Influenza Virus Drug Resistance: A Time-Sampled Population Genetics Perspective

The challenge of distinguishing genetic drift from selection remains a central focus of population genetics. Time-sampled data may provide a powerful tool for distinguishing these processes, and we here propose approximate Bayesian, maximum likelihood, and analytical methods for the inference of demography and selection from time course data. Utilizing these novel statistical and computational tools, we evaluate whole-genome datasets of an influenza A H1N1 strain in the presence and absence of oseltamivir (an inhibitor of neuraminidase) collected at thirteen time points. Results reveal a striking consistency amongst the three estimation procedures developed, showing strongly increased selection pressure in the presence of drug treatment. Importantly, these approaches re-identify the known oseltamivir resistance site, successfully validating the approaches used. Enticingly, a number of previously unknown variants have also been identified as being positively selected. Results are interpreted in the light of Fisher''s Geometric Model, allowing for a quantification of the increased distance to optimum exerted by the presence of drug, and theoretical predictions regarding the distribution of beneficial fitness effects of contending mutations are empirically tested. Further, given the fit to expectations of the Geometric Model, results suggest the ability to predict certain aspects of viral evolution in response to changing host environments and novel selective pressures.     

新编人类群体遗传学实验一组

本文介绍了一组新编的人群嗅阈测量实验。该实验既兼顾了培养学生进行人类群体遗传调查的基本方法与技能和调查当地人群的嗅觉相关基因频率与分布两方面,又兼顾了课堂实验与课外研究两方面,是实验教学改革中比较成功的一种类型。 Abstract:This paper presents a group of new experiments on human olfactory threshold measurement.It is a successful educational reform in teaching of genetic experiment.It considered not only training students' skills in the research on population genetics and investigating local population's olfactory allelic frequency,but also class experiments and research out of the class.     

A Population Genetics Model of Marker-Assisted Selection

A deterministic two-loci model was developed to predict genetic response to marker-assisted selection (MAS) in one generation and in multiple generations. Formulas were derived to relate linkage disequilibrium in a population to the proportion of additive genetic variance used by MAS, and in turn to an extra improvement in genetic response over phenotypic selection. Predictions of the response were compared to those predicted by using an infinite-loci model and the factors affecting efficiency of MAS were examined. Theoretical analyses of the present study revealed the nonlinearity between the selection intensity and genetic response in MAS. In addition to the heritability of the trait and the proportion of the marker-associated genetic variance, the frequencies of the selectively favorable alleles at the two loci, one marker and one quantitative trait locus, were found to play an important role in determining both the short- and long-term efficiencies of MAS. The evolution of linkage disequilibrium and thus the genetic response over several generations were predicted theoretically and examined by simulation. MAS dissipated the disequilibrium more quickly than drift alone. In some cases studied, the rate of dissipation was as large as that to be expected in the circumstance where the true recombination fraction was increased by three times and selection was absent.     

Population Genetics of SARS-CoV-2: Disentangling Effects of Sampling Bias and Infection Clusters

A novel RNA virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is responsible for the ongoing outbreak of coronavirus disease 2019 (COVID-19). Population genetic analysis could be useful for investigating the origin and evolutionary dynamics of COVID-19. However, due to extensive sampling bias and existence of infection clusters during the epidemic spread, direct applications of existing approaches can lead to biased parameter estimations and data misinterpretation. In this study, we first present robust estimator for the time to the most recent common ancestor (TMRCA) and the mutation rate, and then apply the approach to analyze 12,909 genomic sequences of SARS-CoV-2. The mutation rate is inferred to be 8.69 × 10⁻⁴ per site per year with a 95% confidence interval (CI) of [8.61 × 10⁻⁴, 8.77 × 10⁻⁴], and the TMRCA of the samples inferred to be Nov 28, 2019 with a 95% CI of [Oct 20, 2019, Dec 9, 2019]. The results indicate that COVID-19 might originate earlier than and outside of Wuhan Seafood Market. We further demonstrate that genetic polymorphism patterns, including the enrichment of specific haplotypes and the temporal allele frequency trajectories generated from infection clusters, are similar to those caused by evolutionary forces such as natural selection. Our results show that population genetic methods need to be developed to efficiently detangle the effects of sampling bias and infection clusters to gain insights into the evolutionary mechanism of SARS-CoV-2. Software for implementing VirusMuT can be downloaded at https://bigd.big.ac.cn/biocode/tools/BT007081.     

DNA Polymorphism in Population Genetics

In the review, the literature evidence on DNA polymorphism obtained in the last 10–15 years using various molecular-genetic methods is summarized. All main types of DNA variation are considered but attention is focused on those extensively used in population genetics. The areas of using DNA markers are outlined and the limitations of their potential in analyzing genetic processes in populations are discussed. Particular emphasis is placed on the relationship between the earlier developed biochemical genetics based on protein polymorphism analysis and modern molecular population genetics based on DNA polymorphism. The possible role of selection in maintaining DNA variation is considered.     

Lack of Support for the Association between Facial Shape and Aggression: A Reappraisal Based on a Worldwide Population Genetics Perspective

Antisocial and criminal behaviors are multifactorial traits whose interpretation relies on multiple disciplines. Since these interpretations may have social, moral and legal implications, a constant review of the evidence is necessary before any scientific claim is considered as truth. A recent study proposed that men with wider faces relative to facial height (fWHR) are more likely to develop unethical behaviour mediated by a psychological sense of power. This research was based on reports suggesting that sexual dimorphism and selection would be responsible for a correlation between fWHR and aggression. Here we show that 4,960 individuals from 94 modern human populations belonging to a vast array of genetic and cultural contexts do not display significant amounts of fWHR sexual dimorphism. Further analyses using populations with associated ethnographical records as well as samples of male prisoners of the Mexico City Federal Penitentiary condemned by crimes of variable level of inter-personal aggression (homicide, robbery, and minor faults) did not show significant evidence, suggesting that populations/individuals with higher levels of bellicosity, aggressive behaviour, or power-mediated behaviour display greater fWHR. Finally, a regression analysis of fWHR on individual''s fitness showed no significant correlation between this facial trait and reproductive success. Overall, our results suggest that facial attributes are poor predictors of aggressive behaviour, or at least, that sexual selection was weak enough to leave a signal on patterns of between- and within-sex and population facial variation.     

Population Genetics of Gene Function

This paper shows that differentiating the lifetimes of two phenotypes independently from their fertility can lead to a qualitative change in the equilibrium of a population: since survival and reproduction are distinct functional aspects of an organism, this observation contributes to extend the population-genetical characterisation of biological function. To support this statement a mathematical relation is derived to link the lifetime ratio T ₁/T ₂, which parameterizes the different survival ability of two phenotypes, with population variables that quantify the amount of neutral variation underlying a population’s phenotypic distribution.     

Gene Conversion: A Hitherto Overlooked Parameter in Population Genetics

Gene conversion causes deviations from the 2:2 segregation of allele pairs in meiosis. Thus, gene conversion is a potential cause for changes of allele frequencies in populations. Equations are derived for the effects of conversion in a large random-mating population. The influence of gene conversion on allele frequencies is compared with that of spontaneous mutation and meiotic drive.     

Molecular Population Genetics of Rice Domestication

Domestication is a selection process that genetically modifies species to meet human needs. A most intriguing feature of domestication is the extreme phenotypic diversification among breeds. What could be the ultimate source of such genetic variations? Another notable outcome of artificial selection is the reduction in the fitness of domesticated species when they live in the wild without human assistance. The complete sequences of the two subspecies of rice cultivars provide an opportunity to address these questions. Between the two subspecies, we found much higher rates of non‐synonymous (N) than synonymous (S) substitutions and the N/S ratios are higher between cultivars than between wild species. Most interestingly, substitutions of highly dissimilar amino acids that are deleterious and uncommon between natural species are disproportionately common between the two subspecies of rice. We suggest strong selection in the absence of effective recombination may be the driving force, which we called the domestication‐associated Hill‐Robertson effect. These hitchhiking mutations may contribute to some fitness reduction in cultivars. Comparisons of the two genomes also reveal the existence of highly divergent regions in the genomes. Haplotypes in these regions often form highly polymorphic linkage blocks that are much older than speciation between wild species. Genes from such regions could contribute to the differences between indica and japonica and are likely to be involved in the diversifying selection under domestication. Their existence suggests that the amount of genetic variation within the single progenitor species Oryza rufipogon may be insufficient to account for the variation among rice cultivars, which may come from a more inclusive gene pool comprising most of the A‐genome wild species. Genes from the highly polymorphic regions also provide strong support for the independent domestication of the two subspecies. The genomic variation in rice has revealing implications for studying the genetic basis of indica‐japonica differentiation under rice domestication and subsequent improvement.     

The Population Genetics of Sperm Displacement

This article reports the results of some sperm displacement experiments, as well as the results of a theoretical study of selection arising from genetic differences in displacing ability. The experimental work involved the use of three genetic marker stocks in double and triple matings. The speed of displacement following the matings was determined by scoring the progeny of each female daily. There were clear differences between strains in their displacing ability. It is shown how new information concerning the displacement process results when three markers are used; however, no new light is shed by these experiments on the mechanism of displacement.

The theoretical study of selection resulting from displacement uses a one-locus, two-allele model in which three diploid male genotypes confer different displacing abilities. The results indicate stable equilibria if (1) there is heterosis, and (2) there are certain nontransitive relationships in displacing ability among the different kinds of double matings.

Some evolutionary consequences are discussed in which sperm displacement is regarded as a form of sexual selection.

     

Population Genetics Theory: Another View

In this reply to Kempthorne's critique of current populationgenetics theory (this symposium), I describe the differencesin viewpoint and in choice of evidence which lead me to a morefavorable conclusion. Kempthorne's attacks on the general selectionmodel and on Fisher's Fundamental Theorem of Natural Selectionhave considerable justification; in both cases, however, qualificationis preferable to demolition. Furthermore, recent advances inselection theory really meet Kempthorne's well-founded objections.Finally, the most substantial point in Kempthorne's critiqueis not that current population genetics theory is inoperable,but that it is practically impossible to apply to life-historyproblems. Computers, properly programmed, may provide a valuableway around this impasse. In addition, the necessity and thedifficulty of manipulating one variable at a time have beenwith science for a long and exasperating time.     

Population Genetics of Polymorphism and Divergence

Frequencies of mutant sites are modeled as a Poisson random field in two species that share a sufficiently recent common ancestor. The selective effect of the new alleles can be favorable, neutral, or detrimental. The model is applied to the sample configurations of nucleotides in the alcohol dehydrogenase gene (Adh) in Drosophila simulans and Drosophila yakuba. Assuming a synonymous mutation rate of 1.5 x 10(-8) per site per year and 10 generations per year, we obtain estimates for the effective population size (N(e) = 6.5 x 10(6)), the species divergence time (tdiv = 3.74 million years), and an average selection coefficient (sigma = 1.53 x 10(-6) per generation for advantageous or mildly detrimental replacements), although it is conceivable that only two of the amino acid replacements were selected and the rest neutral. The analysis, which includes a sampling theory for the independent infinite sites model with selection, also suggests the estimate that the number of amino acids in the enzyme that are susceptible to favorable mutation is in the range 2-23 at any one time. The approach provides a theoretical basis for the use of a 2 x 2 contingency table to compare fixed differences and polymorphic sites with silent sites and amino acid replacements.     

寄生蠕虫的群体遗传学研究

寄生蠕虫群体遗传学研究常用的遗传标记有等位酶、线粒体DNA、随机扩增多态性DNA或扩增性片段长度多态性和微卫星DNA等。应用这些遗传标记的研究表明,大多数寄生蠕虫群体遗传结构有不同水平的变异,这些变异的产生主要与寄生虫的生活史和群体生态、宿主的地理分布和环境等因素有关,并因此提出了有关遗传变异的一些假说。本文对寄生蠕虫群体遗传学的研究作一综述。 Abstract:Genetic markers including allozyme,mtDNA,RAPD/RFLP and micro DNA have been used in the research of helminth population genetics.Available data on helminth genetic variability have shown that most helminth populations exhibit different levels of genetic variation resulting mainly from the pattern of life cycle,geographical distribution and parasite-host interaction,and several hypotheses have been proposed to explain the genetic variation.     

Evaluation of Current Population Genetics Theory

My aim is to give a partial evaluation or critique of the stateof population genetics theory. A decent theory must includethe following components: the development of concepts of fitnessthat have demonstrated epistemic correlations, life tables,mating, fecundity, finite (even if large) niche size, and, ofcourse, Mendelism and mutation. It must in the end also includevarying environment and competition between species. The extentto which the desiderata are met is discussed. The big lacunaein the whole theory appear to be the inadequate treatment offitness and the ignoring of niche capacity. Some theorems thatare given as fundamental must be questioned and even discarded.Integration of ideas of simple Mendelism, quantitative geneticvariation, and ecology is the big task ahead. It is criticalthat more complete theory be developed.