Biomedical subjects

Yuseob Kim

Publications and source records attributed to Yuseob Kim.

12 recordsLinked to original sources

PubMed2006

Spread of an inactive form of caspase-12 in humans is due to recent positive selection.

The human caspase-12 gene is polymorphic for the presence or absence of a stop codon, which results in the occurrence of both active (ancestral) and inactive (derived) forms of the gene in the population. It has been shown elsewhere that carriers of the inactive gene are more resistant to severe sepsis. We have now investigated whether the inactive form has spread because of neutral drift or positive selection. We determined its distribution in a worldwide sample of 52 populations and resequenced the gene in 77 individuals from the HapMap Yoruba, Han Chinese, and European populations. There is strong evidence of positive selection from low diversity, skewed allele-frequency spectra, and the predominance of a single haplotype. We suggest that the inactive form of the gene arose in Africa approximately 100-500 thousand years ago (KYA) and was initially neutral or almost neutral but that positive selection beginning approximately 60-100 KYA drove it to near fixation. We further propose that its selective advantage was sepsis resistance in populations that experienced more infectious diseases as population sizes and densities increased.

Base Sequence↗

PubMed2005

Allele frequency distribution under recurrent selective sweeps.

The allele frequency of a neutral variant in a population is pushed either upward or downward by directional selection on a linked beneficial mutation ("selective sweeps"). DNA sequences sampled after the fixation of the beneficial allele thus contain an excess of rare neutral alleles. This study investigates the allele frequency distribution under selective sweep models using analytic approximation and simulation. First, given a single selective sweep at a fixed time, I derive an expression for the sampling probabilities of neutral mutants. This solution can be used to estimate the time of the fixation of a beneficial allele from sequence data. Next, I obtain an approximation to mean allele frequencies under recurrent selective sweeps. Under recurrent sweeps, the frequency spectrum is skewed toward rare alleles. However, the excess of high-frequency derived alleles, previously shown to be a signature of single selective sweeps, disappears with recurrent sweeps. It is shown that, using this approximation and multilocus polymorphism data, genomewide parameters of directional selection can be estimated.

Biological Evolution↗

PubMed2005

Adaptation in sexuals vs. asexuals: clonal interference and the Fisher-Muller model.

Fisher and Muller's theory that recombination speeds adaptation by eliminating competition among beneficial mutations has proved a popular explanation for the advantage of sex. Recent theoretical studies have attempted to quantify the speed of adaptation under the Fisher-Muller model, partly in an attempt to understand the role of "clonal interference" in microbial experimental evolution. We reexamine adaptation in sexuals vs. asexuals, using a model of DNA sequence evolution. In this model, a modest number of sites can mutate to beneficial alleles and the fitness effects of these mutations are unequal. We study (1) transition probabilities to different beneficial mutations; (2) waiting times to the first and the last substitutions of beneficial mutations; and (3) trajectories of mean fitness through time. We find that some of these statistics are surprisingly similar between sexuals and asexuals. These results highlight the importance of the choice of substitution model in assessing the Fisher-Muller advantage of sex.

Adaptation, Biological↗

PubMed2005

Distinguishing between selective sweeps and demography using DNA polymorphism data.

In 2002 Kim and Stephan proposed a promising composite-likelihood method for localizing and estimating the fitness advantage of a recently fixed beneficial mutation. Here, we demonstrate that their composite-likelihood-ratio (CLR) test comparing selective and neutral hypotheses is not robust to undetected population structure or a recent bottleneck, with some parameter combinations resulting in a false positive rate of nearly 90%. We also propose a goodness-of-fit test for discriminating rejections due to directional selection (true positive) from those due to population and demographic forces (false positives) and demonstrate that the new method has high sensitivity to differentiate the two classes of rejections.

Computer Simulation↗

PubMed2005

Genomic scans for selective sweeps using SNP data.

Detecting selective sweeps from genomic SNP data is complicated by the intricate ascertainment schemes used to discover SNPs, and by the confounding influence of the underlying complex demographics and varying mutation and recombination rates. Current methods for detecting selective sweeps have little or no robustness to the demographic assumptions and varying recombination rates, and provide no method for correcting for ascertainment biases. Here, we present several new tests aimed at detecting selective sweeps from genomic SNP data. Using extensive simulations, we show that a new parametric test, based on composite likelihood, has a high power to detect selective sweeps and is surprisingly robust to assumptions regarding recombination rates and demography (i.e., has low Type I error). Our new test also provides estimates of the location of the selective sweep(s) and the magnitude of the selection coefficient. To illustrate the method, we apply our approach to data from the Seattle SNP project and to Chromosome 2 data from the HapMap project. In Chromosome 2, the most extreme signal is found in the lactase gene, which previously has been shown to be undergoing positive selection. Evidence for selective sweeps is also found in many other regions, including genes known to be associated with disease risk such as DPP10 and COL4A3.

Black or African American↗

PubMed2004

Pattern of polymorphism after strong artificial selection in a domestication event.

The process of strong artificial selection during a domestication event is modeled, and its effect on the pattern of DNA polymorphism is investigated. The model also considers population bottleneck during domestication. Artificial selection during domestication is different from a regular selective sweep because artificial selection acts on alleles that may have been neutral variants before domestication. Therefore, the fixation of such a beneficial allele does not always wipe out DNA variation in the surrounding region. The amount by which variation is reduced largely depends on the initial frequency of the beneficial allele, p. As a consequence, p has a strong effect on the likelihood of detecting the signature of selection during domestication from patterns of polymorphism. These theoretical results are discussed in light of data collected from maize. Although the main focus of this article is on domestication, this model can also be generalized to describe selective sweeps from standing genetic variation.

Alleles↗

PubMed2004

Linkage disequilibrium as a signature of selective sweeps.

The hitchhiking effect of a beneficial mutation, or a selective sweep, generates a unique distribution of allele frequencies and spatial distribution of polymorphic sites. A composite-likelihood test was previously designed to detect these signatures of a selective sweep, solely on the basis of the spatial distribution and marginal allele frequencies of polymorphisms. As an excess of linkage disequilibrium (LD) is also known to be a strong signature of a selective sweep, we investigate how much statistical power is increased by the inclusion of information regarding LD. The expected pattern of LD is predicted by a genealogical approach. Both theory and simulation suggest that strong LD is generated in narrow regions at both sides of the location of beneficial mutation. However, a lack of LD is expected across the two sides. We explore various ways to detect this signature of selective sweeps by statistical tests. A new composite-likelihood method is proposed to incorporate information regarding LD. This method enables us to detect selective sweeps and estimate the parameters of the selection model better than the previous composite-likelihood method that does not take LD into account. However, the improvement made by including LD is rather small, suggesting that most of the relevant information regarding selective sweeps is captured by the spatial distribution and marginal allele frequencies of polymorphisms.

Computer Simulation↗

PubMed2004

Identification of a locus under complex positive selection in Drosophila simulans by haplotype mapping and composite-likelihood estimation.

The recent action of positive selection is expected to influence patterns of intraspecific DNA sequence variation in chromosomal regions linked to the selected locus. These effects include decreased polymorphism, increased linkage disequilibrium, and an increased frequency of derived variants. These effects are all expected to dissipate with distance from the selected locus due to recombination. Therefore, in regions of high recombination, it should be possible to localize a target of selection to a relatively small interval. Previously described patterns of intraspecific variation in three tandemly arranged, testes-expressed genes (janusA, janusB, and ocnus) in Drosophila simulans included all three of these features. Here we expand the original sample and also survey nucleotide polymorphism at three neighboring loci. On the basis of recombination events between derived and ancestral alleles, we localize the target of selection to a 1.5-kb region surrounding janusB. A composite-likelihood-ratio test based on the spatial distribution and frequency of derived polymorphic variants corroborates this result and provides an estimate of the strength of selection. However, the data are difficult to reconcile with the simplest model of positive selection, whereas a new composite-likelihood method suggests that the data are better described by a model in which the selected allele has not yet gone to fixation.

Animals↗

PubMed2004

A pseudohitchhiking model of X vs. autosomal diversity.

We study levels of X-linked vs. autosomal diversity using a model developed to analyze the hitchhiking effect. Repeated bouts of hitchhiking are thought to lower X-linked diversity for two reasons: first, because sojourn times of beneficial mutations are shorter on the X, and second, because adaptive substitutions may be more frequent on the X. We investigate whether each of these effects does, in fact, cause reduced X-linked diversity under hitchhiking. We study the strength of the hitchhiking effect on the X vs. autosomes when there is no recombination and under two different recombination schemes. When recombination occurs in both sexes, X-linked vs. autosomal diversity is reduced by hitchhiking under a broad range of conditions, but when there is no recombination in males, as in Drosophila, the required conditions are considerably more restrictive.

Animals↗

PubMed2003

Effect of strong directional selection on weakly selected mutations at linked sites: implication for synonymous codon usage.

The fixation of weakly selected mutations can be greatly influenced by strong directional selection at linked loci. Here, I investigate a two-locus model in which weakly selected, reversible mutations occur at one locus and recurrent strong directional selection occurs at the other locus. This model is analogous to selection on codon usage at synonymous sites linked to nonsynonymous sites under strong directional selection. Two approximations obtained here describe the expected frequency of the weakly selected preferred alleles at equilibrium. These approximations, as well as simulation results, show that the level of codon bias declines with an increasing rate of substitution at the strongly selected locus, as expected from the well-understood theory that selection at one locus reduces the efficacy of selection at linked loci. These solutions are used to examine whether the negative correlation between codon bias and nonsynonymous substitution rates recently observed in Drosophila can be explained by this hitchhiking effect. It is shown that this observation can be reasonably well accounted for if a large fraction of the nonsynonymous substitutions on genes in the data set are driven by strong directional selection.

Alleles↗

PubMed2003

Selective sweeps in the presence of interference among partially linked loci.

Recurrent directional selection on a partially recombining chromosome may cause a substantial reduction of standing genetic variation in natural populations. Previous studies of this effect, commonly called selective sweeps, assumed that at most one beneficial allele is on the way to fixation at a given time. However, for a high rate of selected substitutions and a low recombination rate, this assumption can easily be violated. We investigated this problem using full-forward simulations and analytical approximations. We found that interference between linked beneficial alleles causes a reduction of their fixation probabilities. The hitchhiking effect on linked neutral variation for a given substitution also slightly decreases due to interference. As a result, the strength of recurrent selective sweeps is weakened. However, this effect is significant only in chromosomal regions of relatively low recombination rates where the level of variation is greatly reduced. Therefore, previous results on recurrent selective sweeps although derived for a restricted parameter range are still valid. Analytical approximations are obtained for the case of complete linkage for which interference between competing beneficial alleles is maximal.

Computer Simulation↗

PubMed2002

Detecting a local signature of genetic hitchhiking along a recombining chromosome.

The theory of genetic hitchhiking predicts that the level of genetic variation is greatly reduced at the site of strong directional selection and increases as the recombinational distance from the site of selection increases. This characteristic pattern can be used to detect recent directional selection on the basis of DNA polymorphism data. However, the large variance of nucleotide diversity in samples of moderate size imposes difficulties in detecting such patterns. We investigated the patterns of genetic variation along a recombining chromosome by constructing ancestral recombination graphs that are modified to incorporate the effect of genetic hitchhiking. A statistical method is proposed to test the significance of a local reduction of variation and a skew of the frequency spectrum caused by a hitchhiking event. This method also allows us to estimate the strength and the location of directional selection from DNA sequence data.

Chromosomes↗