Search PubMed⌕ Search

Biomedical subjects

N H Barton

Publications and source records attributed to N H Barton.

At least 19 recordsLinked to original sources
PubMed2002

Understanding quantitative genetic variation.

Until recently, it was impracticable to identify the genes that are responsible for variation in continuous traits, or to directly observe the effects of their different alleles. Now, the abundance of genetic markers has made it possible to identify quantitative trait loci (QTL)--the regions of a chromosome or, ideally, individual sequence variants that are responsible for trait variation. What kind of QTL do we expect to find and what can our observations of QTL tell us about how organisms evolve? The key to understanding the evolutionary significance of QTL is to understand the nature of inherited variation, not in the immediate mechanistic sense of how genes influence phenotype, but, rather, to know what evolutionary forces maintain genetic variability.

Animals↗
PubMed2001

The role of hybridization in evolution.

Hybridization may influence evolution in a variety of ways. If hybrids are less fit, the geographical range of ecologically divergent populations may be limited, and prezygotic reproductive isolation may be reinforced. If some hybrid genotypes are fitter than one or both parents, at least in some environments, then hybridization could make a positive contribution. Single alleles that are at an advantage in the alternative environment and genetic background will introgress readily, although such introgression may be hard to detect. 'Hybrid speciation', in which fit combinations of alleles are established, is more problematic; its likelihood depends on how divergent populations meet, and on the structure of epistasis. These issues are illustrated using Fisher's model of stabilizing selection on multiple traits, under which reproductive isolation evolves as a side-effect of adaptation in allopatry. This confirms a priori arguments that while recombinant hybrids are less fit on average, some gene combinations may be fitter than the parents, even in the parental environment. Fisher's model does predict heterosis in diploid F1s, asymmetric incompatibility in reciprocal backcrosses, and (when dominance is included) Haldane's Rule. However, heterosis arises only when traits are additive, whereas the latter two patterns require dominance. Moreover, because adaptation is via substitutions of small effect, Fisher's model does not generate the strong effects of single chromosome regions often observed in species crosses.

Alleles↗
PubMed2001

Selection for recombination in small populations.

The reasons that sex and recombination are so widespread remain elusive. One popular hypothesis is that sex and recombination promote adaptation to a changing environment. The strongest evidence that increased recombination may evolve because recombination promotes adaptation comes from artificially selected populations. Recombination rates have been found to increase as a correlated response to selection on traits unrelated to recombination in several artificial selection experiments and in a comparison of domesticated and nondomesticated mammals. There are, however, several alternative explanations for the increase in recombination in such populations, including two different evolutionary explanations. The first is that the form of selection is epistatic, generating linkage disequilibria among selected loci, which can indirectly favor modifier alleles that increase recombination. The second is that random genetic drift in selected populations tends to generate disequilibria such that beneficial alleles are often found in different individuals; modifier alleles that increase recombination can bring together such favorable alleles and thus may be found in individuals with greater fitness. In this paper, we compare the evolutionary forces acting on recombination in finite populations subject to strong selection. To our surprise, we found that drift accounted for the majority of selection for increased recombination observed in simulations of small to moderately large populations, suggesting that, unless selected populations are large, epistasis plays a secondary role in the evolution of recombination.

Animals↗
PubMed2000

Genetic hitchhiking.

Selection on one or more genes inevitably perturbs other genes, even when those genes have no direct effect on fitness. This article reviews the theory of such genetic hitchhiking, concentrating on effects on neutral loci. Maynard Smith and Haigh introduced the classical case where the perturbation is due to a single favourable mutation. This is contrasted with the apparently distinct effects of inherited variation in fitness due to loosely linked loci. A model of fluctuating selection is analysed which bridges these alternative treatments. When alleles sweep between extreme frequencies at a rate lambda, the rate of drift is increased by a factor (1 + E[1/pq]lambda/(2(2lambda + r))), where the recombination rate r is much smaller than the strength of selection. In spatially structured populations, the effects of any one substitution are weaker, and only cause a local increase in the frequency of a neutral allele. This increase depends primarily on the rate of recombination relative to selection (r/s), and more weakly, on the neighbourhood size, Nb = 4(pi rho sigma)2. Spatial subdivision may allow local selective sweeps to occur more frequently than is indicated by the overall rate of molecular evolution. However, it seems unlikely that such sweeps can be sufficiently frequent to increase significantly the drift of neutral alleles.

Animals↗
PubMed2000

The stability of symmetric solutions to polygenic models.

Analysis of multilocus evolution is usually intractable for more than n approximately 10 genes, because the frequencies of very large numbers of genotypes must be followed. An exact analysis of up to n approximately 100 loci is feasible for a symmetrical model, in which a set of unlinked loci segregate for two alleles (labeled "0" and "1") with interchangeable effects on fitness. All haploid genotypes with the same number of 1 alleles can then remain equally frequent. However, such a symmetrical solution may be unstable: for example, under stabilizing selection, populations tend to fix any one genotype which approaches the optimum. Here, we show how the 2(n)x2(n) stability matrix can be decomposed into a set of matrices, each no larger than nxn. This allows the stability of symmetrical solutions to be determined. We apply the method to stabilizing and disruptive selection in a single deme and to selection against heterozygotes in a linear cline.

Emigration and Immigration↗
PubMed2000

The effect of epistasis on the structure of hybrid zones.

Within hybrid zones that are maintained by a balance between selection and dispersal, linkage disequilibrium is generated by the mixing of divergent populations. This linkage disequilibrium causes selection on each locus to act on all other loci, thereby steepening clines, and generating a barrier to gene flow. Diffusion models predict simple relations between the strength of linkage disequilibrium and the dispersal rate, sigma, and between the barrier to gene flow, B, and the reduction in mean fitness, W. The aim of this paper is to test the accuracy of these predictions by comparison with an exact deterministic model of unlinked loci (r = 0.5). Disruptive selection acts on the proportion of alleles from the parental populations (p,q): W = exp[-S(4pq)beta], such that the least fit genotype has fitness e-s. Where beta << 1, fitness is reduced for a wide range of intermediate genotypes; where beta >> 1, fitness is only reduced for those genotypes close to p = 0.5. Even with strong epistasis, linkage disequilibria are close to sigma 2p'ip'j/rij, where p'i, p'j are the gradients in allele frequency at loci i, j. The barrier to gene flow, which is reflected in the steepening of neutral clines, is given by [formula: see text] where r, the harmonic mean recombination rate between the neural and selected loci, is here 0.5. This is a close approximation for weak selection, but underestimates B for strong selection. The barrier is stronger for small beta, because hybrid fitness is then reduced over a wider range of p. The widths of the selected clines are harder to predict: though simple approximations are accurate for beta = 1, they become inaccurate for extreme beta because, then, fitness changes sharply with p. Estimates of gene number, made from neutral clines on the assumption that selection acts against heterozygotes, are accurate for weak selection when beta = 1; however, for strong selection, gene number is overestimated. For beta > 1, gene number is systematically overestimated and, conversely, when beta < 1, it is underestimated.

Alleles↗
PubMed2000

Measuring fitness by means of balancer chromosomes.

We present the theoretical background to a new method for measuring genetic variation for total fitness in Drosophila. The method allows heterozygous effects on total fitness of whole wild-type chromosomes to be measured under normal demography with overlapping generations. The wild-type chromosomes are competed against two balancer chromosomes (B1, B2, say), providing a standard genotype B1/B2 against which variation in the fitness effects of the wild-type chromosomes can be assessed. Fitness can be assessed in two ways: (i) at equilibrium of all three chromosomes under heterozygote advantage, and (ii) during displacement of one balancer by the other. Equilibrium with all three chromosomes present will be achieved only if the wild-type homozygote is not too fit, and if the fitnesses of the three heterozygotes are not too unequal. These conditions were not satisfied for any of a sample of 12 lethal-bearing chromosomes isolated from a random-bred laboratory population of Drosophila. At equilibrium, genotypic frequencies show low sensitivity to changes in genotypic fitness. Furthermore, where all four genotypes are viable and fertile, supplementary information from cages with only two chromosomes present and from direct measurements of pre-adult viability are required to estimate fitnesses from frequencies. The invasion method has the advantages of a greater sensitivity and of not requiring further data to estimate fitnesses if the wild-type homozygote is fertile. However, it requires that multiple samples be taken as the invasion progresses. In a discrete generation model, generation time influences fitness estimates from this method and is difficult to estimate accurately from the data. A full age-structured model can also be applied to the data from both types of experiment. For the invasion method, this gives fitness estimates close to those from the discrete generation model.

Adaptation, Physiological↗
PubMed2000

Estimating multilocus linkage disequilibria.

The state of a diploid population segregating for two alleles at each of n loci is described by 22n genotype frequencies, or equivalently, by allele frequencies and by multilocus moments or cumulants of various orders. These measures of linkage disequilibrium cannot usually be determined, both because one cannot tell whether a gene came from the maternal or paternal gamete, and because such a large number of parameters cannot be estimated even from large samples. Simplifying assumptions must therefore be made. This paper sets out methods for estimating multilocus genotype frequencies which are appropriate for unlinked neutral loci, and for populations that are ultimately derived by mixing of two source populations. In such a hybrid population, all multilocus associations depend primarily on the number of loci involved that derive from the maternal genome, and the number derived from the paternal genome. Allele frequencies may differ across loci, and the contribution of each locus to multilocus associations may be scaled by the difference in allele frequency between source populations for that locus (deltap </= 1). For example, the cumulant describing the association between genes i, j, k from the maternal genome, and genes i, l from the paternal genome is kappai,j,k,i*l*, = deltapi2 deltapj deltapk deltapl kappa3,2. The state of the population is described by n allele frequencies; n divergences, deltap; and by a symmetric matrix of cumulants, kappaJ,K (J=0,ellipsis, n, K=0, ellipsis, n). Expressions for these cumulants under short- and long-range migration are given. Two methods for estimating the cumulants are described: a simple method based on multivariate moments, and a maximum likelihood procedure, which uses the Metropolis algorithm. Both methods perform well when tested against simulations with two or four loci.

Algorithms↗
PubMed2000

Detecting bottlenecks and selective sweeps from DNA sequence polymorphism.

A coalescence-based maximum-likelihood method is presented that aims to (i) detect diversity-reducing events in the recent history of a population and (ii) distinguish between demographic (e.g., bottlenecks) and selective causes (selective sweep) of a recent reduction of genetic variability. The former goal is achieved by taking account of the distortion in the shape of gene genealogies generated by diversity-reducing events: gene trees tend to be more star-like than under the standard coalescent. The latter issue is addressed by comparing patterns between loci: demographic events apply to the whole genome whereas selective events affect distinct regions of the genome to a varying extent. The maximum-likelihood approach allows one to estimate the time and strength of diversity-reducing events and to choose among competing hypotheses. An application to sequence data from an African population of Drosophila melanogaster shows that the bottleneck hypothesis is unlikely and that one or several selective sweeps probably occurred in the recent history of this population.

DNA↗
PubMed1999

Clines in polygenic traits.

This article outlines theoretical models of clines in additive polygenic traits, which are maintained by stabilizing selection towards a spatially varying optimum. Clines in the trait mean can be accurately predicted, given knowledge of the genetic variance. However, predicting the variance is difficult, because it depends on genetic details. Changes in genetic variance arise from changes in allele frequency, and in linkage disequilibria. Allele frequency changes dominate when selection is weak relative to recombination, and when there are a moderate number of loci. With a continuum of alleles, gene flow inflates the genetic variance in the same way as a source of mutations of small effect. The variance can be approximated by assuming a Gaussian distribution of allelic effects; with a sufficiently steep cline, this is accurate even when mutation and selection alone are better described by the 'House of Cards' approximation. With just two alleles at each locus, the phenotype changes in a similar way: the mean remains close to the optimum, while the variance changes more slowly, and over a wider region. However, there may be substantial cryptic divergence at the underlying loci. With strong selection and many loci, linkage disequilibria are the main cause of changes in genetic variance. Even for strong selection, the infinitesimal model can be closely approximated by assuming a Gaussian distribution of breeding values. Linkage disequilibria can generate a substantial increase in genetic variance, which is concentrated at sharp gradients in trait means.

Alleles↗
PubMed1999

Hemochromatosis probands as blood donors.

BACKGROUND: There has been no estimate of the potential eligibility of hemochromatosis probands or patients as blood donors or the suitability for transfusion of their blood that was removed by therapeutic phlebotomy. STUDY DESIGN AND METHODS: According to guidelines of the American Association of Blood Banks, a retrospective estimate of these factors in 211 adult white hemochromatosis probands diagnosed during routine medical care was performed. The findings were compared to those in volunteer white whole-blood donors. RESULTS: Before diagnosis of hemochromatosis, 49 probands had voluntarily donated 597 units of blood; 88 percent were donated by men. After diagnosis, 142 (67%) of 211 probands were potentially eligible. Data on each unit removed during iron-depletion therapy and during the first year of maintenance therapy (therapeutic phlebotomy) were available in 86 eligible probands. Of 1592 units, 1029 (65%) obtained during iron-depletion therapy in eligible probands were potentially suitable; 86 percent were from men. During maintenance therapy, 106 (88%) of 121 units from eligible probands were potentially suitable. In volunteer donors, 255,567 (94%) of 273,302 presenting donors were accepted. After testing and laboratory losses, 239,300 (94%) units were acceptable for transfusion. CONCLUSIONS: In comparison with normal volunteers, hemochromatosis probands at diagnosis are less likely to be eligible as blood donors. The percentage of units obtained from patients during iron-depletion therapy that are suitable for transfusion is also lower, although the percentage increases during maintenance therapy.

Adult↗
PubMed1999

Introgression through rare hybridization: A genetic study of a hybrid zone between red and sika deer (genus Cervus) in Argyll, Scotland.

In this article we describe the structure of a hybrid zone in Argyll, Scotland, between native red deer (Cervus elaphus) and introduced Japanese sika deer (Cervus nippon), on the basis of a genetic analysis using 11 microsatellite markers and mitochondrial DNA. In contrast to the findings of a previous study of the same population, we conclude that the deer fall into two distinct genetic classes, corresponding to either a sika-like or red-like phenotype. Introgression is rare at any one locus, but where the taxa overlap up to 40% of deer carry apparently introgressed alleles. While most putative hybrids are heterozygous at only one locus, there are rare multiple heterozygotes, reflecting significant linkage disequilibrium within both sika- and red-like populations. The rate of backcrossing into the sika population is estimated as H = 0.002 per generation and into red, H = 0.001 per generation. On the basis of historical evidence that red deer entered Kintyre only recently, a diffusion model evaluated by maximum likelihood shows that sika have increased at approximately 9.2% yr-1 from low frequency and disperse at a rate of approximately 3.7 km yr-1. Introgression into the red-like population is greater in the south, while introgression into sika varies little along the transect. For both sika- and red-like populations, the degree of introgression is 30-40% of that predicted from the rates of current hybridization inferred from linkage disequilibria; however, in neither case is this statistically significant evidence for selection against introgression.

Alleles↗
PubMed1999

A comparison of multilocus clines maintained by environmental adaptation or by selection against hybrids.

There has recently been considerable debate over the relative importance of selection against hybrids ("endogenous" selection) vs. adaptation to different environments ("exogenous") in maintaining stable hybrid zones and hence in speciation. Single-locus models of endogenous and exogenous viability selection generate clines of similar shape, but the comparison has not been extended to multilocus systems, which are both quantitatively and qualitatively very different from the single-locus case. Here we develop an analytical multilocus model of differential adaptation across an environmental transition and compare it to previous heterozygote disadvantage models. We show that the shape of clines generated by exogenous selection is indistinguishable from that generated by endogenous selection. A stochastic simulation model is used to test the robustness of the analytical description to the effects of drift and strong selection, and confirms the prediction that pairwise linkage disequilibria are predominantly generated by migration. However, although analytical predictions for the width of clines maintained by heterozygote disadvantage fit well with the simulation results, those for environmental adaptation are consistently too narrow; reasons for the discrepancy are discussed. There is a smooth transition between a system in which a set of loci effectively act independently of each other and one in which they act as a single nonrecombining unit.

Adaptation, Physiological↗
PubMed1998

Why sex and recombination?

REVIEW Most higher organisms reproduce sexually, despite the automatic reproductive advantage experienced by asexual variants. This implies the operation of selective forces that confer an advantage to sexuality and genetic recombination, at either the population or individual level. The effect of sex and recombination in breaking down negative correlations between favorable variants at different genetic loci, which increases the efficiency of natural selection, is likely to be a major factor favoring their evolution and maintenance. Various processes that can cause such an effect have been studied theoretically. It has, however, so far proved hard to discriminate among them empirically.

Animals↗
PubMed1998

Testing for epistasis between deleterious mutations.

Determining the way in which deleterious mutations interact in their effects on fitness is crucial to numerous areas in population genetics and evolutionary biology. For example, if each additional mutation leads to a greater decrease in log fitness than the last (synergistic epistasis), then the evolution of sex and recombination may be favored to facilitate the elimination of deleterious mutations. However, there is a severe shortage of relevant data. Three relatively simple experimental methods to test for epistasis between deleterious mutations in haploid species have recently been proposed. These methods involve crossing individuals and examining the mean and/or skew in log fitness of the offspring and parents. The main aim of this paper is to formalize these methods, and determine the most effective way in which tests for epistasis could be carried out. We show that only one of these methods is likely to give useful results: crossing individuals that have very different numbers of deleterious mutations, and comparing the mean log fitness of the parents with that of their offspring. We also reconsider experimental data collected on Chlamydomonas moewussi using two of the three methods. Finally, we suggest how the test could be applied to diploid species.

Animals↗