent? One measure that is commonly used in such cases is fitness value: by how much, on average, an individual's fitness would increase if it behaved optimally with the new information, compared to its average fitness without the information. Another measure, often used to describe neural responses to sensory stimuli, is the mutual information – a measure of reduction in uncertainty, as introduced by Shannon in communication theory. However, mutual information has generally not been considered to be an appropriate measure for describing developmental or behavioral responses at the organismal level, because it is blind to function; it does not distinguish between relevant and irrelevant information. In this paper we show that there is in fact a surprisingly tight connection between these two measures in the important context of evolution in an uncertain environment. In this case, a useful measure of fitness benefit is the increase in the long-term growth rate, or the fold increase in number of surviving lineages. We show that in many cases the fitness value of a developmental cue, when measured this way, is exactly equal to the reduction in uncertainty about the environment, as described by the mutual information.
In response to COVID-19, schools across the United States closed in early 2020; many did not fully reopen until late 2021. Although regular testing of asymptomatic students, teachers, and staff can ...reduce transmission risks, few school systems consistently used proactive testing to safeguard return to classrooms. Socioeconomically diverse public school districts might vary testing levels across campuses to ensure fair, effective use of limited resources. We describe a test allocation approach to reduce overall infections and disparities across school districts. Using a model of SARS-CoV-2 transmission in schools fit to data from a large metropolitan school district in Texas, we reduced incidence between the highest and lowest risk schools from a 5.6-fold difference under proportional test allocation to 1.8-fold difference under our optimized test allocation. This approach provides a roadmap to help school districts deploy proactive testing and mitigate risks of future SARS-CoV-2 variants and other pathogen threats.
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