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Demographic bottlenecks generally reduce genetic diversity through more intense genetic drift, but their net effect may vary along the genome due to the random nature of genetic drift and to local effects of recombination, mutation, and selection. Here, we analyzed the changes in genetic diversity following a bottleneck by comparing whole-genome diversity patterns in populations with and without severe recent documented declines of Iberian (Lynx pardinus, n = 31) and Eurasian lynx (Lynx lynx, n = 29). As expected, overall genomic diversity correlated negatively with bottleneck intensity and/or duration. Correlations of genetic diversity with divergence, chromosome size, gene or functional site content, GC content, or recombination were observed in nonbottlenecked populations, but were weaker in bottlenecked populations. Also, functional features under intense purifying selection and the X chromosome showed an increase in the observed density of variants, even resulting in higher θW diversity than in nonbottlenecked populations. Increased diversity seems to be related to both a higher mutational input in those regions creating a large collection of low-frequency variants, a few of which increase in frequency during the bottleneck to the point they become detectable with our limited sample, and the reduced efficacy of purifying selection, which affects not only protein structure and function but also the regulation of gene expression. The results of this study alert to the possible reduction of fitness and adaptive potential associated with the genomic erosion in regulatory elements. Further, the detection of a gain of diversity in ultra-conserved elements can be used as a sensitive and easy-to-apply signature of genetic erosion in wild populations.

Biotechnology has the potential to deliver solutions to many global problems in medicine, materials science, nutrition, agriculture, natural resource preservation, and energy. Engineered cells and enzymes can perform chemical transformations that are rare or unknown in nature, and even catalyze reactions not accessible to traditional synthetic chemistry while also operating at gentler, more environmentally friendly conditions. Decreases in the price of DNA sequencing and synthesis has led to generation of vast databases that can be screened for any imaginable function. These sequence databases are even more powerful now due to the development of software to enable rapid generation of 3D protein structures, like AlphaFold2. However, tools to predict the function of these proteins or their performance in engineered cells are not yet robust, leading to long development times and limited successful applications to date. New tools and methods must be developed for the true potential of biotechnology to be unlocked.For my thesis, I explore metabolic pathway construction and screening, protein design, and protein sequence-structure-function relationships across broad contexts with the objective of tool and knowledge development for future efforts in biotechnology. My first chapter discusses the introduction of the triazine degradation pathway, of interest for remediation of contaminated sites, into E. coli and methods for characterizing pathway flux and identifying bottlenecks to guide engineering efforts and limit accumulation of metabolic intermediates. My second chapter focuses on methods for the design of supercharged proteins, which have many interesting potential applications, and parameters that increase the likelihood of successful design of these proteins. My third chapter regards the generation and characterization of a library of single point mutations in the enzyme B-glucosidase B and use of kinetic data to predict the effects of changes in sequence on enzyme function. These seemingly disparate topics all serve to improve tools for protein screening, production, functional prediction, and application, addressing several gaps toward improved development timelines and success rates for biocatalysts.

Understanding of the present-day genetic diversity, population structure, and evolutionary history of tree species can inform resource management and conservation activities, including response to pressures presented by a changing climate. Cercis canadensis (Eastern Redbud) is an economically valuable understory tree species native to the United States (U.S.) that is also important for forest ecosystem and wildlife health. Here, we document and explain the population genetics and evolutionary history of this deciduous tree species across its distributed range. In this study, we used twelve microsatellite markers to investigate 691 wild-type trees sampled at 74 collection sites from 23 Eastern U.S. states. High genetic diversity and limited gene flow were revealed in wild, natural stands of C. canadensis with populations that are explained by two major genetic clusters. These findings indicate that an ancient population bottleneck occurred coinciding with the last glacial maximum (LGM) in North America. The structure in current populations likely originated from an ancient population in the eastern U.S. that survived LGM and then later diverged into two contemporary clusters. Data suggests that populations have expanded since the last glaciation event from one into several post-glacial refugia that now occupy this species’ current geographic range. Our enhanced understanding benchmarks the genetic variation preserved within this species and can direct future efforts in conservation, and resource utilization of adaptively resilient populations that present the greatest genetic and structural diversity.

With the rapid development of genetic analysis techniques and crop population size, phenotyping has become the bottleneck restricting crop breeding. Breaking through this bottleneck will require phenomics, defined as the accurate, high-throughput acquisition and analysis of multi-dimensional phenotypes during crop growth at organism-wide levels, ranging from cells to organs, individual plants, plots, and fields. Here we offer an overview of crop phenomics research from technological and platform viewpoints at various scales, including microscopic, ground-based, and aerial phenotyping and phenotypic data analysis. We describe recent applications of high-throughput phenotyping platforms for abiotic/biotic stress and yield assessment. Finally, we discuss current challenges and offer perspectives on future phenomics research.

Metabolic engineering is a key technology for cell factories construction by rewiring cellular resources to achieve efficient production of target chemicals. However, the existence of bottlenecks in synthetic pathway can seriously affect production efficiency, which is also one of the core issues for metabolic engineers to solve. Therefore, developing an approach for diagnosing potential metabolic bottlenecks in a faster and simpler manner is of great significance to accelerate cell factories construction. The cell-free reaction system based on cell lysates can transfer metabolic reactions from in vivo to in vitro, providing a flexible access to directly change protein and metabolite variables, thus provides a potential solution for rapid identification of bottlenecks. Here, bottleneck diagnosis of the N-acetylneuraminic acid (NeuAc) biosynthesis pathway in industrially important chassis microorganism Bacillus subtilis was performed using cell-free synthesis system. Specifically, a highly efficient B. subtilis cell-free system for NeuAc de novo synthesis was firstly constructed, which had a 305-fold NeuAc synthesis rate than that in vivo and enabled fast pathway dynamics analysis. Next, through the addition of all potential key intermediates in combination with substrate glucose respectively, it was found that insufficient phosphoenolpyruvate supply was one of the NeuAc pathway bottlenecks. Rational in vivo metabolic engineering of NeuAc-producing B. subtilis was further performed to eliminate the bottleneck. By down-regulating the expression level of pyruvate kinase throughout the growth phase or only in the stationary phase using inhibitory N-terminal coding sequences (NCSs) and growth-dependent regulatory NCSs respectively, the maximal NeuAc titer increased 2.0-fold. Our study provides a rapid method for bottleneck diagnosis, which may help to accelerate the cycle of design, build, test and learn cycle for metabolic engineering.

Significance Mitochondria frequently carry different DNA—a state called heteroplasmy. Heteroplasmic mutations can cause mitochondrial diseases and are involved in cancer and aging, but they are also common in healthy people. Here, we study heteroplasmy in 96 multigenerational healthy families. We show that mothers effectively transmit very few mitochondrial DNA to their offspring. Because of this bottleneck, which intensifies with increasing maternal age at childbirth, mutation frequencies can change dramatically between a mother and her child. Thus, a child might inherit a disease-causing mutation at high frequency from an asymptomatic carrier mother and might develop a disease. We also demonstrate that natural selection acts against disease-causing mutations during germline development. Our study has important implications for genetic counseling of mitochondrial diseases., Heteroplasmy—the presence of multiple mitochondrial DNA (mtDNA) haplotypes in an individual—can lead to numerous mitochondrial diseases. The presentation of such diseases depends on the frequency of the heteroplasmic variant in tissues, which, in turn, depends on the dynamics of mtDNA transmissions during germline and somatic development. Thus, understanding and predicting these dynamics between generations and within individuals is medically relevant. Here, we study patterns of heteroplasmy in 2 tissues from each of 345 humans in 96 multigenerational families, each with, at least, 2 siblings (a total of 249 mother–child transmissions). This experimental design has allowed us to estimate the timing of mtDNA mutations, drift, and selection with unprecedented precision. Our results are remarkably concordant between 2 complementary population-genetic approaches. We find evidence for a severe germline bottleneck (7–10 mtDNA segregating units) that occurs independently in different oocyte lineages from the same mother, while somatic bottlenecks are less severe. We demonstrate that divergence between mother and offspring increases with the mother’s age at childbirth, likely due to continued drift of heteroplasmy frequencies in oocytes under meiotic arrest. We show that this period is also accompanied by mutation accumulation leading to more de novo mutations in children born to older mothers. We show that heteroplasmic variants at intermediate frequencies can segregate for many generations in the human population, despite the strong germline bottleneck. We show that selection acts during germline development to keep the frequency of putatively deleterious variants from rising. Our findings have important applications for clinical genetics and genetic counseling.

Prochlorococcus are the most abundant photosynthetic organisms in the modern ocean. A massive DNA loss event occurred in their early evolutionary history, leading to highly reduced genomes in nearly all lineages, as well as enhanced efficiency in both nutrient uptake and light absorption. The environmental landscape that shaped this ancient genome reduction, however, remained unknown. Through careful molecular clock analyses, we established that this Prochlorococcus genome reduction occurred during the Neoproterozoic Snowball Earth climate catastrophe. The lethally low temperature and exceedingly dim light during the Snowball Earth event would have inhibited Prochlorococcus growth and proliferation, and caused severe population bottlenecks. These bottlenecks are recorded as an excess of deleterious mutations accumulated across genomic regions and inherited by descendant lineages. Prochlorococcus adaptation to extreme environmental conditions during Snowball Earth intervals can be inferred by tracing the evolutionary paths of genes that encode key metabolic potential. Key metabolic innovation includes modified lipopolysaccharide structure, strengthened peptidoglycan biosynthesis, the replacement of a sophisticated circadian clock with an hourglass-like mechanism that resets daily for dim light adaption and the adoption of ammonia diffusion as an efficient membrane transporter-independent mode of nitrogen acquisition. In this way, the Neoproterozoic Snowball Earth event may have altered the physiological characters of Prochlorococcus , shaping their ecologically vital role as the most abundant primary producers in the modern oceans.

Background Current patterns of population genetic variation may have been shaped by long-term evolutionary history and contemporary demographic processes. Understanding the underlying mechanisms that yield those patterns is crucial for informed conservation of endangered species. The critically endangered white-headed langur, Trachypithecus leucocephalus, is endemic to a narrow range in southwest China. This species shows very low genetic diversity in its 2 main relict populations, Fusui and Chongzuo. Whether this has been caused by a short evolutionary history or recent population declines is unknown. Therefore, we investigated the contributions of historical and recent population demographic changes to population genetic diversity by using 15 nuclear microsatellite markers and mitochondrial DNA (mtDNA) control region sequences. Results Using genetic data from 214 individuals we found a total of 9 mtDNA haplotypes in the Fusui population but only 1 haplotype in the Chongzuo population, and we found an overall low genetic diversity (haplotype and nucleotide diversities: h = 0.486 ± 0.036; π = 0.0028 ± 0.0003). The demographic history inferred from mtDNA and microsatellite markers revealed no evidence for historical population size fluctuations or recent population bottlenecks. Simulations of possible population divergence histories inferred by DIYABC analysis supported a recent divergence of the Chongzuo population from the Fusui population and no population bottlenecks. Conclusions Despite severe population declines caused by anthropogenic activities in the last century, the low genetic diversity of the extant white-headed langur populations is most likely primarily due to the species’ shallow evolutionary history and to a recent, local population founder event. Electronic supplementary material The online version of this article (10.1186/s12862-019-1451-y) contains supplementary material, which is available to authorized users.

Genetic bottlenecks can limit the success of populations colonizing new ranges. However, successful colonizations can occur despite bottlenecks, a phenomenon known as the genetic paradox of invasion. Eusocial Hymenoptera such as bumblebees (Bombusspp.) should be particularly vulnerable to genetic bottlenecks, since homozygosity at the sex-determining locus leads to costly diploid male production (DMP). The Tree Bumblebee (Bombus hypnorum) has rapidly colonized the UK since 2001 and has been highlighted as exemplifying the genetic paradox of invasion. Using microsatellite genotyping, combined with the first genetic estimates of DMP in UKB. hypnorum, we tested two alternative genetic hypotheses (‘bottleneck’ and ‘gene flow’ hypotheses) forB. hypnorum's colonization of the UK. We found that the UK population has not undergone a recent severe genetic bottleneck and exhibits levels of genetic diversity falling between those of widespread and range-restrictedBombusspecies. Diploid males occurred in 15.4% of reared colonies, leading to an estimate of 21.5 alleles at the sex-determining locus. Overall, the findings show that this population is not bottlenecked, instead suggesting that it is experiencing continued gene flow from the continental European source population with only moderate loss of genetic diversity, and does not exemplify the genetic paradox of invasion.

This paper chooses car travel and bus travel as the research objects, establishes a dual-mode equilibrium model based on the bottleneck model, and compares the travel characteristics of the no-toll and fine-toll schemes. We find that the fine-toll scheme can eliminate the queuing time at the bottleneck, but it also increases the congestion risk cost of bus travel. In order to eliminate the queuing time at the bottleneck and reduce the congestion risk cost of bus travel without increasing the car travel cost and bus travel cost, we propose an optimization scheme of fine toll and bus departure quantity and analyze its travel characteristics theoretically. Through the numerical example, we calculate and analyze the equilibrium results of no-toll scheme, fine-toll scheme, and optimization scheme of fine toll and bus departure quantity. The results indicate that the optimization scheme of fine toll and bus departure quantity can help travelers to choose a reasonable travel mode and travel time to travel in the rush hour.

Viral populations undergo a repeated cycle of within-host growth followed by transmission. Viral evolution is affected by each stage of this cycle. The number of viral particles transmitted from one host to another, known as the transmission bottleneck, is an important factor in determining how the evolutionary dynamics of the population play out, restricting the extent to which the evolved diversity of the population can be passed from one host to another. Previous study of viral sequence data has suggested that the transmission bottleneck size for influenza A transmission between human hosts is small. Reevaluating these data using a novel and improved method, we largely confirm this result, albeit that we infer a slightly higher bottleneck size in some cases, of between 1 and 13 virions. While a tight bottleneck operates in human influenza transmission, it is not extreme in nature; some diversity can be meaningfully retained between hosts., The transmission bottleneck is defined as the number of viral particles that transmit from one host to establish an infection in another. Genome sequence data have been used to evaluate the size of the transmission bottleneck between humans infected with the influenza virus; however, the methods used to make these estimates have some limitations. Specifically, viral allele frequencies, which form the basis of many calculations, may not fully capture a process which involves the transmission of entire viral genomes. Here, we set out a novel approach for inferring viral transmission bottlenecks; our method combines an algorithm for haplotype reconstruction with maximum likelihood methods for bottleneck inference. This approach allows for rapid calculation and performs well when applied to data from simulated transmission events; errors in the haplotype reconstruction step did not adversely affect inferences of the population bottleneck. Applied to data from a previous household transmission study of influenza A infection, we confirm the result that the majority of transmission events involve a small number of viruses, albeit with slightly looser bottlenecks being inferred, with between 1 and 13 particles transmitted in the majority of cases. While influenza A transmission involves a tight population bottleneck, the bottleneck is not so tight as to universally prevent the transmission of within-host viral diversity. IMPORTANCE Viral populations undergo a repeated cycle of within-host growth followed by transmission. Viral evolution is affected by each stage of this cycle. The number of viral particles transmitted from one host to another, known as the transmission bottleneck, is an important factor in determining how the evolutionary dynamics of the population play out, restricting the extent to which the evolved diversity of the population can be passed from one host to another. Previous study of viral sequence data has suggested that the transmission bottleneck size for influenza A transmission between human hosts is small. Reevaluating these data using a novel and improved method, we largely confirm this result, albeit that we infer a slightly higher bottleneck size in some cases, of between 1 and 13 virions. While a tight bottleneck operates in human influenza transmission, it is not extreme in nature; some diversity can be meaningfully retained between hosts.

If they undergo new mutations at each replication cycle, why are RNA viral genomes so fragile, with most mutations being either strongly deleterious or lethal? Here we provide theoretical and numerical evidence for the hypothesis that genetic fragility is partly an evolutionary response to the multiple population bottlenecks experienced by viral populations at various stages of their life cycles. Modelling within-host viral populations as multi-type branching processes, we show that mutational fragility lowers the rate at which Muller’s ratchet clicks and increases the survival probability through multiple bottlenecks. In the context of a susceptible-exposed-infectious-recovered epidemiological model, we find that the attack rate of fragile viral strains can exceed that of more robust strains, particularly at low infectivities and high mutation rates. Our findings highlight the importance of demographic events such as transmission bottlenecks in shaping the genetic architecture of viral pathogens., Funding for this work was provided by the Alexander von Humboldt Foundation in the framework of the Sofja Kovalevskaja Award endowed by the German Federal Ministry of Education and Research to M.S. Work in València was supported by Spain Agencia Estatal de Investigación - FEDER grant PID2019-103998GB-I00 and Generalitat Valenciana grant PROMETEO2019/012 to S.F.E.

Mixed infections provide opportunities for viruses to increase genetic diversity by facilitating genomic reassortment or recombination, and they may lead to the emergence of new virus species. Mixed infections of two economically important orthotospoviruses, Tomato spotted wilt orthotospovirus (TSWV) and Impatiens necrotic spot orthotospovirus (INSV), were found in recent years, but no natural reassortants between INSV and TSWV were ever reported. The goal of this study was to establish how vector preferences and the ability to transmit INSV and TSWV influence transmission and establishment of mixed infections. Our results demonstrate that thrips prefer to oviposit on TSWV and INSV mixed-infected plants over singly infected or healthy plants, providing young nymphs with the opportunity to acquire both viruses. Conversely, we observed that thrips served as a bottleneck during transmission and favored transmission of one of the two viruses over the second one, or over transmission of both viruses simultaneously. This constraint was relaxed in plants, when transmission of TSWV and INSV occurred sequentially, demonstrating that plants serve as orthotospovirus permissive hosts, while thrips serve as a bottleneck. Viral fitness, as measured by virus replication, transmission, and competition with other viral strains, is not well studied in mixed infection. Our study looks at the success of transmission during mixed infection of orthotopoviruses, enhancing the understanding of orthotospovirus epidemiology and evolution.

RNA viruses exist as populations of closely related genomes, characterized by a high diversity of low-frequency variants. As viral genomes from one population disperse to establish new sites of replication, the fate of these low-frequency variants depends to a large extent on the size of the founding population. Focusing on foot-and-mouth disease virus (FMDV) we conjecture that variants are more likely to be transmitted through wide bottlenecks, but more likely to approach fixation in new populations following narrow bottlenecks; therefore, the longer-term rate of accumulation of ‘nearly neutral’ variants at high frequencies is likely to be inversely related to the bottleneck size. We examine this conjecturein vivoby estimating bottleneck sizes relating ‘parent’ and ‘daughter’ populations observed at different scales ranging from within host to between host (within the same herd, and in different herds) using a previously established method. Within hosts, we find bottleneck sizes to range from 5 to 20 viral genomes between populations transmitted from the pharynx to the serum, and from 4 to 54 between serum and lesion populations. Between hosts, we find bottleneck sizes to range from 2 to 39, suggesting inter-host bottlenecks are of a similar size to intra-host bottlenecks. We establish a statistically significant negative relationship between the probability of genomic consensus level change and bottleneck size, and present a simple sampling model that captures this empirical relationship. We also present a novelin vitroexperiment to investigate the impact of bottleneck size on the frequency of mutations within FMDV populations, demonstrate that variant frequency in a population increases more rapidly during small population passages, and provide evidence for positive selection during the passage of large populations.

The bottleneck governing infectious disease transmission describes the size of the pathogen population transferred from the donor to the recipient host. Accurate quantification of the bottleneck size is particularly important for rapidly evolving pathogens such as influenza virus, as narrow bottlenecks reduce the amount of transferred viral genetic diversity and, thus, may decrease the rate of viral adaptation. Previous studies have estimated bottleneck sizes governing viral transmission by using statistical analyses of variants identified in pathogen sequencing data. These analyses, however, did not account for variant calling thresholds and stochastic viral replication dynamics within recipient hosts. Because these factors can skew bottleneck size estimates, we introduce a new method for inferring bottleneck sizes that accounts for these factors. Through the use of a simulated data set, we first show that our method, based on beta-binomial sampling, accurately recovers transmission bottleneck sizes, whereas other methods fail to do so. We then apply our method to a data set of influenza A virus (IAV) infections for which viral deep-sequencing data from transmission pairs are available. We find that the IAV transmission bottleneck size estimates in this study are highly variable across transmission pairs, while the mean bottleneck size of 196 virions is consistent with a previous estimate for this data set. Furthermore, regression analysis shows a positive association between estimated bottleneck size and donor infection severity, as measured by temperature. These results support findings from experimental transmission studies showing that bottleneck sizes across transmission events can be variable and influenced in part by epidemiological factors. IMPORTANCE The transmission bottleneck size describes the size of the pathogen population transferred from the donor to the recipient host and may affect the rate of pathogen adaptation within host populations. Recent advances in sequencing technology have enabled bottleneck size estimation from pathogen genetic data, although there is not yet a consistency in the statistical methods used. Here, we introduce a new approach to infer the bottleneck size that accounts for variant identification protocols and noise during pathogen replication. We show that failing to account for these factors leads to an underestimation of bottleneck sizes. We apply this method to an existing data set of human influenza virus infections, showing that transmission is governed by a loose, but highly variable, transmission bottleneck whose size is positively associated with the severity of infection of the donor. Beyond advancing our understanding of influenza virus transmission, we hope that this work will provide a standardized statistical approach for bottleneck size estimation for viral pathogens.

Forest loss and fragmentation are the main threats to the maintenance of the Atlantic Forest, an important global biodiversity hotspot. Because of the current critical level of deforestation, ecological corridors are needed to facilitate species dispersion and gene flow among fragments. This study was conducted to investigate the genetic variability and gene pool sharing of Eschweilera ovata in five forest remnants in southern Bahia, Brazil using nuclear simple sequence repeat (nSSR) and plastid simple sequence repeat (cpSSR) microsatellite markers. cpSSR marker analysis revealed the domains of four haplotypes, showing that 80% of the individuals had only four maternal origins, reflecting a founder effect and/or genetic bottleneck. The results of cpSSR and nSSR analyses indicated moderate genetic diversity, particularly in conservation units with full protection, which showed the best parameters of all areas evaluated. Another indication of the susceptibility of these populations to forest loss and fragmentation was the strong genetic bottleneck observed. In contrast, genetic structure analyses (FST and discriminant analysis of principal components) revealed gene pool sharing between the subpopulations, which may reflect the historical gene flow that occurred before forest fragmentation.

Cognitive control, with a limited capacity, is a core process in human cognition for the coordination of thoughts and actions. Although the regions involved in cognitive control have been identified as the cognitive control network (CCN), it is still unclear whether a specific region of the CCN serves as a bottleneck limiting the capacity of cognitive control (CCC). Here, we used a perceptual decision-making task with conditions of high cognitive load to challenge the CCN and to assess the CCC in a functional magnetic resonance imaging study. We found that the activation of the right anterior insular cortex (AIC) of the CCN increased monotonically as a function of cognitive load, reached its plateau early, and showed a significant correlation to the CCC. In a subsequent study of patients with unilateral lesions of the AIC, we found that lesions of the AIC were associated with a significant impairment of the CCC. Simulated lesions of the AIC resulted in a reduction of the global efficiency of the CCN in a network analysis. These findings suggest that the AIC, as a critical hub in the CCN, is a bottleneck of cognitive control.

The relationship between population size, inbreeding, loss of genetic variation and evolutionary potential of fitness traits is still unresolved, and large-scale empirical studies testing theoretical expectations are surprisingly scarce. Here we present a highly replicated experimental evolution setup with 120 lines of Drosophila melanogaster having experienced inbreeding caused by low population size for a variable number of generations. Genetic variation in inbred lines and in outbred control lines was assessed by genotyping-by-sequencing (GBS) of pooled samples consisting of 15 males per line. All lines were reared on a novel stressful medium for 10 generations during which body mass, productivity, and extinctions were scored in each generation. In addition, we investigated egg-to-adult viability in the benign and the stressful environments before and after rearing at the stressful conditions for 10 generations. We found strong positive correlations between levels of genetic variation and evolutionary response in all investigated traits, and showed that genomic variation was more informative in predicting evolutionary responses than population history reflected by expected inbreeding levels. We also found that lines with lower genetic diversity were at greater risk of extinction. For viability, the results suggested a trade-off in the costs of adapting to the stressful environments when tested in a benign environment. This work presents convincing support for long-standing evolutionary theory, and it provides novel insights into the association between genetic variation and evolutionary capacity in a gradient of diversity rather than dichotomous inbred/outbred groups., Author summary Genetic variation is a prerequisite for evolution to occur. Quantifying, utilizing and understanding the role of this variation for the survival and persistence of populations is central to several research disciplines including evolutionary biology, animal and plant breeding and conservation genetics. Environments are changing at a rate unpreceded for millennia and rates of local and global extinction of populations and species are alarming. The ability to cope with environmental change through genetic changes is therefore key in order to adapt and survive. Here we provide insights into the association between genetic variation and evolutionary and demographic response to environmental stress. We do this based on results from a long-term experimental evolution study on 130 genome-wide sequenced inbred and outbred lines of vinegar flies (Drosophila melanogaster). We found 1) strong positive correlations between levels of genetic variation and evolutionary response, 2) that genomic variation is predicting evolutionary responses better than expected inbreeding levels, and 3) that lines with lower genetic diversity are at greater risk of extinction. This work presents convincing support for long-standing evolutionary theory, reinforces the importance on maintaining genetic variation in wild and domestic populations and pinpoints applied benefits of high-throughput sequencing.

Isolated populations with enrichment of variants due to recent population bottlenecks provide a powerful resource for identifying disease-associated genetic variants and genes. As a model of an isolate population, we sequenced the genomes of 1463 Finnish individuals as part of the Sequencing Initiative Suomi (SISu) Project. We compared the genomic profiles of the 1463 Finns to a sample of 1463 British individuals that were sequenced in parallel as part of the UK10K Project. Whereas there were no major differences in the allele frequency of common variants, a significant depletion of variants in the rare frequency spectrum was observed in Finns when comparing the two populations. On the other hand, we observed >2.1 million variants that were twice as frequent among Finns compared with Britons and 800 000 variants that were more than 10 times more frequent in Finns. Furthermore, in Finns we observed a relative proportional enrichment of variants in the minor allele frequency range between 2 and 5% (P

A relationship between winter weather and survival of northern ungulates has long been established, yet the possible roles of biological (e.g., nutritional status) and environmental (e.g., weather) conditions make it important to determine which potential limiting factors are most influential.Our objective was to examine the potential effects of individual (body mass and age) and extrinsic (winter severity and snowmelt conditions) factors on the magnitude and timing of mortality for adult (>2.5 years old) female white‐tailed deer (Odocoileus virginianus [Zimmerman, 1780]) during February–May in the Upper Peninsula of Michigan, USA.One hundred and fifty deer were captured and monitored during 2009–2015 in two areas with varying snowfall. February–May survival ranged from 0.24 to 0.89 (mean = 0.69) across years. Mortality risk increased 1.9% with each unit increase in cumulative winter severity index, decreased 8.2% with each cumulative snow‐free day, and decreased 4.3% with each kg increase in body mass. Age and weekly snow depth did not influence weekly deer survival. Predation, primarily from coyote (Canis latrans [Say, 1823]) and wolves (Canis lupus [L., 1758]), accounted for 78% of known‐cause mortalities.Our results suggest that cumulative winter severity, and possibly to a lesser degree deer condition entering winter, impacted deer winter survival. However, the timing of spring snowmelt appeared to be the most influential factor determining late‐winter mortality of deer in our study. This supports the hypothesis that nutrition and energetic demands from weather conditions are both important to northern ungulate winter ecology. Under this model, a delay of several weeks in the timing of spring snowmelt could exert a large influence on deer survival, resulting in a survival bottleneck., Northern ungulate population dynamics are correlated with winter weather patterns, and our goal was to evaluate when and why white‐tailed deer winter mortality occurs. We modeled weekly mortality risk of 150 adult female white‐tailed deer in Michigan in response to environmental and biological factors. The results suggested that body mass, severity of winter weather, and timing of spring snowmelt are influential on deer mortality, with the timing of snowmelt explaining the greatest amount of variation.

Multipartite viruses package their genomic segments independently and thus incur the risk of being unable to transmit their entire genome during host-to-host transmission if they undergo severe bottlenecks. In this paper, we estimated the bottleneck size during one infection cycle of Faba bean necrotic stunt virus (FBNSV), an octopartite nanovirus whose segments have been previously shown to converge to particular and unequal relative frequencies within host plants and aphid vectors. Two methods were used to derive this estimate, one based on the probability of transmission of the virus and the other based on the temporal evolution of the relative frequency of markers for two genomic segments, one frequent and one rare (segment N and S, respectively), both in plants and vectors. Our results show that FBNSV undergoes severe bottlenecks during aphid transmission. Further, even though the bottlenecks are always narrow under our experimental conditions, they slightly widen with the number of transmitting aphids. In particular, when several aphids are used for transmission, the bottleneck size of the segments is also affected by within-plant processes and, importantly, significantly differs across segments. These results indicate that genetic drift not only must be an important process affecting the evolution of these viruses but also that these effects vary across genomic segments and, thus, across viral genes, a rather unique and intriguing situation. We further discuss the potential consequences of our findings for the transmission of multipartite viruses. IMPORTANCE Multipartite viruses package their genomic segments in independent capsids. The most obvious cost of such genomic structure is the risk of losing at least one segment during host-to-host transmission. A theoretical study has shown that for nanoviruses, composed of 6 to 8 segments, hundreds of copies of each segment need to be transmitted to ensure that at least one copy of each segment was present in the host. These estimations seem to be very high compared to the size of the bottlenecks measured with other viruses. Here, we estimated the bottleneck size during one infection cycle of FBNSV, an octopartite nanovirus. We show that these bottlenecks are always narrow (few viral particles) and slightly widen with the number of transmitting aphids. These results contrast with theoretical predictions and illustrate the fact that a new conceptual framework is probably needed to understand the transmission of highly multipartite viruses.

Many congestion charging projects charge traffic only within part of a day with predetermined congestion tolls. Demand peaks have been witnessed just around the time when the charge jumps up or down. Such peaks may not be desirable, in particular (a) when the resulting peaks are much higher than available capacities; (b) traffic speeding up to get into the charging zone causes more incidents just before the toll rises up to a higher level; or (c) traffic slowing down or parking on the roadside decreases road traffic throughput just before the toll falls sharply. We term these types of demand peaks ‘boundary effects’ of congestion charging. This paper investigates these effects in a bottleneck scenario and aims to design charging schemes that reduce undesired demand peaks. For this purpose, we observe and analyse the boundary effects utilising a bottleneck model under three types of toll profiles that are indicative of real charging schemes. The first type maintains a constant toll across the charging period, the second type allows the toll to increase from zero to a given maximum level and then decrease back to zero and the third type allows the toll to rise from zero to a given maximum level, remain at this level for a fixed period and then fall down to zero. This investigation shows that all three types of toll profiles can produce greater boundary peak demands than the bottleneck capacity. A significant contribution of this work is that instead of designing an optimal traffic congestion pricing scheme we analyse how existing sub-optimal congestion pricing schemes could be improved and suggest how observed problems may be overcome. Hence, we propose a set of extra requirements to supplement existing principles or requirements for design and implementation of congestion charging, which aim to reduce the adverse consequences of boundary effects. Concluding remarks are made on implications of this investigation for the improvement of existing congestion charging projects and for future research. First published online 13 July 2015

The countries of Central America and the island of Hispaniola have set the goal of eliminating malaria in less than a decade. Although efforts to reduce the malaria burden in the region have been successful, there has been an alarming increase in cases in the Nicaraguan Moskitia since 2014. The continuous decrease in cases between 2000 and 2014, followed by a rapid expansion from 2015 to the present, has generated a potential bottleneck effect in the populations of Plasmodium spp. Consequently, this study aimed to evaluate the genetic diversity of P. falciparum and the decrease in allelic richness in this population. The polymorphic regions of the pfmsp-1 and pfmsp-2 genes of patients with falciparum malaria from Honduras and Nicaragua were analyzed using nested PCR and sequencing. Most of the samples were classified into the K1 allelic subfamily of the pfmsp-1 gene and into the 3D7 subfamily of the pfmsp-2 gene. Despite the low genetic diversity found, more than half of the samples presented a polyclonal K1/RO33 haplotype. No sequence polymorphisms were found within each allelic subfamily. This study describes a notable decrease in the genetic diversity of P. falciparum in the Moskitia region after a bottleneck phenomenon. These results will be useful for future epidemiological investigations and the monitoring of malaria transmission in Central America.

Background Diabetes induces many complications including reduced fertility and low oocyte quality, but whether it causes increased mtDNA mutations is unknown. Methods We generated a T2D mouse model by using high-fat-diet (HFD) and Streptozotocin (STZ) injection. We examined mtDNA mutations in oocytes of diabetic mice by high-throughput sequencing techniques. Results T2D mice showed glucose intolerance, insulin resistance, low fecundity compared to the control group. T2D oocytes showed increased mtDNA mutation sites and mutation numbers compared to the control counterparts. mtDNA mutation examination in F1 mice showed that the mitochondrial bottleneck could eliminate mtDNA mutations. Conclusions T2D mice have increased mtDNA mutation sites and mtDNA mutation numbers in oocytes compared to the counterparts, while these adverse effects can be eliminated by the bottleneck effect in their offspring. This is the first study using a small number of oocytes to examine mtDNA mutations in diabetic mothers and offspring. Electronic supplementary material The online version of this article (10.1186/s12958-018-0423-1) contains supplementary material, which is available to authorized users.

In spite of many genetic studies that contributed for a deep knowledge about the peopling of the Americas, no consensus has emerged about important parameters such as the effective size of the Native Americans founder population. Previous estimates based on genomic datasets may have been biased by the use of admixed individuals from Latino populations, while other recent studies using samples from Native American individuals relied on approximated analytical approaches. In this study we use resequencing data for nine independent regions in a set of Native American and Siberian individuals and a full-likelihood approach based on isolation-with-migration scenarios accounting for recent flow between Asian and Native American populations. Our results suggest that, in agreement with previous studies, the effective size of the Native American population was small, most likely in the order of a few hundred individuals, with point estimates close to 250 individuals, even though credible intervals include a number as large as ~4,000 individuals. Recognizing the size of the genetic bottleneck during the peopling of the Americas is important for determining the extent of genetic markers needed to characterize Native American populations in genome-wide studies and to evaluate the adaptive potential of genetic variants in this population.

Cynomolgus macaques (Macaca fascicularis) were introduced to the island of Mauritius by humans around the 16th century. The unique demographic history of the Mauritian cynomolgus macaques provides the opportunity to not only examine the genetic background of well-established nonhuman primates for biomedical research but also understand the effect of an extreme population bottleneck on the pattern of polymorphisms in genomes. We sequenced the whole genomes of six Mauritian cynomolgus macaques and obtained an average of 20-fold coverage of the genome sequences for each individual. The overall level of nucleotide diversity was 23% smaller than that of the Malaysian cynomolgus macaques, and a reduction of low-frequency polymorphisms was observed. In addition, we also confirmed that the Mauritian cynomolgus macaques were genetically closer to a representative of the Malaysian population than to a representative of the Indochinese population. Excess of nonsynonymous polymorphisms in low frequency, which has been observed in many other species, was not very strong in the Mauritian samples, and the proportion of heterozygous nonsynonymous polymorphisms relative to synonymous polymorphisms is higher within individuals in Mauritian than Malaysian cynomolgus macaques. Those patterns indicate that the extreme population bottleneck made purifying selection overwhelmed by the power of genetic drift in the population. Finally, we estimated the number of founding individuals by using the genome-wide site frequency spectrum of the six samples. Assuming a simple demographic scenario with a single bottleneck followed by exponential growth, the estimated number of founders (∼20 individuals) is largely consistent with previous estimates.

The plant microbiome may be bottlenecked at the level of endophytes of individual seeds. Strong defense of developing seeds is predicted by optimal defense theory, and we have experimentally demonstrated exclusionary interactions among endophytic microbes infecting individual seeds of Centaurea stoebe. Having found a single, PDA-culturable microbe per seed or none in an exploratory study with Centaurea stoebe, we completed a more extensive survey of an additional 98 plant species representing 39 families. We again found that individual, surface-sterilized seeds of all species hosted only one PDA-culturable bacterial or fungal endophyte per seed, or none. PDA-unculturables were not determined but we expect them to also be bottlenecked in individual seeds, as they too should be governed by exclusionary interactions. If the bottleneck were confirmed with high-throughput sequencing of individual seeds then it would make sense to further investigate the Primary Symbiont Hypothesis (PSH). This includes the prediction that primary symbionts (i.e., the winners of the exclusionary battles among seed endophytes) have strong effects on seedlings depending on symbiont identity.

Background. The captive cetacean industry is very profitable and popular worldwide, focusing mainly on leisure activities such as “Swim-with-dolphins” (SWD) programs. However, there is a concern for how captivity could affect the bottlenose dolphin Tursiops truncatus, which in nature is a highly social and widespread species. To date, there is little information regarding to the impact of restricted population size on their genetic structure and variability. Methods. The aim of this study was to estimate the genetic diversity of a confined population of T. truncatus, composed of wild-born (n=25) from Cuba, Quintana Roo and Tabasco, and captive-born (n=24) dolphins in southern Mexico, using the hypervariable portion of the mitochondrial DNA and ten nuclear microsatellite markers: TexVet3, TexVet5, TexVet7, D18, D22, Ttr19, Tur4_80, Tur4_105, Tur4_141 and GATA098. Results. Exclusive mtDNA haplotypes were found in at least one individual from each wild-born origin populations and in one captive-born individual; total mean haplotype and nucleotide diversities were 0.912 (±0.016) and 0.025 (±0.013) respectively. At microsatellite loci, low levels of genetic diversity were found with a mean number of alleles per locus of 4 (±2.36), and an average expected heterozygosity over all loci of 0.544 (±0.163). Measures of allelic richness and effective number of alleles were similar between captive-born and wild-born dolphins. No significant genetic structure was found with microsatellite markers, whereas the mtDNA data revealed a significant differentiation between wild-born organisms from Cuba and Quintana ROO. Discussion. Data analysis suggests the occurrence of a recent genetic bottleneck in the confined population probably because of a strong founder effect, given that only a small number of dolphins with a limited fraction of the total species genetic variation were selected at random to start this captive population. The results herein provide the first genetic baseline information on a captive bottlenose dolphin population in Mexico.

Summary The peptide-loading complex is a bottleneck in antigen presentation by major histocompatibility complex (MHC) class I molecules. While the structures of its individual components were known, the recent report of the 7.2 A structure of the entire complex now fits them into their functional context, explaining this monumental step in antigen acquisition by MHC class I molecules.

WOS: 000417160500001, The historical changes in European Black Pine population size across the whole natural distribution in Europe and Asia Minor were analyzed facing the Plio-Pleistocene climatic fluctuations. Thirteen chloroplast SSRs and SNPs markers have been studied under the assumptions of "neutral evolution." Populations and meta-populations had different histories of migration routes, and they were strongly affected by complex patterns of isolation, fragmentation, speciation, expansion (1.88-4.28 Ma), purification selection (2.09-21.41 Ma) and bottleneck (1.85-21.76 Ma). A significant number of populations (min. 29-41%) were in equilibrium for very long periods. Generally, the bottleneck revealed by chloroplast DNA is weaker than the bottleneck revealed by nuclear DNA. The N (e) immediately after the bottleneck reaches between 1820 and 3640 individuals. Generally, the historical effective population sizes shrink significantly for the Tertiary period from 10-15 up to 2.5 Ma in Western Europe (by 82%), followed by Asia Minor (69%) and the Balkan Peninsula (28%), likely resulting from important climatic changes. The rates and frequencies of stepwise westwards migration waves have been not sufficient to prevent isolation between the meta-populations and to suppress "sympatric speciation." The migration was weak for the Pliocene, but was maximal for the Pleistocene, and finally silent for the present interglacial period, namely the Holocene.

The genetic consequences of population bottlenecks on patterns of deleterious genetic variation in human populations are of tremendous interest. Based on exome sequencing of 18 Greenlandic Inuit we show that the Inuit have undergone a severe ∼20,000-year-long bottleneck. This has led to a markedly more extreme distribution of allele frequencies than seen for any other human population tested to date, making the Inuit the perfect population for investigating the effect of a bottleneck on patterns of deleterious variation. When comparing proxies for genetic load that assume an additive effect of deleterious alleles, the Inuit show, at most, a slight increase in load compared to European, East Asian, and African populations. Specifically, we observe

Numerous species of marine megafauna are at risk of extinction and understanding their genetic population structure and demographic history is essential for their conservation. We used mitochondrial DNA and 18 nuclear microsatellite loci, on the largest genetic dataset compiled to date on Australian humpback dolphins (eight sampling sites, 159 samples), to assess their genetic diversity, gene flow and past demographic history along the east coast of Queensland, Australia. Levels of genetic diversity were low (mtDNA: h = 0–0.52, π = 0–0.007; nDNA: Ho = 0.27–0.41; AR = 1.7–2.4). Both mitochondrial (ΦST = 0.49, P = 0.001) and nuclear markers (FST = 0.14, P = 0.001) showed strong genetic structure among sampling sites. Four putative populations were identified, with little contemporary gene flow (m = 0.017 to 0.047) among populations. Genetic divergence follows an isolation-by-distance model (r = 0.38, P = 0.0001), with an apparent restriction in gene flow occurring at scales of 382–509 km. Estimates of contemporary effective population size were low (Ne = 11.5–31.2), with signatures of genetic bottlenecks for all putative populations about 50–150 generations ago. The current low levels of genetic diversity, gene flow, and effective population size in Australian humpback dolphins indicate the effects of historical population bottlenecks and/or founder events during the late Holocene period (~1250–3750 years ago); probably associated with sea level fall and increased intensity of El Nino Southern Oscillation-climatic events. Our results raise important conservation concerns and emphasize the vulnerability of Australian humpback dolphins to stochastic demographic, genetic and environmental processes. Conservation strategies should focus on promoting connectivity among local populations and reducing direct causes of human-related mortality.

Aim: The present study was undertaken in Salem Black goat population for genetic analysis at molecular level to exploit the breed for planning sustainable improvement, conservation and utilization, which subsequently can improve the livelihood of its stakeholders. Materials and Methods: Genomic DNA was isolated from blood samples of 50 unrelated Salem Black goats with typical phenotypic features in several villages in the breeding tract and the genetic characterization and bottleneck analysis in Salem Black goat was done using 25 microsatellite markers as recommended by the Food and Agricultural Organization, Rome, Italy. The basic measures of genetic variation were computed using bioinformatic software. To evaluate the Salem Black goats for mutation drift equilibrium, three tests were performed under three different mutation models, viz., infinite allele model (IAM), stepwise mutation model (SMM) and two-phase model (TPM) and the observed gene diversity (He) and expected equilibrium gene diversity (Heq) were estimated under different models of microsatellite evolution. Results: The study revealed that the observed number of alleles ranged from 4 (ETH10, ILSTS008) to 17 (BM64444) with a total of 213 alleles and mean of 10.14±0.83 alleles across loci. The overall observed heterozygosity, expected heterozygosity, inbreeding estimate and polymorphism information content values were 0.631±0.041, 0.820±0.024, 0.233±0.044 and 0.786±0.023 respectively indicating high genetic diversity. The average observed gene diversities (He) pooled over different markers was 0.829±0.024 and the average expected gene diversities under IAM, TPM and SMM models were 0.769±0.026, 0.808±0.024 and 0.837±0.020 respectively. The number of loci found to exhibit gene diversity excess under IAM, TPM and SMM models were 18, 17 and 12 respectively. Conclusion: All the three statistical tests, viz., sign test, standardized differences test and Wilcoxon sign rank test, revealed significant deviation of Salem Black goats from mutation-drift equilibrium under IAM and TPM models, however, nonsignificant deviation under SMM model. The qualitative test of mode shift analysis supported the results under SMM indicating the absence of the genetic bottleneck in the recent past in Salem Black goats.

Mitochondrial DNA (mtDNA) and plastid DNA (ptDNA) encode vital bioenergetic apparatus, and mutations in these organelle DNA (oDNA) molecules can be devastating. In the germline of several animals, a genetic “bottleneck” increases cell-to-cell variance in mtDNA heteroplasmy, allowing purifying selection to act to maintain low proportions of mutant mtDNA. However, most eukaryotes do not sequester a germline early in development, and even the animal bottleneck remains poorly understood. How then do eukaryotic organelles avoid Muller’s ratchet—the gradual buildup of deleterious oDNA mutations? Here, we construct a comprehensive and predictive genetic model, quantitatively describing how different mechanisms segregate and decrease oDNA damage across eukaryotes. We apply this comprehensive theory to characterise the animal bottleneck with recent single-cell observations in diverse mouse models. Further, we show that gene conversion is a particularly powerful mechanism to increase beneficial cell-to-cell variance without depleting oDNA copy number, explaining the benefit of observed oDNA recombination in diverse organisms which do not sequester animal-like germlines (for example, sponges, corals, fungi, and plants). Genomic, transcriptomic, and structural datasets across eukaryotes support this mechanism for generating beneficial variance without a germline bottleneck. This framework explains puzzling oDNA differences across taxa, suggesting how Muller’s ratchet is avoided in different eukaryotes., A comprehensive model for mitochondrial and plasmid DNA segregation, supported by with genomic, transcriptomic, and single-cell data, shows how the attritional effects of Muller’s ratchet can be avoided in the organelles of diverse eukaryotes.

This paper analyzes efficient pricing at a congested airport dominated by a single firm. Unlike much of the previous literature, we combine a dynamic bottleneck model of congestion and a vertical structure model that explicitly considers the role of airlines and passengers. We show that a Stackelberg leader interacting with a competitive fringe partially internalizes congestion, and that there are various toll regimes that induce the welfare maximizing outcome, widening the set of choices for regulators. In particular, charging the congestion toll that would apply for fully competitive carriers and that ignores any internalization, to both the leader and the fringe, yields the first-best outcome. © 2013 Elsevier Inc.

In various crops, genetic bottlenecks occurring through domestication can limit crop resilience to biotic and abiotic stresses. In the present study, we investigated nucleotide diversity in tomato chloroplast genome through sequencing seven plastomes of cultivated accessions from the Campania region (Southern Italy) and two wild species among the closest (Solanum pimpinellifolium) and most distantly related (S. neorickii) species to cultivated tomatoes. Comparative analyses among the chloroplast genomes sequenced in this work and those available in GenBank allowed evaluating the variability of plastomes and defining phylogenetic relationships. A dramatic reduction in genetic diversity was detected in cultivated tomatoes, nonetheless, a few de novo mutations, which still differentiated the cultivated tomatoes from the closest wild relative S. pimpinellifolium, were detected and are potentially utilizable as diagnostic markers. Phylogenetic analyses confirmed that S. pimpinellifolium is the closest ancestor of all cultivated tomatoes. Local accessions all clustered together and were strictly related with other cultivated tomatoes (S. lycopersicum group). Noteworthy, S. lycopersicum var. cerasiforme resulted in a mixture of both cultivated and wild tomato genotypes since one of the two analyzed accessions clustered with cultivated tomato, whereas the other with S. pimpinellifolium. Overall, our results revealed a very reduced cytoplasmic variability in cultivated tomatoes and suggest the occurrence of a cytoplasmic bottleneck during their domestication.

`It is well established that most new systemic infections of HIV-1 can be traced back to one or a limited number of founder viruses. Usually, these founders are more closely related to minor HIV-1 populations in the blood of the presumed donor than to more abundant lineages. This has led to the widely accepted idea that transmission selects for viral characteristics that facilitate crossing the mucosal barrier of the recipient's genital tract, although the specific selective forces or advantages are not completely defined. However, there are other steps along the way to becoming a founder virus at which selection may occur. These steps include the transition from the donor's general circulation to the genital tract compartment, survival within the transmission fluid, and establishment of a nascent stable local infection in the recipient's genital tract. Finally, there is the possibility that important narrowing events may also occur during establishment of systemic infection. This is suggested by the surprising observation that the number of founder viruses detected after transmission in intravenous drug users is also limited. Although some of these steps may be heavily selective, others may result mostly in a stochastic narrowing of the available founder pool. Collectively, they shape the initial infection in each recipient.

The Tibetan antelope (chiru, Pantholops hodgsoni) is one of the most endangered mammals native to the Qinghai-Tibetan Plateau. The population size has rapidly declined over the last century due to illegal hunting and habitat damage. In the past 10 years, the population has reportedly been expanding due to conservation efforts. Several lines of evidence suggest that the Tibetan antelope has undergone a demographic bottleneck. However, the consequences of the bottleneck on genetic diversity and the post-bottleneck genetic recovery remain unknown. In this study, we investigate the genetic variation of 15 microsatellite loci from two Tibetan antelope populations sampled in 2003 (Pop2003) and 2013 (Pop2013). A higher level of genetic diversity (NA, 13.286; He, 0.840; PIC, 0.813; I, 2.114) was detected in Pop2013, compared to Pop2003 (NA, 12.929; He, 0.818; PIC, 0.789; I, 2.033). We observe that despite passing through the bottleneck, the Tibetan antelope retains high levels of genetic diversity. Furthermore, our results show significant or near significant increases in genetic diversity (He, PIC and I) in Pop2013 compared with Pop2003, which suggests that protection efforts did not arrive too late for the Tibetan antelope.

It is commonly thought that human genetic diversity in non-African populations was primarily shaped by a recent out-of-Africa dispersal. Here we present a large geographical Y chromosome study using 459 high coverage sequences, including 302 newly reported here. We date the Y chromosomal Most Recent Common Ancestor (MRCA) in Africa at 254 (95% CI 192- 307) kya and differentiation of African and non-African lineages 52-121 kya. The age estimates for major non-African founder haplogroups cluster closely in a narrow time interval at 47-52 kya, consistent with a rapid initial colonization model of Eurasia and Oceania after the out-of-Africa bottleneck. We find that the highest basal Y chromosome diversity outside Africa has been preserved in South and Southeast Asians while extant Y chromosome diversity in Europe and the Near East stems from a small number of mid-Holocene founders. In contrast to demographic reconstructions based on mtDNA, we infer a second strong bottleneck, followed by a fast recovery in Old World populations dating to the last 10 ky. We hypothesize that this bottleneck is caused by cultural changes affecting variance of reproductive success among males.

When analysing the effects of transport policies it is important to adequately control for heterogeneity: previous studies note that ignoring heterogeneity biases the estimated welfare effects of tolling. This paper examines the effects of tolling, in a bottleneck model, with a continuously distributed value of time. With homogeneous users, first-best public tolling has no effect on prices. With heterogeneity it does: low values of time lose, and high values of time gain. The average congestion externality decreases with the heterogeneity in the value of time. Consequently, the welfare gain of first-best tolling also decreases. The more heterogeneous the value of time is, the lower the relative efficiency of a public pay-lane. This finding contrasts with the previous literature. Earlier studies, using static flow congestion, conclude that the relative efficiency increases with this type of heterogeneity. With more heterogeneity in the value of time, the relative efficiency of a private pay-lane is also lower, while that of a public time-invariant toll is higher. Our results suggest that the welfare gains of different tolling schemes are affected differently by heterogeneity. Further, the impact of heterogeneity on the effects of a policy also depends on the type of congestion considered. © 2010 Elsevier Ltd.

SummaryPeople simply cannot do two things at once, as shown by research on the so-called psychological refractory period. A new neuroimaging study has now localized the response-selection bottleneck underlying the psychological refractory period to a frontoparietal network.

Although oncogenic mutations predispose tissue stem cells to tumor initiation, the rate-limiting processes for stem cell immortalization remain unknown. In this issue of Cell, Bonnay et al. identify enhanced electron transport chain activity as a critical determinant of this process, establishing metabolic reprogramming as limiting for tumor initiation.

In previous years, several kinases, such as phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and extracellular-signal-regulated kinase (ERK), have been linked to important human diseases, although some kinase families remain neglected in terms of research, hiding their relevance to therapeutic approaches. Here, a review regarding the NEK family is presented, shedding light on important information related to NEKs and human diseases. NEKs are a large group of homologous kinases with related functions and structures that participate in several cellular processes such as the cell cycle, cell division, cilia formation, and the DNA damage response. The review of the literature points to the pivotal participation of NEKs in important human diseases, like different types of cancer, diabetes, ciliopathies and central nervous system related and inflammatory-related diseases. The different known regulatory molecular mechanisms specific to each NEK are also presented, relating to their involvement in different diseases. In addition, important information about NEKs remains to be elucidated and is highlighted in this review, showing the need for other studies and research regarding this kinase family. Therefore, the NEK family represents an important group of kinases with potential applications in the therapy of human diseases.