Assembly theory explains and quantifies selection and evolution.

Scientists have grappled with reconciling biological evolution1,2 with the immutable laws of the Universe defined by physics. These laws underpin life's origin, evolution and the development of human culture and technology, yet they do not predict the emergence of these phenomena. Evolutionary theory explains why some things exist and others do not through the lens of selection. To comprehend how diverse, open-ended forms can emerge from physics without an inherent design blueprint, a new approach to understanding and quantifying selection is necessary3-5. We present assembly theory (AT) as a framework that does not alter the laws of physics, but redefines the concept of an 'object' on which these laws act. AT conceptualizes objects not as point particles, but as entities defined by their possible formation histories. This allows objects to show evidence of selection, within well-defined boundaries of individuals or selected units. We introduce a measure called assembly (A), capturing the degree of causation required to produce a given ensemble of objects. This approach enables us to incorporate novelty generation and selection into the physics of complex objects. It explains how these objects can be characterized through a forward dynamical process considering their assembly. By reimagining the concept of matter within assembly spaces, AT provides a powerful interface between physics and biology. It discloses a new aspect of physics emerging at the chemical scale, whereby history and causal contingency influence what exists.

The effectiveness of COVID-19 testing and contact tracing in a US city.

Although testing, contact tracing, and case isolation programs can mitigate COVID-19 transmission and allow the relaxation of social distancing measures, few countries worldwide have succeeded in scaling such efforts to levels that suppress spread. The efficacy of test-trace-isolate likely depends on the speed and extent of follow-up and the prevalence of SARS-CoV-2 in the community. Here, we use a granular model of COVID-19 transmission to estimate the public health impacts of test-trace-isolate programs across a range of programmatic and epidemiological scenarios, based on testing and contact tracing data collected on a university campus and surrounding community in Austin, TX, between October 1, 2020, and January 1, 2021. The median time between specimen collection from a symptomatic case and quarantine of a traced contact was 2 days (interquartile range [IQR]: 2 to 3) on campus and 5 days (IQR: 3 to 8) in the community. Assuming a reproduction number of 1.2, we found that detection of 40% of all symptomatic cases followed by isolation is expected to avert 39% (IQR: 30% to 45%) of COVID-19 cases. Contact tracing is expected to increase the cases averted to 53% (IQR: 42% to 58%) or 40% (32% to 47%), assuming the 2- and 5-day delays estimated on campus and in the community, respectively. In a tracing-accelerated scenario, in which 75% of contacts are notified the day after specimen collection, cases averted increase to 68% (IQR: 55% to 72%). An accelerated contact tracing program leveraging rapid testing and electronic reporting of test results can significantly curtail local COVID-19 transmission.

Real-time pandemic surveillance using hospital admissions and mobility data.

Forecasting the burden of COVID-19 has been impeded by limitations in data, with case reporting biased by testing practices, death counts lagging far behind infections, and hospital census reflecting time-varying patient access, admission criteria, and demographics. Here, we show that hospital admissions coupled with mobility data can reliably predict severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission rates and healthcare demand. Using a forecasting model that has guided mitigation policies in Austin, TX, we estimate that the local reproduction number had an initial 7-d average of 5.8 (95% credible interval [CrI]: 3.6 to 7.9) and reached a low of 0.65 (95% CrI: 0.52 to 0.77) after the summer 2020 surge. Estimated case detection rates ranged from 17.2% (95% CrI: 11.8 to 22.1%) at the outset to a high of 70% (95% CrI: 64 to 80%) in January 2021, and infection prevalence remained above 0.1% between April 2020 and March 1, 2021, peaking at 0.8% (0.7-0.9%) in early January 2021. As precautionary behaviors increased safety in public spaces, the relationship between mobility and transmission weakened. We estimate that mobility-associated transmission was 62% (95% CrI: 52 to 68%) lower in February 2021 compared to March 2020. In a retrospective comparison, the 95% CrIs of our 1, 2, and 3 wk ahead forecasts contained 93.6%, 89.9%, and 87.7% of reported data, respectively. Developed by a task force including scientists, public health officials, policy makers, and hospital executives, this model can reliably project COVID-19 healthcare needs in US cities.

Evaluation of individual and ensemble probabilistic forecasts of COVID-19 mortality in the United States.

Short-term probabilistic forecasts of the trajectory of the COVID-19 pandemic in the United States have served as a visible and important communication channel between the scientific modeling community and both the general public and decision-makers. Forecasting models provide specific, quantitative, and evaluable predictions that inform short-term decisions such as healthcare staffing needs, school closures, and allocation of medical supplies. Starting in April 2020, the US COVID-19 Forecast Hub (https://covid19forecasthub.org/) collected, disseminated, and synthesized tens of millions of specific predictions from more than 90 different academic, industry, and independent research groups. A multimodel ensemble forecast that combined predictions from dozens of groups every week provided the most consistently accurate probabilistic forecasts of incident deaths due to COVID-19 at the state and national level from April 2020 through October 2021. The performance of 27 individual models that submitted complete forecasts of COVID-19 deaths consistently throughout this year showed high variability in forecast skill across time, geospatial units, and forecast horizons. Two-thirds of the models evaluated showed better accuracy than a naïve baseline model. Forecast accuracy degraded as models made predictions further into the future, with probabilistic error at a 20-wk horizon three to five times larger than when predicting at a 1-wk horizon. This project underscores the role that collaboration and active coordination between governmental public-health agencies, academic modeling teams, and industry partners can play in developing modern modeling capabilities to support local, state, and federal response to outbreaks.

Optimizing COVID-19 testing strategies on college campuses: Evaluation of the health and economic costs.

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.

Disproportionate impacts of COVID-19 in a large US city.

COVID-19 has disproportionately impacted individuals depending on where they live and work, and based on their race, ethnicity, and socioeconomic status. Studies have documented catastrophic disparities at critical points throughout the pandemic, but have not yet systematically tracked their severity through time. Using anonymized hospitalization data from March 11, 2020 to June 1, 2021 and fine-grain infection hospitalization rates, we estimate the time-varying burden of COVID-19 by age group and ZIP code in Austin, Texas. During this 15-month period, we estimate an overall 23.7% (95% CrI: 22.5-24.8%) infection rate and 29.4% (95% CrI: 28.0-31.0%) case reporting rate. Individuals over 65 were less likely to be infected than younger age groups (11.2% [95% CrI: 10.3-12.0%] vs 25.1% [95% CrI: 23.7-26.4%]), but more likely to be hospitalized (1,965 per 100,000 vs 376 per 100,000) and have their infections reported (53% [95% CrI: 49-57%] vs 28% [95% CrI: 27-30%]). We used a mixed effect poisson regression model to estimate disparities in infection and reporting rates as a function of social vulnerability. We compared ZIP codes ranking in the 75th percentile of vulnerability to those in the 25th percentile, and found that the more vulnerable communities had 2.5 (95% CrI: 2.0-3.0) times the infection rate and only 70% (95% CrI: 60%-82%) the reporting rate compared to the less vulnerable communities. Inequality persisted but declined significantly over the 15-month study period. Our results suggest that further public health efforts are needed to mitigate local COVID-19 disparities and that the CDC's social vulnerability index may serve as a reliable predictor of risk on a local scale when surveillance data are limited.

COVID-19 Test Allocation Strategy to Mitigate SARS-CoV-2 Infections across School Districts.

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.

Effects of COVID-19 Vaccination Timing and Risk Prioritization on Mortality Rates, United States.

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.

Real-Time Projections of SARS-CoV-2 B.1.1.7 Variant in a University Setting, Texas, USA.

We used the incidence of spike gene target failures identified during PCR testing to provide an early projection of the prevalence of severe acute respiratory syndrome coronavirus 2 variant B.1.1.7 in a university setting in Texas, USA, before sequencing results were available. Findings from a more recent evaluation validated those early projections.

On the fitness of informative cues in complex environments.

To be able to deal with uncertainty is of primary importance to most living organisms. When cues provide information about the state of the environment, organisms can use them to respond flexibly. Life forms have evolved complex adaptations and sensory mechanisms to use these environmental cues and extract valuable information about the environment. Previous work has shown a theoretical limit to the amount of fitness benefit possible to be extracted from the cues. We show that the previously used information theoretical approaches can be generalised to scenarios involving any potential relationship between the number of possible phenotypes and environmental states. Such cases are relevant when physiological constraints or complex ecological scenarios lead to the number of environmental states exceeding potential phenotypes. We illustrate cases in which these scenarios can emerge: along environmental gradients, such as geographical transects or complex environments, where organisms adopt different bet-hedging strategies, switching stochastically between phenotypes or developing intermediate ones. In conclusion, we develop an information-theoretic extensible approach for investigating and quantifying fitness in ecological studies.

Genome sequence of a 45,000-year-old modern human from western Siberia.

We present the high-quality genome sequence of a ∼45,000-year-old modern human male from Siberia. This individual derives from a population that lived before-or simultaneously with-the separation of the populations in western and eastern Eurasia and carries a similar amount of Neanderthal ancestry as present-day Eurasians. However, the genomic segments of Neanderthal ancestry are substantially longer than those observed in present-day individuals, indicating that Neanderthal gene flow into the ancestors of this individual occurred 7,000-13,000 years before he lived. We estimate an autosomal mutation rate of 0.4 × 10(-9) to 0.6 × 10(-9) per site per year, a Y chromosomal mutation rate of 0.7 × 10(-9) to 0.9 × 10(-9) per site per year based on the additional substitutions that have occurred in present-day non-Africans compared to this genome, and a mitochondrial mutation rate of 1.8 × 10(-8) to 3.2 × 10(-8) per site per year based on the age of the bone.

The complete genome sequence of a Neanderthal from the Altai Mountains.

We present a high-quality genome sequence of a Neanderthal woman from Siberia. We show that her parents were related at the level of half-siblings and that mating among close relatives was common among her recent ancestors. We also sequenced the genome of a Neanderthal from the Caucasus to low coverage. An analysis of the relationships and population history of available archaic genomes and 25 present-day human genomes shows that several gene flow events occurred among Neanderthals, Denisovans and early modern humans, possibly including gene flow into Denisovans from an unknown archaic group. Thus, interbreeding, albeit of low magnitude, occurred among many hominin groups in the Late Pleistocene. In addition, the high-quality Neanderthal genome allows us to establish a definitive list of substitutions that became fixed in modern humans after their separation from the ancestors of Neanderthals and Denisovans.

Great ape genetic diversity and population history.

Most great ape genetic variation remains uncharacterized; however, its study is critical for understanding population history, recombination, selection and susceptibility to disease. Here we sequence to high coverage a total of 79 wild- and captive-born individuals representing all six great ape species and seven subspecies and report 88.8 million single nucleotide polymorphisms. Our analysis provides support for genetically distinct populations within each species, signals of gene flow, and the split of common chimpanzees into two distinct groups: Nigeria-Cameroon/western and central/eastern populations. We find extensive inbreeding in almost all wild populations, with eastern gorillas being the most extreme. Inferred effective population sizes have varied radically over time in different lineages and this appears to have a profound effect on the genetic diversity at, or close to, genes in almost all species. We discover and assign 1,982 loss-of-function variants throughout the human and great ape lineages, determining that the rate of gene loss has not been different in the human branch compared to other internal branches in the great ape phylogeny. This comprehensive catalogue of great ape genome diversity provides a framework for understanding evolution and a resource for more effective management of wild and captive great ape populations.

The bonobo genome compared with the chimpanzee and human genomes.

Two African apes are the closest living relatives of humans: the chimpanzee (Pan troglodytes) and the bonobo (Pan paniscus). Although they are similar in many respects, bonobos and chimpanzees differ strikingly in key social and sexual behaviours, and for some of these traits they show more similarity with humans than with each other. Here we report the sequencing and assembly of the bonobo genome to study its evolutionary relationship with the chimpanzee and human genomes. We find that more than three per cent of the human genome is more closely related to either the bonobo or the chimpanzee genome than these are to each other. These regions allow various aspects of the ancestry of the two ape species to be reconstructed. In addition, many of the regions that overlap genes may eventually help us understand the genetic basis of phenotypes that humans share with one of the two apes to the exclusion of the other.

Excess maternal transmission of variants in the THADA gene to offspring with type 2 diabetes.

AIMS/HYPOTHESIS: Genome-wide association studies (GWAS) have identified more than 65 genetic loci associated with risk of type 2 diabetes. However, the contribution of distorted parental transmission of alleles to risk of type 2 diabetes has been mostly unexplored. Our goal was therefore to search for parent-of-origin effects (POE) among type 2 diabetes loci in families. METHODS: Families from the Botnia study (n = 4,211, 1,083 families) were genotyped for 72 single-nucleotide polymorphisms (SNPs) associated with type 2 diabetes and assessed for POE on type 2 diabetes. The family-based Hungarian Transdanubian Biobank (HTB) (n = 1,463, >135 families) was used to replicate SNPs showing POE. Association of type 2 diabetes loci within families was also tested. RESULTS: Three loci showed nominal POE, including the previously reported variants in KCNQ1, for type 2 diabetes in families from Botnia (rs2237895: p POE = 0.037), which can be considered positive controls. The strongest POE was seen for rs7578597 SNP in the THADA gene, showing excess transmission of the maternal risk allele T to diabetic offspring (Botnia: p POE = 0.01; HTB p POE = 0.045). These data are consistent with previous evidence of allelic imbalance for expression in islets, suggesting that the THADA gene can be imprinted in a POE-specific fashion. Five CpG sites, including those flanking rs7578597, showed differential methylation between diabetic and non-diabetic donor islets. CONCLUSIONS/INTERPRETATION: Taken together, the data emphasise the need for genetic studies to consider from which parent an offspring has inherited a susceptibility allele.

Effectiveness of interventions to reduce COVID-19 transmission in schools.

School reopenings in 2021 and 2022 coincided with the rapid emergence of new SARS-CoV-2 variants in the United States. In-school mitigation efforts varied, depending on local COVID-19 mandates and resources. Using a stochastic age-stratified agent-based model of SARS-CoV-2 transmission, we estimate the impacts of multiple in-school strategies on both infection rates and absenteeism, relative to a baseline scenario in which only symptomatic cases are tested and positive tests trigger a 10-day isolation of the case and 10-day quarantine of their household and classroom. We find that monthly asymptomatic screening coupled with the 10-day isolation and quarantine period is expected to avert 55.4% of infections while increasing absenteeism by 104.3%. Replacing quarantine with test-to-stay would reduce absenteeism by 66.3% (while hardly impacting infection rates), but would require roughly 10-fold more testing resources. Alternatively, vaccination or mask wearing by 50% of the student body is expected to avert 54.1% or 43.1% of infections while decreasing absenteeism by 34.1% or 27.4%, respectively. Separating students into classrooms based on mask usage is expected to reduce infection risks among those who wear masks (by 23.1%), exacerbate risks among those who do not (by 27.8%), but have little impact on overall risk. A combined strategy of monthly screening, household and classroom quarantine, a 50% vaccination rate, and a 50% masking rate (in mixed classrooms) is expected to avert 81.7% of infections while increasing absenteeism by 90.6%. During future public health emergencies, such analyses can inform the rapid design of resource-constrained strategies that mitigate both public health and educational risks.

Inferring the history of population size change from genome-wide SNP data.

Dense, genome-wide single-nucleotide polymorphism (SNP) data can be used to reconstruct the demographic history of human populations. However, demographic inferences from such data are complicated by recombination and ascertainment bias. We introduce two new statistics, allele frequency-identity by descent (AF-IBD) and allele frequency-identity by state (AF-IBS), that make use of linkage disequilibrium information and show defined relationships to the time of coalescence. These statistics, when conditioned on the derived allele frequency, are able to infer complex population size changes. Moreover, the AF-IBS statistic, which is based on genome-wide SNP data, is robust to varying ascertainment conditions. We constructed an efficient approximate Bayesian computation (ABC) pipeline based on AF-IBD and AF-IBS that can accurately estimate demographic parameters, even for fairly complex models. Finally, we applied this ABC approach to genome-wide SNP data and inferred the demographic histories of two human populations, Yoruba and French. Our results suggest a rather stable ancestral population size with a mild recent expansion for Yoruba, whereas the French seemingly experienced a long-lasting severe bottleneck followed by a drastic population growth. This approach should prove useful for new insights into populations, especially those with complex demographic histories.

The Neandertal genome and ancient DNA authenticity.

Recent advances in high-thoughput DNA sequencing have made genome-scale analyses of genomes of extinct organisms possible. With these new opportunities come new difficulties in assessing the authenticity of the DNA sequences retrieved. We discuss how these difficulties can be addressed, particularly with regard to analyses of the Neandertal genome. We argue that only direct assays of DNA sequence positions in which Neandertals differ from all contemporary humans can serve as a reliable means to estimate human contamination. Indirect measures, such as the extent of DNA fragmentation, nucleotide misincorporations, or comparison of derived allele frequencies in different fragment size classes, are unreliable. Fortunately, interim approaches based on mtDNA differences between Neandertals and current humans, detection of male contamination through Y chromosomal sequences, and repeated sequencing from the same fossil to detect autosomal contamination allow initial large-scale sequencing of Neandertal genomes. This will result in the discovery of fixed differences in the nuclear genome between Neandertals and current humans that can serve as future direct assays for contamination. For analyses of other fossil hominins, which may become possible in the future, we suggest a similar 'boot-strap' approach in which interim approaches are applied until sufficient data for more definitive direct assays are acquired.

When unreliable cues are good enough.

In many species, nongenetic phenotypic variation helps mitigate risk associated with an uncertain environment. In some cases, developmental cues can be used to match phenotype to environment-a strategy known as predictive plasticity. When environmental conditions are entirely unpredictable, generating random phenotypic diversity may improve the long-term success of a lineage-a strategy known as diversified bet hedging. When partially reliable information is available, a well-adapted developmental strategy may strike a balance between the two strategies. We use information theory to analyze a model of development in an uncertain environment, where cue reliability is affected by variation both within and between generations. We show that within-generation variation in cues decreases the reliability of cues without affecting their fitness value. This transpires because the optimal balance of predictive plasticity and diversified bet hedging is unchanged. However, within-generation variation in cues does change the developmental mechanisms used to create that balance: developmental sensitivity to such cues not only helps match phenotype to environment but also creates phenotypic diversity that may be useful for hedging bets against environmental change. Understanding the adaptive role of developmental sensitivity thus depends on a proper assessment of both the predictive power and the structure of variation in environmental cues.

MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain.

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.