scholarly journals Resolving the conflict between associative overdominance and background selection

2016 ◽  
Author(s):  
Lei Zhao ◽  
Brian Charlesworth
Keyword(s):  
Selective Advantage ◽  
Heterozygote Advantage ◽  
Background Selection ◽  
Effective Population ◽  
Infinite Population ◽  
Recessive Mutations ◽  
Neutral Locus ◽  
Large Populations ◽  
Marker Loci ◽  
Shed Light

In small populations, genetic linkage between a polymorphic neutral locus and loci subject to selection, either against partially recessive mutations or in favor of heterozygotes, may result in an apparent selective advantage to heterozygotes at the neutral locus (associative overdominance), and a retardation of the rate of loss of variability by genetic drift at this locus. In large populations, selection against deleterious mutations has previously been shown to reduce variability at linked neutral loci (background selection). We describe analytical, numerical and simulation studies that shed light on the conditions under which retardation versus acceleration of loss of variability occurs at a neutral locus linked to a locus under selection. We consider a finite, randomly mating population initiated from an infinite population in equilibrium at a locus under selection, with no linkage disequilibrium. With mutation and selection, retardation only occurs when S, the product of twice the effective population size and the selection coefficient, is of order one. With S >> 1, background selection always causes an acceleration of loss of variability. Apparent heterozygote advantage at the neutral locus is, however, always observed when mutations are partially recessive, even if there is an accelerated rate of loss of variability. With heterozygote advantage at the selected locus, there is nearly always a retardation of loss of variability. The results shed light on experiments on the loss of variability at marker loci in laboratory populations, and on the results of computer simulations of the effects of multiple selected loci on neutral variability.

scholarly journals The pattern of neutral molecular variation under the background selection model.

Genetics ◽  
1995 ◽  
Vol 141 (4) ◽  
pp. 1619-1632 ◽  
Author(s):  
D Charlesworth ◽  
B Charlesworth ◽  
M T Morgan
Keyword(s):  
Genetic Diversity ◽  
Genomic Region ◽  
Stochastic Simulations ◽  
Background Selection ◽  
Effective Population ◽  
Frequency Spectra ◽  
Low Genetic Diversity ◽  
Neutral Locus ◽  
Large Populations ◽  
Site Diversity

Abstract Stochastic simulations of the infinite sites model were used to study the behavior of genetic diversity at a neutral locus in a genomic region without recombination, but subject to selection against deleterious alleles maintained by recurrent mutation (background selection). In large populations, the effect of background selection on the number of segregating sites approaches the effect on nucleotide site diversity, i.e., the reduction in genetic variability caused by background selection resembles that caused by a simple reduction in effective population size. We examined, by coalescence-based methods, the power of several tests for the departure from neutral expectation of the frequency spectra of alleles in samples from randomly mating populations (Tajima's, Fu and Li's, and Watterson's tests). All of the tests have low power unless the selection against mutant alleles is extremely weak. In Drosophila, significant Tajima's tests are usually not obtained with empirical data sets from loci in genomic regions with restricted recombination frequencies and that exhibit low genetic diversity. This is consistent with the operation of background selection as opposed to selective sweeps. It remains to be decided whether background selection is sufficient to explain the observed extent of reduction in diversity in regions of restricted recombination.

Selection in natural and experimental populations of Drosophila pseudoobscura

Genome ◽  
1989 ◽  
Vol 31 (1) ◽  
pp. 239-245 ◽  
Author(s):  
Wyatt W. Anderson
Keyword(s):  
Natural Populations ◽  
Selective Advantage ◽  
Drosophila Pseudoobscura ◽  
Heterozygote Advantage ◽  
Male Mating ◽  
Fitness Components ◽  
Balanced Polymorphism ◽  
Experimental Populations ◽  
Shed Light

The inverted gene arrangements of Drosophila pseudoobscura were used by Th. Dobzhansky in pioneering analyses of natural selection. Recent experiments have shed light on the mechanisms of selection contributing to the balanced polymorphism for the gene arrangements. In experimental populations, both major components of fitness, viability and fertility, are frequency dependent, and rare genotypes often have a selective advantage. Viabilities are also density dependent. The frequency dependence and density dependence of the fitness components are not universal. Some karyotypes are strongly influenced by frequency or density, some are slightly influenced, and some do not appear to be influenced at all. The role of heterozygote advantage in the selection on the gene arrangements is not clear. It is probably one important element in the overall selection, but viability and fertility do not always show a heterozygote advantage. Viability and fertility components of selection seem to be about equally important in changing inversion frequencies. Male mating success is an important component of selection in natural populations, and in one population rare male karyotypes have been found to have a pronounced mating advantage.Key words: selection, selection components, Drosophila pseudoobscura, inversions.

scholarly journals The apparent selection on neutral marker loci in partially inbreeding populations

1991 ◽  
Vol 57 (2) ◽  
pp. 159-175 ◽  
Author(s):  
D. Charlesworth
Keyword(s):  
Inbreeding Depression ◽  
Relative Fitness ◽  
Heterozygote Advantage ◽  
Neutral Locus ◽  
Fitness Value ◽  
Marker Loci ◽  
Neutral Marker ◽  
Computer Calculations

SummaryDeterministic computer calculations were used to investigate the effects on the fitnesses of genotypes at neutral loci that are caused by associations with several linked or unlinked selected loci, in partially self fertilizing populations. Both mutation to partially recessive alleles and heterozygote advantage at the selected loci were studied. In the heterozygote advantage models, either arbitrary linkage between all loci was modelled, with a single neutral locus, or many unlinked selected and neutral loci were modelled. Large apparent overdominance could be generated in all types of model studied. As has previously been suggested, these types of effect can explain the observed associations between fitness and heterozygosity in partially inbreeding populations. There were also apparent fitness differences between the genotypes at the neutral locus among the progeny produced by selfing, especially with linkage between the neutral and selected loci. There is thus no genotype-independent fitness value for these progeny. Marker based methods for estimating the relative fitness of selfed and outcrossed progeny assume equality of these fitnesses, and will therefore be inaccurate (with in most cases a bias towards overestimating the degree of inbreeding depression) when there is linkage between the neutral marker loci and loci determining fitness.

scholarly journals Obstruction of adaptation in diploids by recessive, strongly deleterious alleles

2015 ◽  
Vol 112 (20) ◽  
pp. E2658-E2666 ◽  
Author(s):  
Zoe June Assaf ◽  
Dmitri A. Petrov ◽  
Jamie R. Blundell
Keyword(s):  
Genetic Disorders ◽  
Natural Populations ◽  
Selective Advantage ◽  
Adaptive Mutation ◽  
Heterozygote Advantage ◽  
Deleterious Mutations ◽  
Beneficial Mutation ◽  
Recessive Mutations ◽  
Deleterious Alleles ◽  
Signature Of Selection

Recessive deleterious mutations are common, causing many genetic disorders in humans and producing inbreeding depression in the majority of sexually reproducing diploids. The abundance of recessive deleterious mutations in natural populations suggests they are likely to be present on a chromosome when a new adaptive mutation occurs, yet the dynamics of recessive deleterious hitchhikers and their impact on adaptation remains poorly understood. Here we model how a recessive deleterious mutation impacts the fate of a genetically linked dominant beneficial mutation. The frequency trajectory of the adaptive mutation in this case is dramatically altered and results in what we have termed a “staggered sweep.” It is named for its three-phased trajectory: (i) Initially, the two linked mutations have a selective advantage while rare and will increase in frequency together, then (ii), at higher frequencies, the recessive hitchhiker is exposed to selection and can cause a balanced state via heterozygote advantage (the staggered phase), and (iii) finally, if recombination unlinks the two mutations, then the beneficial mutation can complete the sweep to fixation. Using both analytics and simulations, we show that strongly deleterious recessive mutations can substantially decrease the probability of fixation for nearby beneficial mutations, thus creating zones in the genome where adaptation is suppressed. These mutations can also significantly prolong the number of generations a beneficial mutation takes to sweep to fixation, and cause the genomic signature of selection to resemble that of soft or partial sweeps. We show that recessive deleterious variation could impact adaptation in humans and Drosophila.

scholarly journals The effect of background selection at a single locus on weakly selected, partially linked variants

1999 ◽  
Vol 73 (2) ◽  
pp. 133-146 ◽  
Author(s):  
WOLFGANG STEPHAN ◽  
BRIAN CHARLESWORTH ◽  
GILEAN McVEAN
Keyword(s):  
Sampling Method ◽  
Genetic Parameters ◽  
Single Locus ◽  
Background Selection ◽  
Effective Population ◽  
Weak Selection ◽  
Potential Significance ◽  
Neutral Locus ◽  
Site Diversity ◽  
Rates Of Molecular Evolution

Previous work has shown that genetic diversity at a neutral locus is affected by background selection due to recurrent deleterious mutations as though the effective population size Ne is reduced by a factor that is calculable from genetic parameters such as mutation rates, selection coefficients, and the rates of recombination between sites subject to selection and the neutral locus. Given that silent changes at third coding positions are often subject to weak selection pressures, it is important to develop similar quantitative predictions of the effects of background selection on variation and evolution at weakly selected sites. A diffusion approximation is derived that describes the effects of the presence of a single locus subject to mutation and strongly deleterious selection on variation and evolution at a partially linked, weakly selected locus. The results are validated by computer simulations using the Ito pseudo-sampling method. We show that both nucleotide site diversity and rates of molecular evolution at a weakly selected locus are affected by background selection as though Ne is reduced in the same way as for a neutral locus. Heuristic arguments are presented as to why the change in Ne for the neutral case also applies with weak selection. As in the case of a neutral locus, the number of segregating sites in the population is poorly predicted from the change in Ne. The potential significance of the results in relation to the effects of recombinational environment on molecular variation and evolution is discussed.

scholarly journals Coalescence with background and balancing selection in systems with bi- and uniparental reproduction: contrasting partial asexuality and selfing

2015 ◽  
Author(s):  
Aneil Agrawal ◽  
Matthew Hartfield
Keyword(s):  
Asexual Reproduction ◽  
Balancing Selection ◽  
Stochastic Simulations ◽  
Heterozygote Advantage ◽  
Background Selection ◽  
Effective Population ◽  
Sexual And Asexual Reproduction ◽  
Segregation Effect ◽  
Neutral Marker ◽  
Coalescent Time

Uniparental reproduction in diploids, via asexual reproduction or selfing, reduces the independence with which separate loci are transmitted across generations. This is expected to increase the extent to which a neutral marker is affected by selection elsewhere in the genome. Such effects have previously been quantified in coalescent models involving selfing. Here we examine the effects of background selection and balancing selection in diploids capable of both sexual and asexual reproduction (i.e., partial asexuality). We find that the effect of background selection on reducing coalescent time (and effective population size) can be orders of magnitude greater when rates of sex are low than when sex is common. This is because asexuality enhances the effects of background selection through both a recombination effect and a segregation effect. We show that there are several reasons that the strength of background selection differs between systems with partial asexuality and those with comparable levels of uniparental reproduction via selfing. Expectations for reductions in Ne via background selection have been verified using stochastic simulations. In contrast to background selection, balancing selection increases the coalescent time for a linked neutral site. With partial asexuality, the effect of balancing selection is somewhat dependent upon the mode of selection (e.g., heterozygote advantage vs. negative frequency dependent selection) in a manner that does not apply to selfing. This is because the frequency of heterozygotes, which are required for recombination onto alternative genetic backgrounds, is more dependent on the pattern of selection with partial asexuality than with selfing.

Genetic Drift in an Infinite Population: The Pseudohitchhiking Model

Genetics ◽  
2000 ◽  
Vol 155 (2) ◽  
pp. 909-919 ◽  
Author(s):  
John H Gillespie
Keyword(s):  
Genetic Drift ◽  
Stochastic Dynamics ◽  
Diffusion Theory ◽  
Stochastic Effects ◽  
Stochastic Force ◽  
Infinite Population ◽  
Sample Paths ◽  
Neutral Locus ◽  
Linked Selection ◽  
Number Of Branches

Abstract 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.

scholarly journals Molecular markers applying in forest trees gene pool conservation

2009 ◽  
pp. 101-113
Author(s):  
Jelena Milovanovic ◽  
Mirjana Sijacic-Nikolic
Keyword(s):  
Population Genetics ◽  
Molecular Markers ◽  
Gene Flow ◽  
Gene Pool ◽  
Statistical Power ◽  
Forest Trees ◽  
Effective Population ◽  
Migration Patterns ◽  
Geographic Diversity ◽  
Marker Loci

Many studies performed during the last years demonstrated the usefulness of neutral molecular markers in the field of conservation and population genetics of forest trees, in particular to understand the importance of migration patterns in shaping current genetic and geographic diversity and to measure important parameters such as effective population size, gene flow and past bottleneck. During the next years, a large amount of data at marker loci or at sequence level is expected to be collected, and to become excellent statistical power for the assessment of biological and evolutionary value.

scholarly journals Detrimental genes with partial selfing and effects on a neutral locus

1974 ◽  
Vol 23 (2) ◽  
pp. 191-200 ◽  
Author(s):  
Tomoko Ohta ◽  
C. Clark Cockerham
Keyword(s):  
Linkage Disequilibrium ◽  
Mutational Load ◽  
Complete Linkage ◽  
Single Mutant ◽  
Infinite Population ◽  
Neutral Locus ◽  
Dominant Mutant ◽  
Self Fertilization ◽  
Recessive Mutant ◽  
Mutant Genes

SUMMARYGene and genotypic frequencies for a deleterious mutant in mutation selection balance are derived for an infinite population undergoing partial self-fertilization. These provide formulations of mean survival and the mutational load. Obtained also are the average number of mutant genes and affected individuals stemming from a single mutant.As a concomitant effect on frequencies at a neutral locus the mutational load is distributed disproportionately among the neutral genotypes. For partially recessive mutant genes on the 1, 1-sh, 1-s scale, the effect is to increase the frequency of the heterozygote and to decrease the frequencies of homozygotes at the neutral locus relative to the frequencies expected with complete neutrality. This apparent overdominance at the neutral locus has been shown to be connected with identity disequilibrium rather than linkage disequilibrium. It increases generally as s and h decrease, and as the proportion of self-fertilization and the degree of linkage increase. The apparent overdominance with complete linkage is generally less than double that for free recombination. For partially dominant mutant genes, h ≥ ½, the effects on the frequencies of heterozygote and homozygotes at the neutral locus are reversed.

The dynamics of neutral mutation

1978 ◽  
Vol 203 (1150) ◽  
pp. 91-91
Keyword(s):  
Stochastic Models ◽  
Diffusion Approximations ◽  
Neutral Systems ◽  
Effective Population ◽  
Gene Frequencies ◽  
Deterministic Models ◽  
New Approach ◽  
Large Populations ◽  
Quantitative Results ◽  
Infinite Alleles Model

A variety of mathematical models have been proposed, over the years since the pioneering work of Fisher and Wright, for the evolution of gene frequencies in large populations under the pressure of selection and mutation. It is broadly true to say that deterministic models are adequate, at least to a first approximation, when selective differences are large compared with the reciprocal of the effective population size. When selection is weaker than this, genetic drift is sufficiently obtrusive to make stochastic models essential. Such models are typically much more difficult to analyse than deterministic ones, and detailed studies have usually been confined to the very special situation of statistical equilibrium. But of course no biological system is really in equilibrium for very long, and moreover the relaxation of nearly neutral systems is usually slow; hence the need for dynamical stochastic models and for their analysis outside a state of equilibrium. The usual way of attacking this problem is by diffusion approximations, and the theory of such processes is surveyed. Questions of existence, uniqueness and adequacy of approximation are well understood, but much less is known about methods of deriving explicit quantitative results or qualitative insight. A new approach is suggested which is particularly useful for studying a locus at which many different alleles are possible. It leads, for example, to a dynamical picture (in terms of a diffusing Poisson process) for the neutral infinite-alleles model of Kimura & Crow.

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