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Biomedical subjects

C Wiuf

Publications and source records attributed to C Wiuf.

15 recordsLinked to original sources
PubMed2001

Rare alleles and selection.

A subpopulation D of rare alleles is considered. The subpopulation is part of a large population that evolves according to a Moran model with selection and growth. Conditional on the current frequency, q, of the rare allele, an approximation to the distribution of the genealogy of D is derived. In particular, the density of the age, T(1), of the rare allele is approximated. It is shown that time naturally is measured in units of qN(0) generations, where N(0) is the present day population size, and that the distribution of the genealogy of D depends on the compound parameters rho=rqN(0) and sigma=sqN(0) only. Here, s is the fitness per generation of heterozygote carriers of the rare allele and r is the growth rate per generation of the population. Amongst more, it is shown that for constant population size (rho=0) the distribution of D depends on sigma only through the absolute value /sigma/, not the direction of selection.

Alleles↗
PubMed2001

Do delta F508 heterozygotes have a selective advantage?

In this paper the fitness of the delta F508 heterozygote is assessed and the age of the delta F508 mutation in the cystic fibrosis locus is estimated. Data from three microsatellite loci are applied. The analysis is performed conditional on the present-day frequency of the delta F508 mutation and based on assumptions about the demographic history of the European population and the mutation rate in the three microsatellite loci. It is shown that the data gives evidence of positive selection (up to 2-3% per delta F508 heterozygote), but also that data could be explained by negative selection of roughly the same order of magnitude. The age of the delta F508 mutation is subsequently estimated; it is found that the mutation is at least 580 generations old, but could be much older depending on the microsatellite mutation rate and the exact number of substitutions experienced in the history of the three microsatellite loci.

Biological Evolution↗
PubMed2001

Recombination in human mitochondrial DNA?

The possibility of recombination in human mitochondrial DNA (mtDNA) has been hotly debated over the last few years. In this study, a general model of recombination in circular molecules is developed and applied to a recently published African sample (n = 21) of complete mtDNA sequences. It is shown that the power of correlation measures to detect recombination in circular molecules can be vanishingly small and that the data are consistent with the given model and no recombination only if the overall heterogeneity in mutation rate is <0.09.

DNA, Mitochondrial↗
PubMed2001

A simulation study of the reliability of recombination detection methods.

There exist many methods to detect recombination or mosaic structure in a sample of DNA sequences. But how reliable are they? Four methods were investigated with respect to their power to detect recombination in simulated samples with different amounts of recombination and mutation. In addition, we investigated the impact of the shape of the underlying genealogy on their performances. We found that the methods detected far fewer recombinations than were theoretically possible and that methods based on the principle of incompatibility in general had more power than methods that did not make use of this principle explicitly. This seemed, in particular, to be the case for phylogenies generated under population expansion scenarios which result in long branches at the tips and small deep branches. In addition to the results obtained through simulations, a series of new theoretical results on recombination is presented.

Algorithms↗
PubMed2000

Statistical alignment: computational properties, homology testing and goodness-of-fit.

The model of insertions and deletions in biological sequences, first formulated by Thorne, Kishino, and Felsenstein in 1991 (the TKF91 model), provides a basis for performing alignment within a statistical framework. Here we investigate this model.Firstly, we show how to accelerate the statistical alignment algorithms several orders of magnitude. The main innovations are to confine likelihood calculations to a band close to the similarity based alignment, to get good initial guesses of the evolutionary parameters and to apply an efficient numerical optimisation algorithm for finding the maximum likelihood estimate. In addition, the recursions originally presented by Thorne, Kishino and Felsenstein can be simplified. Two proteins, about 1500 amino acids long, can be analysed with this method in less than five seconds on a fast desktop computer, which makes this method practical for actual data analysis.Secondly, we propose a new homology test based on this model, where homology means that an ancestor to a sequence pair can be found finitely far back in time. This test has statistical advantages relative to the traditional shuffle test for proteins.Finally, we describe a goodness-of-fit test, that allows testing the proposed insertion-deletion (indel) process inherent to this model and find that real sequences (here globins) probably experience indels longer than one, contrary to what is assumed by the model.

Algorithms↗
PubMed2000

A coalescence approach to gene conversion.

In this paper we develop a coalescent model with intralocus gene conversion. Such models are of increasing importance in the analysis of intralocus variability and linkage disequilibrium. We derive the distribution of the waiting time until a gene conversion event occurs in a sample in terms of the distribution of the length of the transferred segment, zeta. We do not assume any specific form of the distribution of zeta. Further, given that a gene conversion event occurs we find the distribution of (sigma, tau), the end points of the transferred segment and derive results on correlations between local trees in positions chi(1) and chi(2). Among other results we show that the correlation between the branch lengths of two local trees in the coalescent with gene conversion (and no recombination) decreases toward a nonzero constant when the distance between chi(1) and chi(2) increases. Finally, we show that a model including both recombination and gene conversion might account for the lack of intralocus associations found in, e.g., Drosophila melanogaster.

Gene Conversion↗
PubMed2000

On the genealogy of a sample of neutral rare alleles.

This paper concerns the genealogical structure of a sample of chromosomes sharing a neutral rare allele. We suppose that the mutation giving rise to the allele has only happened once in the history of the entire population, and that the allele is of known frequency q in the population. Within a coalescent framework C. Wiuf and P. Donnelly (1999, Theor. Popul. Biol. 56, 183-201) derived an exact analysis of the conditional genealogy but it is inconvenient for applications. Here, we develop an approximation to the exact distribution of the conditional genealogy, including an approximation to the distribution of the time at which the mutation arose. The approximations are accurate for frequencies q<5-10%. In addition, a simple and fast simulation scheme is constructed. We consider a demography parameterized by a d-dimensional vector alpha=(alpha(1), em leader, alpha(d)). It is shown that the conditional genealogy and the age of the mutation have distributions that depend on a=qalpha and q only, and that the effect of q is a linear scaling of times in the genealogy; if q is doubled, the lengths of all branches in the genealogy are doubled. The theory is exemplified in two different demographies of some interest in the study of human evolution: (1) a population of constant size and (2) a population of exponentially decreasing size (going backward in time).

Algorithms↗
PubMed2000

The coalescent with gene conversion.

In this article we develop a coalescent model with intralocus gene conversion. The distribution of the tract length is geometric in concordance with results published in the literature. We derive a simulation scheme and deduce a number of analytical results for this coalescent with gene conversion. We compare patterns of variability in samples simulated according to the coalescent with recombination with similar patterns simulated according to the coalescent with gene conversion alone. Further, an expression for the expected number of topology shifts in a sample of present-day sequences caused by gene conversion events is derived.

Gene Conversion↗
PubMed1999

Recombination as a point process along sequences.

Histories of sequences in the coalescent model with recombination can be simulated using an algorithm that takes as input a sample of extant sequences. The algorithm traces the history of the sequences going back in time, encountering recombinations and coalescence (duplications) until the ancestral material is located on one sequence for homologous positions in the present sequences. Here an alternative algorithm is formulated not as going back in time and operating on sequences, but by moving spatially along the sequences, updating the history of the sequences as recombination points are encountered. This algorithm focuses on spatial aspects of the coalescent with recombination rather than on temporal aspects as is the case of familiar algorithms. Mathematical results related to spatial aspects of the coalescent with recombination are derived.

Algorithms↗
PubMed1999

Conditional genealogies and the age of a neutral mutant.

This paper is concerned with the structure of the genealogy of a sample in which it is observed that some subset of chromosomes carries a particular mutation, assumed to have arisen uniquely in the history of the population. A rigorous theoretical study of this conditional genealogy is given using coalescent methods. Particular results include the mean, variance, and density of the age of the mutation conditional on its frequency in the sample. Most of the development relates to populations of constant size, but we discuss the extension to populations which have grown exponentially to their present size.

Alleles↗
PubMed1999

The ancestry of a sample of sequences subject to recombination.

In this article we discuss the ancestry of sequences sampled from the coalescent with recombination with constant population size 2N. We have studied a number of variables based on simulations of sample histories, and some analytical results are derived. Consider the leftmost nucleotide in the sequences. We show that the number of nucleotides sharing a most recent common ancestor (MRCA) with the leftmost nucleotide is approximately log(1 + 4N Lr)/4Nr when two sequences are compared, where L denotes sequence length in nucleotides, and r the recombination rate between any two neighboring nucleotides per generation. For larger samples, the number of nucleotides sharing MRCA with the leftmost nucleotide decreases and becomes almost independent of 4N Lr. Further, we show that a segment of the sequences sharing a MRCA consists in mean of 3/8Nr nucleotides, when two sequences are compared, and that this decreases toward 1/4Nr nucleotides when the whole population is sampled. A measure of the correlation between the genealogies of two nucleotides on two sequences is introduced. We show analytically that even when the nucleotides are separated by a large genetic distance, but share MRCA, the genealogies will show only little correlation. This is surprising, because the time until the two nucleotides shared MRCA is reciprocal to the genetic distance. Using simulations, the mean time until all positions in the sample have found a MRCA increases logarithmically with increasing sequence length and is considerably lower than a theoretically predicted upper bound. On the basis of simulations, it turns out that important properties of the coalescent with recombinations of the whole population are reflected in the properties of a sample of low size.

Genome, Human↗
PubMed1998

A codon-based model designed to describe lentiviral evolution.

A codon-based model designed to describe lentiviral evolution is developed. The model incorporates unequal base compositions in the three codon positions and selection against the CpG dinucleotide within codons to account for a deficit of this dinucleotide exhibited by lentiviral genes. The model is, to a large extent, able to account for the pattern of codon usage exhibited by the HIV1 genes gag, pol, and env, in spite of its parameter paucity. The model is extended to a similar model which operates on pentets (codons and their neighboring bases). The results obtained by the pentet model establish the importance of depression of CpGs across codon boundaries as well as within codons. The goodness of fit of the CpG depression model to the observed evolution in pairwise alignments of HIV1 sequences is assessed. The model provides a significantly better description of the observed evolution than the simpler models examined. The parameter estimates indicate that part of the unusually large biases in nucleotide frequencies observed in HIV1 genes is caused by selection against CpGs. We find that the estimates of expected numbers of substitutions, of transitions to transversions, and of synonymous to nonsynonymous substitution rates are robust to CpG depression, whereas the ratio of CpG-generating substitutions to other substitutions is strongly influenced by the choice of model.

Base Composition↗
PubMed1997

On the number of ancestors to a DNA sequence.

If homologous sequences in a population are not subject to recombination, they can all be traced back to one ancestral sequence. However, the rest of our genome is subject to recombination and will be spread out on a series of individuals. The distribution of ancestral material to an extant chromosome is here investigated by the coalescent with recombination, and the results are discussed relative to humans. In an ancestral population of actual size 1.3 million a minority of <6.4% will carry material ancestral to any present human. The estimated actual population size can be even higher, 5 million, reducing the percentage to 1.7%.

DNA↗