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Nucleotide sequence diversity at the alcohol dehydrogenase 1 locus in wild barley (Hordeum vulgare ssp. spontaneum): An evaluation of the background selection hypothesis

Cummings, Michael P.; Clegg, Michael T.
Fonte: The National Academy of Sciences Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
Publicado em 12/05/1998 EN
Relevância na Pesquisa
46.09%
The background selection hypothesis predicts a reduction in nucleotide site diversity and an excess of rare variants, owing to linkage associations with deleterious alleles. This effect is expected to be amplified in species that are predominantly self-fertilizing. To examine the predictions of the background selection hypothesis in self-fertilizing species, we sequenced 1,362 bp of adh1, a gene for alcohol dehydrogenase (Adh; alcohol:NAD+ oxidoreductase, EC 1.1.1.1), in a sample of 45 accessions of wild barley, Hordeum vulgare ssp. spontaneum, drawn from throughout the species range. The region sequenced included 786 bp of exon sequence (part of exon 4, all of exons 5–9, and part of exon 10) and 576 bp of intron sequence (all of introns 4–9). There were 19 sites polymorphic for nucleotide substitutions, 8 in introns, and 11 in exons. Of the 11 nucleotide substitutions in codons, 4 were synonymous and 7 were nonsynonymous, occurring uniquely in the sample. There was no evidence of recombination in the region studied, and the estimated effective population size (N̂e) based on synonymous sites was ≈1.8–4.2 × 105. Several tests reveal that the pattern of nonsynonymous substitutions departs significantly from neutral expectations. However...

A test of the background selection hypothesis based on nucleotide data from Drosophila ananassae

Stephan, Wolfgang; Xing, Lin; Kirby, David A.; Braverman, John M.
Fonte: The National Academy of Sciences Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
Publicado em 12/05/1998 EN
Relevância na Pesquisa
46.02%
We estimated DNA sequence variation within and between four populations of Drosophila ananassae at Om(1D) and vermilion (v) by using single-strand conformation polymorphism analysis and direct DNA sequencing. Om(1D) is located on the X chromosome in a region with a normal recombination rate; v is in a region of low recombination. In each population, levels of nucleotide diversity at v are reduced 10- to 25-fold relative to those at Om(1D). Divergence between D. ananassae and its sibling species D. pallidosa, however, is comparable for both loci. This lack of correlation between levels of polymorphism and divergence led to the rejection of a constant-rate, neutral model. To distinguish among alternative models, we propose a test of the background selection hypothesis based on the observed pattern of differentiation between populations. Although the degree of differentiation (measured by FST) among all pairs of subpopulations is similar at Om(1D), we found substantial differences at v. The two northern populations from Burma and Nepal are very homogeneous, whereas comparisons between northern and southern populations (e.g., between Nepal and middle India) produced large FST values. A coalescent-based simulation of the background selection model (in a geographically structured species with a finite number of demes) showed that the observed homogeneity among the northern populations is inconsistent with the background selection hypothesis. Instead...

Fitting background-selection predictions to levels of nucleotide variation and divergence along the human autosomes

Reed, Floyd A.; Akey, Joshua M.; Aquadro, Charles F.
Fonte: Cold Spring Harbor Laboratory Press Publicador: Cold Spring Harbor Laboratory Press
Tipo: Artigo de Revista Científica
Publicado em /09/2005 EN
Relevância na Pesquisa
46.12%
The roles of positive directional selection (selective sweeps) and negative selection (background selection) in shaping the genome-wide distribution of genetic variation in humans remain largely unknown. Here, we optimize the parameter values of a model of the removal of deleterious mutations (background selection) to observed levels of human polymorphism, controlling for mutation rate heterogeneity by using interspecific divergence. A point of “best fit” was found between background-selection predictions and estimates of human effective population sizes, with reasonable parameter estimates whose uncertainty was assessed by bootstrapping. The results suggest that the purging of deleterious alleles has had some influence on shaping levels of human variation, although the effects may be subtle over the majority of the human genome. A significant relationship was found between background-selection predictions and measures of skew in the allele frequency distribution. The genome-wide action of selection (positive and/or negative) is required to explain this observation.

Deleterious Background Selection with Recombination

Hudson, R. R.; Kaplan, N. L.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/1995 EN
Relevância na Pesquisa
45.93%
An analytic expression for the expected nucleotide diversity is obtained for a neutral locus in a region with deleterious mutation and recombination. Our analytic results are used to predict levels of variation for the entire third chromosome of Drosophila melanogaster. The predictions are consistent with the low levels of variation that have been observed at loci near the centromeres of the third chromosome of D. melanogaster. However, the low levels of variation observed near the tips of this chromosome are not predicted using currently available estimates of the deleterious mutation rate and of selection coefficients. If considerably smaller selection coefficients are assumed, the low observed levels of variation at the tips of the third chromosome are consistent with the background selection model.

Joint effects of genetic hitchhiking and background selection on neutral variation.

Kim, Y; Stephan, W
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/2000 EN
Relevância na Pesquisa
46.14%
Due to relatively high rates of strongly selected deleterious mutations, directional selection on favorable alleles (causing hitchhiking effects on linked neutral polymorphisms) is expected to occur while a deleterious mutation-selection balance is present in a population. We analyze this interaction of directional selection and background selection and study their combined effects on neutral variation, using a three-locus model in which each locus is subjected to either deleterious, favorable, or neutral mutations. Average heterozygosity is measured by simulations (1) at the stationary state under the assumption of recurrent hitchhiking events and (2) as a transient level after a single hitchhiking event. The simulation results are compared to theoretical predictions. It is shown that known analytical solutions describing the hitchhiking effect without background selection can be modified such that they accurately predict the joint effects of hitchhiking and background on linked, neutral variation. Generalization of these results to a more appropriate multilocus model (such that background selection can occur at multiple sites) suggests that, in regions of very low recombination rates, stationary levels of nucleotide diversity are primarily determined by hitchhiking...

Distinguishing the hitchhiking and background selection models.

Innan, Hideki; Stephan, Wolfgang
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/2003 EN
Relevância na Pesquisa
45.83%
A simple method to distinguish hitchhiking and background selection is proposed. It is based on the observation that these models make different predictions about the average level of nucleotide diversity in regions of low recombination. The method is applied to data from Drosophila melanogaster and two highly selfing tomato species.

Background Selection in Single Genes May Explain Patterns of Codon Bias

Loewe, Laurence; Charlesworth, Brian
Fonte: Copyright © 2007 by the Genetics Society of America Publicador: Copyright © 2007 by the Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em /03/2007 EN
Relevância na Pesquisa
46.07%
Background selection involves the reduction in effective population size caused by the removal of recurrent deleterious mutations from a population. Previous work has examined this process for large genomic regions. Here we focus on the level of a single gene or small group of genes and investigate how the effects of background selection caused by nonsynonymous mutations are influenced by the lengths of coding sequences, the number and length of introns, intergenic distances, neighboring genes, mutation rate, and recombination rate. We generate our predictions from estimates of the distribution of the fitness effects of nonsynonymous mutations, obtained from DNA sequence diversity data in Drosophila. Results for genes in regions with typical frequencies of crossing over in Drosophila melanogaster suggest that background selection may influence the effective population sizes of different regions of the same gene, consistent with observed differences in codon usage bias along genes. It may also help to cause the observed effects of gene length and introns on codon usage. Gene conversion plays a crucial role in determining the sizes of these effects. The model overpredicts the effects of background selection with large groups of nonrecombining genes...

Rapid and Targeted Introgression of Genes into Popular Wheat Cultivars Using Marker-Assisted Background Selection

Randhawa, Harpinder S.; Mutti, Jasdeep S.; Kidwell, Kim; Morris, Craig F.; Chen, Xianming; Gill, Kulvinder S.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 01/06/2009 EN
Relevância na Pesquisa
45.89%
A marker-assisted background selection (MABS)-based gene introgression approach in wheat (Triticum aestivum L.) was optimized, where 97% or more of a recurrent parent genome (RPG) can be recovered in just two backcross (BC) generations. A four-step MABS method was developed based on ‘Plabsim’ computer simulations and wheat genome structure information. During empirical optimization of this method, double recombinants around the target gene were selected in a step-wise fashion during the two BC cycles followed by selection for recurrent parent genotype on non-carrier chromosomes. The average spacing between carrier chromosome markers was <4 cM. For non-carrier chromosome markers that flanked each of the 48 wheat gene-rich regions, this distance was ∼12 cM. Employed to introgress seedling stripe rust (Puccinia striiformis f. sp. tritici) resistance gene Yr15 into the spring wheat cultivar ‘Zak’, marker analysis of 2,187 backcross-derived progeny resulted in the recovery of a BC2F2∶3 plant with 97% of the recurrent parent genome. In contrast, only 82% of the recurrent parent genome was recovered in phenotypically selected BC4F7 plants developed without MABS. Field evaluation results from 17 locations indicated that the MABS-derived line was either equal or superior to the recurrent parent for the tested agronomic characteristics. Based on these results...

Genetic hitchhiking versus background selection: the controversy and its implications

Stephan, Wolfgang
Fonte: The Royal Society Publicador: The Royal Society
Tipo: Artigo de Revista Científica
Publicado em 27/04/2010 EN
Relevância na Pesquisa
45.89%
The controversy on the relative importance of background selection (BGS; against deleterious mutations) and genetic hitchhiking (associated with positive directional selection) in explaining patterns of nucleotide variation in natural populations stimulated research activities for almost a decade. Despite efforts from many theorists and empiricists, fundamental questions are still open, in particular, for the population genetics of regions of reduced recombination. On the other hand, the development of the BGS and hitchhiking models and the long struggle to distinguish them, all of which seem to be a purely academic exercise, led to quite practical advances that are useful for the identification of genes involved in adaptation and domestication.

The Joint Effects of Background Selection and Genetic Recombination on Local Gene Genealogies

Zeng, Kai; Charlesworth, Brian
Fonte: Genetics Society of America Publicador: Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em /09/2011 EN
Relevância na Pesquisa
46.17%
Background selection, the effects of the continual removal of deleterious mutations by natural selection on variability at linked sites, is potentially a major determinant of DNA sequence variability. However, the joint effects of background selection and genetic recombination on the shape of the neutral gene genealogy have proved hard to study analytically. The only existing formula concerns the mean coalescent time for a pair of alleles, making it difficult to assess the importance of background selection from genome-wide data on sequence polymorphism. Here we develop a structured coalescent model of background selection with recombination and implement it in a computer program that efficiently generates neutral gene genealogies for an arbitrary sample size. We check the validity of the structured coalescent model against forward-in-time simulations and show that it accurately captures the effects of background selection. The model produces more accurate predictions of the mean coalescent time than the existing formula and supports the conclusion that the effect of background selection is greater in the interior of a deleterious region than at its boundaries. The level of linkage disequilibrium between sites is elevated by background selection...

The Role of Background Selection in Shaping Patterns of Molecular Evolution and Variation: Evidence from Variability on the Drosophila X Chromosome

Charlesworth, Brian
Fonte: Genetics Society of America Publicador: Genetics Society of America
Tipo: Artigo de Revista Científica
Publicado em /05/2012 EN
Relevância na Pesquisa
46.07%
In the putatively ancestral population of Drosophila melanogaster, the ratio of silent DNA sequence diversity for X-linked loci to that for autosomal loci is approximately one, instead of the expected “null” value of 3/4. One possible explanation is that background selection (the hitchhiking effect of deleterious mutations) is more effective on the autosomes than on the X chromosome, because of the lack of crossing over in male Drosophila. The expected effects of background selection on neutral variability at sites in the middle of an X chromosome or an autosomal arm were calculated for different models of chromosome organization and methods of approximation, using current estimates of the deleterious mutation rate and distributions of the fitness effects of deleterious mutations. The robustness of the results to different distributions of fitness effects, dominance coefficients, mutation rates, mapping functions, and chromosome size was investigated. The predicted ratio of X-linked to autosomal variability is relatively insensitive to these variables, except for the mutation rate and map length. Provided that the deleterious mutation rate per genome is sufficiently large, it seems likely that background selection can account for the observed X to autosome ratio of variability in the ancestral population of D. melanogaster. The fact that this ratio is much less than one in D. pseudoobscura is also consistent with the model’s predictions...

Comparison of phenotypic versus marker-assisted background selection for the SUB1 QTL during backcrossing in rice

Iftekharuddaula, Khandakar M.; Salam, Muhammad A.; Newaz, Muhammad A.; Ahmed, Helal U.; Collard, Bertrand C. Y.; Septiningsih, Endang M.; Sanchez, Darlene L.; Pamplona, Alvaro M.; Mackill, David J.
Fonte: Japanese Society of Breeding Publicador: Japanese Society of Breeding
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.11%
Marker assisted backcrossing has been used effectively to transfer the submergence tolerance gene SUB1 into popular rice varieties, but the approach can be costly. The selection strategy comprising foreground marker and phenotypic selection was investigated as an alternative. The non-significant correlation coefficients between ranking of phenotypic selection and ranking of background marker selection in BC2F1, BC3F1 and BC3F2 generations indicated inefficiency of phenotypic selection compared to marker-assisted background selection with respect to recovery of the recipient genome. In addition, the introgression size of the chromosome fragment containing SUB1 was approximately 17 Mb, showing the effects of linkage drag. The significant correlation coefficient between rankings of phenotypic selection with the percentage of recipient alleles in the BC1F1 generation suggested that background selection could be avoided in this generation to minimize the genotyping cost. The phenotypically selected best plant of the BC3F1 generation was selfed and backcross recombinant lines were selected in the resulting BC3F4 generation. The selection strategy could be appropriate for the introgression of SUB1 QTL in countries that lack access to high-throughput genotyping facilities.

A coalescent model of background selection with recombination, demography and variation in selection coefficients

Zeng, K
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
46.08%
There is increasing evidence that background selection, the effects of the elimination of recurring deleterious mutations by natural selection on variability at linked sites, may be a major factor shaping genome-wide patterns of genetic diversity. To accurately quantify the importance of background selection, it is vital to have computationally efficient models that include essential biological features. To this end, a structured coalescent procedure is used to construct a model of background selection that takes into account the effects of recombination, recent changes in population size and variation in selection coefficients against deleterious mutations across sites. Furthermore, this model allows a flexible organization of selected and neutral sites in the region concerned, and has the ability to generate sequence variability at both selected and neutral sites, allowing the correlation between these two types of sites to be studied. The accuracy of the model is verified by checking against the results of forward simulations. These simulations also reveal several patterns of diversity that are in qualitative agreement with observations reported in recent studies of DNA sequence polymorphisms. These results suggest that the model should be useful for data analysis.

Genome-wide signals of positive selection in human evolution

Enard, David; Messer, Philipp W.; Petrov, Dmitri A.
Fonte: Cold Spring Harbor Laboratory Press Publicador: Cold Spring Harbor Laboratory Press
Tipo: Artigo de Revista Científica
Publicado em /06/2014 EN
Relevância na Pesquisa
36.07%
The role of positive selection in human evolution remains controversial. On the one hand, scans for positive selection have identified hundreds of candidate loci, and the genome-wide patterns of polymorphism show signatures consistent with frequent positive selection. On the other hand, recent studies have argued that many of the candidate loci are false positives and that most genome-wide signatures of adaptation are in fact due to reduction of neutral diversity by linked deleterious mutations, known as background selection. Here we analyze human polymorphism data from the 1000 Genomes Project and detect signatures of positive selection once we correct for the effects of background selection. We show that levels of neutral polymorphism are lower near amino acid substitutions, with the strongest reduction observed specifically near functionally consequential amino acid substitutions. Furthermore, amino acid substitutions are associated with signatures of recent adaptation that should not be generated by background selection, such as unusually long and frequent haplotypes and specific distortions in the site frequency spectrum. We use forward simulations to argue that the observed signatures require a high rate of strongly adaptive substitutions near amino acid changes. We further demonstrate that the observed signatures of positive selection correlate better with the presence of regulatory sequences...

Background Selection as Baseline for Nucleotide Variation across the Drosophila Genome

Comeron, Josep M.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em 26/06/2014 EN
Relevância na Pesquisa
46%
The constant removal of deleterious mutations by natural selection causes a reduction in neutral diversity and efficacy of selection at genetically linked sites (a process called Background Selection, BGS). Population genetic studies, however, often ignore BGS effects when investigating demographic events or the presence of other types of selection. To obtain a more realistic evolutionary expectation that incorporates the unavoidable consequences of deleterious mutations, we generated high-resolution landscapes of variation across the Drosophila melanogaster genome under a BGS scenario independent of polymorphism data. We find that BGS plays a significant role in shaping levels of variation across the entire genome, including long introns and intergenic regions distant from annotated genes. We also find that a very large percentage of the observed variation in diversity across autosomes can be explained by BGS alone, up to 70% across individual chromosome arms at 100-kb scale, thus indicating that BGS predictions can be used as baseline to infer additional types of selection and demographic events. This approach allows detecting several outlier regions with signal of recent adaptive events and selective sweeps. The use of a BGS baseline...

A Weak Effect of Background Selection on Trinucleotide Microsatellites in Maize

Thuillet, Anne-Céline; Tenaillon, Maud I.; Anderson, Lorinda K.; Mitchell, Sharon E.; Kresovich, Stephen; Stack, Stephen M.; Gaut, Brandon; Doebley, John
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica Formato: text/html
EN
Relevância na Pesquisa
45.99%
Artificial selection during the domestication of maize is thought to have been predominantly positive and to have had little effect on the surrounding neutral diversity because linkage disequilibrium breaks down rapidly when physical distance increases. However, the degree to which indirect selection has shaped neutral diversity in the maize genome during domestication remains unclear. In this study, we investigate the relationship between local recombination rate and neutral polymorphism in maize and in teosinte using both sequence and microsatellite data. To quantify diversity, we estimate 3 parameters expected to differentially reflect the effects of indirect selection and mutation. We find no general correlation between diversity and recombination, indicating that indirect selection has had no genome-wide impact on maize diversity. However, we detect a weak correlation between heterozygosity and recombination for trinucleotide microsatellites deviating from the stepwise mutation model and located within genes (ρ = 0.32, P < 0.03). This result can be explained by a background selection hypothesis. The fact that the same correlation is not confirmed for nucleotide diversity suggests that the strength of purifying selection at or near this class of microsatellites is higher than for nucleotide mutations.

The impact of preparatory activities on medical school selection outcomes: a cross-sectional survey of applicants to the University of Adelaide Medical School in 2007

Laurence, C.; Zajac, I.; Lorimer, M.; Turnbull, D.; Sumner, K.
Fonte: BioMed Central Ltd. Publicador: BioMed Central Ltd.
Tipo: Artigo de Revista Científica
Publicado em //2013 EN
Relevância na Pesquisa
45.89%
Background: Selection into medical school is highly competitive with more applicants than places. Little is known about the preparation that applicants undertake for this high stakes process. The study aims to determine what preparatory activities applicants undertake and what difficulties they encounter for each stage of the application process to medical school and in particular what impact these have on the outcome. Methods: A cross-sectional survey of 1097 applicants who applied for a place in the University of Adelaide Medical School in 2007 and participated in the UMAT (Undergraduate Medicine and Health Sciences Admission Test) and oral assessment components of the selection process. The main outcome measures were an offer of an interview and offer of a place in the medical school and were analysed using logistic regression. Results: The odds of a successful outcome increased with each additional preparatory activity undertaken for the UMAT (odds ratio 1.22, 95% confidence interval 1.11 to 1.33; P < 0.001) and the oral assessment (1.36, 1.19 to 1.55; P < 0.001) stage of selection. The UMAT preparatory activities associated with the offer of an interview were attendance of a training course by a private organisation (1.75...

Using interviewer random effects to remove selection bias from HIV prevalence estimates

McGovern, Mark; Bärnighausen, Till; Salomon, Joshua A.; Canning, David J.
Fonte: Springer Science + Business Media Publicador: Springer Science + Business Media
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
45.92%
Background Selection bias in HIV prevalence estimates occurs if non-participation in testing is correlated with HIV status. Longitudinal data suggests that individuals who know or suspect they are HIV positive are less likely to participate in testing in HIV surveys, in which case methods to correct for missing data which are based on imputation and observed characteristics will produce biased results. Methods The identity of the HIV survey interviewer is typically associated with HIV testing participation, but is unlikely to be correlated with HIV status. Interviewer identity can thus be used as a selection variable allowing estimation of Heckman-type selection models. These models produce asymptotically unbiased HIV prevalence estimates, even when non-participation is correlated with unobserved characteristics, such as knowledge of HIV status. We introduce a new random effects method to these selection models which overcomes non-convergence caused by collinearity, small sample bias, and incorrect inference in existing approaches. Our method is easy to implement in standard statistical software, and allows the construction of bootstrapped standard errors which adjust for the fact that the relationship between testing and HIV status is uncertain and needs to be estimated. Results Using nationally representative data from the Demographic and Health Surveys...

The Pattern of Neutral Molecular Variation under the Background Selection Model

Charlesworth, D.; Charlesworth, B.; Morgan, M. T.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /12/1995 EN
Relevância na Pesquisa
46.14%
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 effct 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.

Statistical Tests of Neutrality of Mutations against Population Growth, Hitchhiking and Background Selection

Fu, Y. X.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1997 EN
Relevância na Pesquisa
46.02%
The main purpose of this article is to present several new statistical tests of neutrality of mutations against a class of alternative models, under which DNA polymorphisms tend to exhibit excesses of rare alleles or young mutations. Another purpose is to study the powers of existing and newly developed tests and to examine the detailed pattern of polymorphisms under population growth, genetic hitchhiking and background selection. It is found that the polymorphic patterns in a DNA sample under logistic population growth and genetic hitchhiking are very similar and that one of the newly developed tests, F(s), is considerably more powerful than existing tests for rejecting the hypothesis of neutrality of mutations. Background selection gives rise to quite different polymorphic patterns than does logistic population growth or genetic hitchhiking, although all of them show excesses of rare alleles or young mutations. We show that Fu and Li's tests are among the most powerful tests against background selection. Implications of these results are discussed.