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Cell division is a necessity of life which can be either mitotic or amitotic. While both are fundamental, amitosis is sometimes considered a relic of little importance in biology. Nevertheless, eukaryotes often have polyploid cells, including cancer cells, which may divide amitotically. To understand how amitosis ensures the completion of cell division, we turn to the macronuclei of ciliates. The grand scheme governing the proliferation of the macronuclei of ciliate cells, which involves chromosomal replication and amitosis, is currently unknown, which is crucial for developing population genetics model of ciliate populations. Using a novel model that encompasses a wide range of mechanisms together with experimental data of the composition of mating types at different stages derived from a single karyonide of Tetrahymena thermophila, we show that the chromosomal replication of the macronucleus has a strong head-start effect, with only about five copies of chromosomes replicated at a time and persistent reuse of the chromosomes involved in the early replication. Furthermore the fission of a fully grown macronucleus is non-random with regard to chromosome composition, with a strong tendency to push chromosomes and their replications to the same daughter cell.

Each mutation in a population sample of DNA sequences can be classified by the number of sequences that inherit the mutant nucleotide, the resulting frequencies are known as mutations of different sizes or site frequency spectrum. Many summary statistics can be defined as a linear function of these frequencies. A flexible class of such linear summary statistics is explored analytically in this paper which include several well-known quantities, such as the number of segregating sizes and the mean number of nucleotide differences between two sequences. Some asymptotic variances and covariances are obtained while the analytical formulas for the variances and covariances of nine such linear summary statistics are derived, most of which are unknown to date. This study not only provides some theoretical foundations for exploring linear summary statistics, but also provides some newlinear summary statistics that may be utilized for analyzing sample polymorphism. Furthermore it is showed that a newly developed linear summary statistics has a smaller variance almost uniformly than Watterson's estimator, and that a class of linear summary statistics given too heavy weights on mutations of smaller sizes result in asymptotically non-zero variance.

The indispensable role of the SARS-CoV-2 main protease (Mpro) in the viral replication cycle and its dissimilarity to human proteases make Mpro a promising drug target. In order to identify the non-covalent Mpro inhibitors, we performed a comprehensive study using a combined computational strategy. We first screened the ZINC purchasable compound database using the pharmacophore model generated from the reference crystal structure of Mpro complexed with the inhibitor ML188. The hit compounds were then filtered by molecular docking and predicted parameters of drug-likeness and pharmacokinetics. The final molecular dynamics (MD) simulations identified three effective candidate inhibitors (ECIs) capable of maintaining binding within the substrate-binding cavity of Mpro. We further performed comparative analyses of the reference and effective complexes in terms of dynamics, thermodynamics, binding free energy (BFE), and interaction energies and modes. The results reveal that, when compared to the inter-molecular electrostatic forces/interactions, the inter-molecular van der Waals (vdW) forces/interactions are far more important in maintaining the association and determining the high affinity. Given the un-favorable effects of the inter-molecular electrostatic interactions—association destabilization by the competitive hydrogen bond (HB) interactions and the reduced binding affinity arising from the un-compensable increase in the electrostatic desolvation penalty—we suggest that enhancing the inter-molecular vdW interactions while avoiding introducing the deeply buried HBs may be a promising strategy in future inhibitor optimization.

Cell division is a necessity of life which can be either mitotic or amitotic. While both are fundamental, amitosis is sometimes considered a relic of little importance in biology. Nevertheless, eukaryotes often have polyploid cells, including cancer cells, which may divide amitotically. To understand how amitosis ensures the completion of cell division, we turn to the macronuclei of ciliates. The grand scheme governing the proliferation of the macronuclei of ciliate cells, which involves chromosomal replication and the amitosis, is currently unknown. Using a novel model that encompasses a wide range of mechanisms together with experimental data of the composition of mating types at different stages derived from a single karyonide ofTetrahymena thermophila, we show that the chromosomal replication of the macronucleus has a strong head-start effect, with only about five copies of chromosomes replicated at a time and persistent reuse of the chromosomes involved in the early replication. Furthermore the fission of a fully grown macronucleus is non-random, with a strong tendency to push chromosomes and their replications to the same daughter cell. Similar strategies may exist for other Tetrahymena species or ciliates, and have implications to the amitosis of polyploid cells of multicellular organisms.

9 páginas, 4 figuras. All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors. Sequencing reads have been submitted to the European Nucleotide Archive (EMBL-EBI) under study accession PRJEB34582 and PRJEB34609. The analysis scripts used in this study are available online at GitHub (https://github.com/StopTB/Single_Colony_Project)., Mycobacterium tuberculosis (Mtb) infection results in a spectrum of clinical and histopathologic manifestations. It has been proposed that the environmental and immune pressures associated with different contexts of infection have different consequences for the associated bacterial populations, affecting drug susceptibility and the emergence of resistance. However, there is little concrete evidence for this model. We prospectively collected sputum samples from 18 newly diagnosed and treatment-naïve patients with tuberculosis and sequenced 795 colony-derived Mtb isolates. Mutant accumulation rates varied considerably between different bacilli isolated from the same individual, and where high rates of mutation were observed, the mutational spectrum was consistent with reactive oxygen species-induced mutagenesis. Elevated bacterial mutation rates were identified in isolates from HIV-negative but not HIV-positive individuals, suggesting that they were immune-driven. These results support the model that mutagenesis of Mtb in vivo is modulated by the host environment, which could drive the emergence of variants associated with drug resistance in a host-dependent manner., This work was supported by the National Natural Science Foundation of China (91631301 and 81661128043 to Q.G., 81701975 to Q.L., and 31771416 to X.L.), the National Science and Technology Major Project of China (2017ZX10201302 to Q.G. and 2018ZX10714002-001-005 to Z.Z.), the Sanming Project of Medicine in Shenzhen (SZSM201611030 to Q.G.), European Research Council 638553-TB-AcCELERATE (to I.C.), the Key Research Program of the Chinese Academy of Sciences (KFZD-SW-220-1 to X.L.), and the CAS Light of West China Program (to X.L.). Y.F. is supported in part by NIH R01HG009524. Support was also received from NIH awards P01 AI132130 and AI142793 to S.M.F.

SummaryRecent de novo mutation data allow the estimation of non-reversible mutation rates for trinucleotide sequence contexts. However, existing tools for simulating DNA sequence evolution are limited to time-reversible models or do not consider trinucleotide context-dependent rates. As this ability is critical to testing evolutionary scenarios under neutrality, we created Trevolver. Sequence evolution is simulated on a bifurcating tree using a 64 × 4 trinucleotide mutation model. Runtime is fast and results match theoretical expectation for CpG sites. Simulations with Trevolver will enable neutral hypotheses to be tested at within-species (polymorphism), between-species (divergence), within-host (e.g., viral evolution), and somatic (e.g., cancer) levels of evolutionary change.Availability and ImplementationTrevolver is implemented in Perl and available on GitHub under GNU General Public License (GPL) version 3 at https://github.com/chasewnelson/trevolver.Contactcnelson@amnh.orgSupplementary informationFurther details and example data are available on GitHub.

Sex is often hailed as one of the major successes in evolution, and in sexual organisms the maintenance of proper sex ratio is crucial. As a large unicellular eukaryotic lineage, ciliates exhibit tremendous variation in mating systems, especially the number of sexes and the mechanism of sex determination (SD), and yet how the populations maintain proper sex ratio is poorly understood. Here Tetrahymena thermophila, a ciliate with seven mating types (sexes) and probabilistic SD mechanism, is analyzed from the standpoint of population genetics. It is found based on a newly developed population genetics model that there are plenty of opportunities for both the co-existence of all seven sexes and the fixation of a single sex, pending on several factors, including the strength of natural selection. To test the validity of predictions, five experimental populations of T. thermophila were maintained in the laboratory so that the factors that can influence the dynamics of sex ratio could be controlled and measured. Furthermore, whole-genome sequencing was employed to examine the impact of newly arisen mutations. Overall, it is found that the experimental observations highly support theoretical predictions. It is expected that the newly established theoretical framework is applicable in principle to other multi-sex organisms to bring more insight into the understanding of the maintenance of multiple sexes in a natural population.

By analysing the connotation and development background of low-carbon tourism( L-c T ), and learning about most of the main researches in L-c T from scholars at home and abroad, this paper studied the demand and behavior characteristics of tourist in each phase of their tour, meaning before, during and after trip. And then from the experience of Jiuzhai Valley, the essay focused on discussing the L-c T services elements and details that providers should target at, and proposed some advcies for the thorough implementation of L-c T.

Both the crystal structures of the HIV-1 gp120 core bound by the CD4 and antigen 17b, and the SIV gp120 core pre-bound by CD4 are known. We built the homology models of gp120 with loops V3 and V4 in the CD4-complex, CD4-free and CD4-unliganded states, and models of the 375 S/W and 423 I/P mutants in the CD4-free and unliganded states, respectively. CONCOORD was utilized for generating ensembles of the seven gp120 models that were analyzed by essential dynamics analyses to identify their preferred concerted motions. The revealed large-scale concerted motions are related to either the receptor association/release or the conformational transition between different conformational states. Essential subspace overlap analyses were performed to quantitatively distinguish the preference for conformational transitions between states of the gp120 mutants and further to ascertain what kind of conformational state that the mutants prefer to adopt. Results indicate that the 375 S/W mutant, in which the tryptophan indole group is predicted to occupy the phe43 pocket in the gp120 interior, favors a conformation close to the CD4-bound state. However, the other mutant 423 I/P inclines to prevent the formation of bridging sheet and stabilize the conformation in the unliganded state. Our theoretical analyses are in agreement with experimentally determined mutation effects, and can be extended to a new approach to design or screen mutants that have effects on conformation/function of a protein.

The complex genome of Rhodobacter sphaeroides 2.4.1, composed of chromosomes I (CI) and II (CII), has been sequenced and assembled. We present data demonstrating that the R. sphaeroides genome possesses an extensive amount of exact DNA sequence duplication, 111 kb or ∼2.7% of the total chromosomal DNA. The chromosomal DNA sequence duplications were aligned to each other by using MUMmer. Frequency and size distribution analyses of the exact DNA duplications revealed that the interchromosomal duplications occurred prior to the intrachromosomal duplications. Most of the DNA sequence duplications in the R. sphaeroides genome occurred early in species history, whereas more recent sequence duplications are rarely found. To uncover the history of gene duplications in the R. sphaeroides genome, 44 gene duplications were sampled and then analyzed for DNA sequence similarity against orthologous DNA sequences. Phylogenetic analysis revealed that ∼80% of the total gene duplications examined displayed type A phylogenetic relationships; i.e., one copy of each member of a duplicate pair was more similar to its orthologue, found in a species closely related to R. sphaeroides , than to its duplicate, counterpart allele. The data reported here demonstrate that a massive level of gene duplications occurred prior to the origin of the R. sphaeroides 2.4.1 lineage. These findings lead to the conclusion that there is an ancient partnership between CI and CII of R. sphaeroides 2.4.1.

Serotype M1 group A Streptococcus strains cause epidemic waves of human infections long thought to be mono- or pauciclonal. The gene encoding an extracellular group A Streptococcus protein (streptococcal inhibitor of complement) that inhibits human complement was sequenced in 1,132 M1 strains recovered from population-based surveillance of infections in Canada, Finland and the United States. Epidemic waves are composed of strains expressing a remarkably heterogeneous array of variants of streptococcal inhibitor of complement that arise very rapidly by natural selection on mucosal surfaces. Thus, our results enhance the understanding of pathogen population dynamics in epidemic waves and infectious disease reemergence.

Linear invariants are random variables with zero expectations under certain assumptions. In this paper, linear invariants under Jukes’ and Cantor’s one-parameter model, both with and without the assumption that nucleotide frequencies are at equilibrium, are studied using the method developed in a previous paper. Phylogenetic linear invariants (random variables that are linear invariants of some but not all trees of the same number of species) for trees with up to seven species are derived and bases of phylogenetic linear invariant spaces for unrooted trees with four, five and six species are presented. All these bases consist of invariants of simple form. The constraints that specify non-phylogenetic linear invariants (invariants shared by all trees of the same number of species) are determined. Under the assumption that nucleotide frequencies are at equilibrium, it is found that (i) each five-species tree has 17 independent phylogenetic linear invariants, and for two different trees with five species, there are at least three phylogenetic linear invariants of one tree that are not invariants of the other tree; (ii) each six-species tree has 98 independent phylogenetic linear invariants, and for two different trees of six species there are at least nine independent phylogenetic linear invariants that are not invariants of the other tree; and (iii) each seven-species tree has 482 independent phylogenetic linear invariants. It is also found that the number of independent phylogenetic linear invariants is much larger without the assumption of equilibrium than with it, but the reverse is true for the number of non-phylogenetic linear invariants. A class of random variables that are phylogenetic linear invariants with or without the equilibrium assumption is also identified.

Shu-Qun Liu1,2 Xing-Lai Ji1,2, Yan Tao1, De-Yong Tan3, Ke-Qin Zhang1 and Yun-Xin Fu1,4 1Laboratory for Conservation and Utilization of Bio-Resources & Key Laboratory for Southwest Biodiversity, Yunnan University, Kunming, 2 Sino-Dutch Biomedial and Information Engineering School, Northeastern University, Shenyang, 3School of Life Sciences, Yunnan University, Kunming, 4Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston, Texas, 1,2,3P. R. China 4USA

1Shu-Qun Liu1,2, Lian-Ming Liang1, Tao Yan1, Li-Quan Yang1, Xing-Lai Ji1,2, Jin-Kui Yang1, Yun-Xin Fu1,3 and Ke-Qin Zhang1 1Laboratory for Conservation and Utilization of Bio-Resources & Key Laboratory for Microbial Resources of the Ministry of Education, Yunnan University, Kunming, 2Sino-Dutch Biomedial and Information Engineering School, Northeastern University, Shenyang 3Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston, Texas, 1,2P. R. China 3USA

Nat Genet. 47, 555–559 (2015); published online 6 April 2015; corrected after print 14 August 2015 In the version of this article initially published, the authors neglected to acknowledge one of the funding sources for their study. The acknowledgements should have recognized support from Chinese NSFgrant 91231120 in addition to the other funding sources listed.

Microarray technology provides a powerful tool for the expression profile of thousands of genes simultaneously, which makes it possible to explore the molecular and metabolic etiology of the development of a complex disease under study. However, classical statistical methods and technologies fail to be applied to microarray data. Therefore, it is necessary and motivated to develop the powerful methods for large-scale statistical analyses. In this paper, we described a novel method, called Ranking Analysis of Microarray data (RAM). RAM, which is a large-scale two-sample t-test method, is based on comparisons between a set of ranked T-statistics and a set of ranked Z-values (a set of ranked estimated null scores) yielded by a “randomly splitting” approach instead of a “permutation” approach and two-simulation strategy for estimating the proportion of genes identified by chance, i.e., the false discovery rate (FDR). The results obtained from the simulated and observed microarray data shows that RAM is more efficient in identification of genes differentially expressed and estimation of FDR under the undesirable conditions such as a large fudge factor, small sample size, or mixture distribution of noises than Significance Analysis of Microarrays (SAM).

BACKGROUND: Racial/ethnic difference in bone mineral density (BMD) exists. The underlying mechanism is unclear and needs investigation. PURPOSE: To determine BMD and its relation to environmental exposure in recent African immigrants. METHODS: BMD in recent sub-Saharan Sudanese immigrants (55 men and 88 premenopausal women) in the United States was measured. Analysis of covariance (ANCOVA) model was performed, with total body, spine and hip BMD as dependent variables; and sex, age, body weight, the length of stay in the United States, and milk intake as independent variables. RESULTS: BMD Z score in the spine but not total body or hip in the Sudanese immigrants was significantly lower compared with the normative values of African Americans and Caucasians. Total body and hip BMD was positively correlated (p < 0.015) with their length of stay in the United States. Hip BMD was significantly correlated with milk intake (p < 0.02) and marginally (p = 0.052) with their length of stay in the United States, independent of body weight. CONCLUSIONS: Spinal BMD was significantly lower in recent Sudanese immigrants than in African Americans or Caucasians. Their hip and total body BMD was associated with their length of stay in the United States, suggesting a potential environmental factors in the ethnic diversity of BMD.

Yunnan snub-nose monkey (Rhinopithecus bieti) is a famous endangered primate in China. So far, however, studies on its population genetics based on DNA sequences are not available. In this paper, the whole mitochondria control region of the samples from Weixi, Yunan Province as well as the whole cytochrome b gene in some individuals were sequenced. A deep divergence was observed within the Weixi population, which was confirmed after excluding the possibility of it being a nuclear pseudogene. Nonetheless, if the effects of population structure and migration are considered, the true level of polymorphism of the Weixi population may be not as high as observed.

Background The outbreak of severe acute respiratory syndrome (SARS) caused a severe global epidemic in 2003 which led to hundreds of deaths and many thousands of hospitalizations. The virus causing SARS was identified as a novel coronavirus (SARS-CoV) and multiple genomic sequences have been revealed since mid-April, 2003. After a quiet summer and fall in 2003, the newly emerged SARS cases in Asia, particularly the latest cases in China, are reinforcing a wide-spread belief that the SARS epidemic would strike back. With the understanding that SARS-CoV might be with humans for years to come, knowledge of the evolutionary mechanism of the SARS-CoV, including its mutation rate and emergence time, is fundamental to battle this deadly pathogen. To date, the speed at which the deadly virus evolved in nature and the elapsed time before it was transmitted to humans remains poorly understood. Results Sixteen complete genomic sequences with available clinical histories during the SARS outbreak were analyzed. After careful examination of multiple-sequence alignment, 114 single nucleotide variations were identified. To minimize the effects of sequencing errors and additional mutations during the cell culture, three strategies were applied to estimate the mutation rate by 1) using the closely related sequences as background controls; 2) adjusting the divergence time for cell culture; or 3) using the common variants only. The mutation rate in the SARS-CoV genome was estimated to be 0.80 – 2.38 × 10-3 nucleotide substitution per site per year which is in the same order of magnitude as other RNA viruses. The non-synonymous and synonymous substitution rates were estimated to be 1.16 – 3.30 × 10-3 and 1.67 – 4.67 × 10-3 per site per year, respectively. The most recent common ancestor of the 16 sequences was inferred to be present as early as the spring of 2002. Conclusions The estimated mutation rates in the SARS-CoV using multiple strategies were not unusual among coronaviruses and moderate compared to those in other RNA viruses. All estimates of mutation rates led to the inference that the SARS-CoV could have been with humans in the spring of 2002 without causing a severe epidemic.

Background: “Mother–child technique” is applicable when the backup support of the guiding catheter is insufficient. We investigated the impact of the size of the mother guiding catheter on the catheter backup support using an in vitro coronary artery tree model. Methods: The backup support was measured for the 4-in-5, 4-in-6, 4-in-7, and 4-in-8 systems as well as for the 5-in-6, 5-in-7, and 5-in8 systems. Results: When a 4-Fr child catheter was advanced by 9 cm, the relative increase in the backup support was 174% in the 4-in-5 system; 203% in the 4-in-6, and 135% in the 4-in-7 (Pb.05 vs. the mother catheter alone). The increase with the 5-Fr child catheter was 289% in the 5-in-6 system, and 152% in the 5-in-7 (Pb.0001 vs. the mother catheter alone). However, the improvement did not reach statistical significance for either the 4-in-8 (115%) or the 5-in8 (112%) system (Fig. 1). Conclusions: The relative increase in the backup support of the mother–child system was inversely related to the size of the mother guiding catheter. Thus, the mother–child technique may be most useful for PCIs in which a small guiding catheter is used, such as transradial coronary interventions.

Streptococcal inhibitor of complement (Sic) is a highly polymorphic extracellular protein made predominantly by serotype M1 group A Streptococcus (GAS). New variants of the Sic protein frequently appear in M1 epidemics as a result of positive natural selection. To gain further understanding of the molecular basis of M1 epidemics, the sic gene was sequenced from 471 pharyngitis and 127 pyogenic and blood isolates recovered from 598 patients living in metropolitan Helsinki, Finland, during a 37-month population-based surveillance study. Most M1 GAS subclones recovered from pyogenic infections and blood were abundantly represented in the pool of subclones causing pharyngitis. Alleles shared among the pharyngitis, pyogenic, and blood samples were identified in throat isolates a mean of 9.8 months before their recovery from pyogenic infections and blood, which indicates that selection of most sic variants occurs on mucosal surfaces. In contrast, no variation was identified in the emm and covR/covS genes.

We study the behavior of cytonuclear disequilibria in a finite monoecious population due to (1) random drift alone, (2) random drift and mutation, and (3) random drift and migration, using exact results on the RUZ (Random Union of Zygotes) model and diffusion approximations. We also show that the RUG (Random Union of Gametes) model is not suitable for a cytonuclear system. The study is also accompanied by a comparison with a two-locus nuclear system. We show that in a finite population of size N without mutation, the rate of decrease of the cytonuclear allelic disequilibrium is the same as that in the corresponding unlinked two-locus nuclear system. The principal rate of decrease of variance in allelic disequilibrium in a cytonuclear system is slightly faster than that in the corresponding nuclear system. However, the expected value of the variance in cytonuclear disequilibria is larger than that in a two-locus nuclear system for at least the first N generations. With mutation, the expected value of steady state variances of both systems are about the same; however, the normalized variance in linkage disequilibrium sigma 2d of the cytonuclear system is about twice as large as that for the corresponding nuclear system. For the migration process, two sets of steady state solutions are provided, one for the variables before migration and the other for the variables after migration. Diffusion approximations for both the principal rate of decay and steady state solutions in both systems are found to be satisfactory. A more accurate backward diffusion equation for a two-locus nuclear system is provided when the recombination fraction R is large.

We study the expected values of gametic-phase disequilibrium in both nuclear and cytonuclear systems in a finite population composed of reproductively isolated subpopulations. Random drift alone within each subpopulation will generate permanent overall non-zero gametic-phase disequilibrium in both a two-locus nuclear system and a cytonuclear system unless the population has an overall initial disequilibrium of zero. We derive formulae for the expected overall disequilibrium when mutation is involved and demonstrate that these values decay to zero at an extremely slow rate compared with the decay of the expected disequilibria within each subpopulation.