Is the population size of a species relevant to its evolution?

This paper examines aspects of genetic draft, the stochastic force induced by substitutions at one locus on the dynamics of a closely linked locus. Of particular interest is the role of population size on genetic draft. Remarkably, the rate of substitution of weakly selected advantageous mutations decreases with increasing population size, whereas that for deleterious mutations increases with population size. This dependency on population size is the opposite of that for genetic drift. Moreover, these rates are only weakly dependent on population size, again contrary to the strong dependency of drift-based dynamics. Four models of the strongly selected loci responsible for genetic draft are examined. Three of these exhibit a very weak dependency on population size, which implies that their induced effects will also be weakly dependent on population size. Together, these results suggest that population size and binomial sampling may not be relevant to a species' evolution. If this is the case, then a number of evolutionary conundrums are resolved.

Genetic drift in an infinite population. The pseudohitchhiking model.

Selected substitutions at one locus can induce stochastic dynamics that resemble genetic drift at a closely linked neutral locus. The pseudohitchhiking model is a one-locus model that approximates these effects and can be used to describe the major consequences of linked selection. As the changes in neutral allele frequencies when hitchhiking are rapid, diffusion theory is not appropriate for studying neutral dynamics. A stationary distribution and some results on substitution processes are presented that use the theory of continuous-time Markov processes with discontinuous sample paths. The coalescent of the pseudohitchhiking model is shown to have a random number of branches at each node, which leads to a frequency spectrum that is different from that of the equilibrium neutral model. If genetic draft, the name given to these induced stochastic effects, is a more important stochastic force than genetic drift, then a number of paradoxes that have plagued population genetics disappear.

The neutral theory in an infinite population.

Selective substitutions at one locus induce stochastic dynamics at a linked neutral locus that resemble genetic drift even when the population size is infinite. This new stochastic force, which is called genetic draft, causes genetic variation at the neutral locus to decrease with population size and the rate of deleterious substitution to increase with population size. The fact that heterozygosities in natural populations are only weakly dependent on population size suggests that genetic draft may be a much more important stochastic force than genetic drift in natural populations. Some of the mathematical properties of genetic draft are explored.

The role of population size in molecular evolution.

The results of a computer simulation study of the role of population size in population genetical models of molecular evolution are presented. If the mutation rate and strength of selection are held fixed and the population size increased, the eight models examined fall into three domains based on their rates of substitution. In the Ohta domain, the rate of substitution decreases with increasing population size; in the Kimura domain, the rate of substitution remains close to the mutation rate; in the Darwin domain, the rate of substitution increases without bound. In the Kimura and Darwin domains, the rate of substitution is much less sensitive to the population size than suggested by two-allele theories. Remarkably, the overdominance model converges to the neutral model with increasing N. The variation at a neutral locus linked to a selected locus is found to be insensitive to the population size for certain models of selection. A selected locus can actually cause the rate of substitution of deleterious alleles at a linked locus to increase with increasing population size. These unexpected results illustrate that intuition based on two-allele theory is often misleading.

Junk ain't what junk does: neutral alleles in a selected context.

A simulation study of the effects of linked selection on a neutral locus is described. Of six models of selection examined, four could be called variation-reducing as they lower the level of molecular variation at the neutral locus. Unfortunately, all four distort the neutral frequency spectrum in similar ways, making the problem of inferring the appropriate model quite difficult. Similarly, an examination of the effects of linked selection on the non-random association of mutations at two linked neutral loci did not suggest that this property would be useful for inferring the nature of linked selection either. Linked selection may have a profound effect on the 'effective population size' of the neutral locus. For two of the variation-reducing models, the effective size at the neutral locus is almost independent of the actual population size.

Substitution processes in molecular evolution. III. Deleterious alleles.

The substitution processes for various models of deleterious alleles are examined using computer simulations and mathematical analyses. Most of the work focuses on the house-of-cards model, which is a popular model of deleterious allele evolution. The rate of substitution is shown to be a concave function of the strength of selection as measured by alpha = 2N sigma, where N is the population size and sigma is the standard deviation of fitness. For alpha < 1, the house-of-cards model is essentially a neutral model; for alpha > 4, the model ceases to evolve. The stagnation for large alpha may be understood by appealing to the theory of records. The house-of-cards model evolves to a state where the vast majority of all mutations are deleterious, but precisely one-half of those mutations that fix are deleterious (the other half are advantageous). Thus, the model is not a model of exclusively deleterious evolution as is frequently claimed. It is argued that there are no biologically reasonable models of molecular evolution where the vast majority of all substitutions are deleterious. Other models examined include the exponential and gamma shift models, the Hartl-Dykhuizen-Dean (HDD) model, and the optimum model. Of all those examined, only the optimum and HDD models appear to be reasonable candidates for silent evolution. None of the models are viewed as good candidates for protein evolution, as none are both biologically reasonable and exhibit the variability in substitutions commonly observed in protein sequence data.

Substitution processes in molecular evolution. I. Uniform and clustered substitutions in a haploid model.

A computer simulation of the process of nucleotide substitutions in a finite haploid population subject to selection in a randomly fluctuating environment provides a number of unexpected results. For rapidly fluctuating environments, substitutions are more regular than random. A small mutation-rate approximation is used to explain the regularity. The explanation does not depend heavily on the particulars of the haploid model, leading to the conjecture that many symmetrical models of molecular evolution with rapidly changing parameters may exhibit substitutions that are more regular than random. When fitnesses change very slowly, the simulation shows that substitutions are more clumped than random. Here a small-mutation approximation shows that the clustering is due to the increase in fitness that accompanies each successive substitution with a consequent lowering of the effective mutation rate. The two observations taken together suggest that the common observation that amino acid substitutions are clustered in time is due to the presence of parameters that change very slowly.

Codon usage divergence of homologous vertebrate genes and codon usage clock.

This paper is concerned with the divergence of synonymous codon usage and its bias in three homologous genes within vertebrate species. Genetic distances among species are described in terms of synonymous codon usage divergence and the correlation is found between the genetic distances and taxonomic distances among species under study. A codon usage clock is reported in alpha-globin and beta-globin. A method is developed to define the synonymous codon preference bias and it is observed that the bias changes considerably among species.

The molecular nature of allelic diversity for two models of balancing selection.

This paper provides a theoretical description of the distribution of the number of mutations that separate alleles that are held in a population by balancing selection. Two models of nucleotide site epistasis are described: parity models and additive site models. Parity models are shown to result in a more uniform distribution of mutations across alleles than the neutral model, while additive sites models show a more extreme distribution. The analytic approach uses strong-selection, weak-mutation approximations to constant-fitness and random-environment diffusion models.

Experimental transmission of bovine viral diseases by insemination with contaminated semen or during embryo transfer.

Three experimental approaches were used to study transmission of blue tongue (BT), infectious bovine rhinotracheitis (IBR) and bovine virus diarrhoea (BVD) viruses. These were insemination with contaminated semen, experimental infection of embryo donor cows, or transfer of embryos experimentally exposed to virus in vitro to normal recipients. Parameters assessed included number and quality of embryos produced, virus detection (isolation and electron microscopy), serology and histopathology. All superovulated sesceptible cows inseminated with semen containing blue tongue virus (BTV) (n = 2) or infectious bovine rhinotracheitis virus (IBRV) (n = 2) became infected. One cow inseminated with semen containing BTV produced seven virus-free seven-day-old embryos; the second cow failed to produce any embryos. One of two cows inseminated with semen containing IBRV produced two underdeveloped, virus-free embryos while no embryos were produced by the second cow. One of two cows inseminated with semen containing bovine viral diarrhoea virus (BVDV) became infected. Two poorly developed, virus-free seven-day-old embryos were recovered from one of these cows. Superovulated susceptible cows inoculated either intramuscularly with BTV (n = 3) or intranasally with IBR virus (n = 2) became infected. Virus was isolated from some tissues of two BTV-infected cows, neither of which produced embryos. A third BTV-infected cow produced two virus-free embryos collected at necropsy five days after inoculation. One of two cows experimentally infected with IBR virus, produced three embryos but virus was not detected either by electron microscopy (1 embryo) or in cell culture by cytopathic alterations (1 embryo).(ABSTRACT TRUNCATED AT 400 WORDS)

Comparison of persistence of seven bovine viruses on bovine embryos following in vitro exposure.

The ability of seven cytopathic strains of bovine viruses to adhere to the zona pellucida of six-to-eight day-old bovine embryos were compared. Embryos were exposed to virus by placing them either in virus suspensions or by culturing them on infected bovine turbinate cultures for 18-24 h. After exposure to bovine virus diarrhea virus (BVDV), infectious bovine rhinotracheitis virus (IBV), bluetongue virus (BTV), pseudorabies virus (PRV), vesicular stomatitis virus (VSV), parainfluenza 3 virus (PI3), or bovine enterovirus virus (BEV), the embryos were tested for virus by culture in bovine turbinate cells and by morphological examination using electron microscopy (EM). A special technique to minimize loss of embryos processed for EM was developed. More embryos had viral particles on the surface of the zona pellucida after exposure to 18-24 hour infected cell cultures than did embryos exposed to viral culture suspensions. The most dramatic finding was that BTV adhered in large numbers to the surface of the zona pellucida of exposed embryos. IBRV, PRV, and VSV comprised an intermediate group, with virions occasionally detected on the surface of exposed embryos after 5 washes. Therefore, extensive washing is required. The PI3 and BEV were easily removed from embryo-exposed virus by washing. BVD was difficult to identify morphologically, making assessment by EM unreliable. There was no evidence that any one of the seven viruses penetrated the intact zona pellucida. Using a micromanipulator, 42 embryos were also directly inoculated through the zona pellucida with +/- 50 picoliters of virus inoculum or medium.(ABSTRACT TRUNCATED AT 250 WORDS)

Lineage effects and the index of dispersion of molecular evolution.

Recent efforts to estimate the index of dispersion [R(t)] of molecular evolution-i.e., the ratio of the variance in the number of substitutions on a lineage to the mean number-have suffered from an inability to adjust the data for lineage effects. These effects may include the generation-time dependency of the rate of evolution or improper assumptions about the branching pattern of a phylogenetic tree. In the present paper a method for correcting for lineage effects in the estimation of R(t) is presented for trees made up of three species. The recent data published by Li et al. for 20 loci in three orders of mammals is examined, and the average R(t), corrected for lineage effects, is shown to be 7.75 for replacement substitutions and 3.3 for silent substitutions. Thus the high values reported earlier may not be dismissed as due to generation-time effects or improper assumptions about phylogenies. Computer simulations are presented to give confidence in the estimate for replacement substitutions but also to demonstrate that the estimate for silent substitutions is sensitive to corrections for multiple substitutions and is not as reliable. This work's implications for our understanding of the mechanism of molecular evolution are discussed, and the arguments in favor of the hypothesis that replacement substitutions are mostly selected while silent substitutions are mostly neutral is presented.

Could natural selection account for molecular evolution and polymorphism?

A model of molecular evolution is presented that is based on the combined action of natural selection, genetic drift, and mutation. The mathematical description of the model uses strong-selection, weak-mutation limits to approximate the dynamics of multidimensional diffusion processes with one dimensional Markov chains. This approach leads to a great simplification of the dynamics and provides a unified method for describing many different mechanisms of natural selection. In this paper two models are examined, one based on selection in a randomly fluctuating environment, the other on overdominance. Both models exhibit similar dynamics, with a rapid buildup phase that introduces new alleles into the population, followed by a relatively quiescent phase where new alleles may enter and leave the population at a low rate. If occasional extreme environmental changes occur that favor particular alleles, the resulting dynamics turn out to be in remarkable agreement with many of the observations on molecular evolution and polymorphism. Thus the model is at least as successful as the neutral theory in accounting for evolutionary events at the molecular level.

Genotype-environment interactions and the maintenance of polygenic variation.

Genotype-environment interactions may be a potent force maintaining genetic variation in quantitative traits in natural populations. This is shown by a simple model of additive polygenic inheritance in which the additive contributions of alleles vary with the environment. Under simplifying symmetry assumptions, the model implies that the variance of the phenotypes produced across environments by a multilocus genotype decreases as the number of heterozygous loci increases. In the region of an optimal phenotype, the mapping from the quantitative trait into fitness is concave, and the mean fitness of a genotype will increase with the number of heterozygous loci. This leads to balancing selection, polymorphism, and potentially high levels of additive genetic variance, even though all allelic effects remain additive within each specific environment. An important implication of the model is that the variation maintained by genotype-environment interactions is difficult to study with the restricted range of environments represented in typical experiments. In particular, if fluctuations in allelic effects are pervasive, as suggested by the extensive literature on genotype-environment interactions, efforts to estimate genetic parameters in a single environment may be of limited value.

Levels of interferon in blood serum and toxicity studies of bacteria-derived bovine alpha I1 interferon in dairy calves.

This paper reports information on the levels of interferon (IFN) in the blood serum of dairy calves given 10(6) U of bacteria-derived bovine alpha I1 interferon per kg of body weight by intravenous (i.v.), intramuscular (i.m.), subcutaneous (s.c.), and intranasal (i.n.) routes. Highest levels (10,000 U/ml) in the vesicular stomatitis viral assay system were obtained after i.v. administration and occurred within 30 min of a dose; levels rapidly declined thereafter to a low of 200 to 300 U/ml by 24 h. Serum inhibitory activity against vesicular stomatitis virus in this range is sometimes found in normal dairy calves. Levels after i.m. and s.c. administration were similar: a plateau of 1,000 to 2,000 U/ml between 2 and 8 h after a treatment with a decline to 200 to 300 U/ml by 24 h. Serum IFN was not detected after i.n. dosing or in the control group given physiological buffered saline by the i.m. route. A transitory moderate febrile response, but no other clinical adverse effects, was noted after the first intramuscular dose of IFN, but not after subsequent i.m. doses. No clinical signs were noted after i.v., s.c., or i.n. dosing or in the control calves given physiological buffered saline intramuscularly. After i.v., s.c., and i.m. administration of IFN, leukopenia, neutropenia, and lymphocytopenia were observed; these were most prominent within the first 24 h after the initial dose of IFN.