Allele Frequencies at Microsatellite Loci: The Stepwise Mutation Model Revisited

We summarize available data on the frequencies of alleles at microsatellite loci in human populations and compare observed distributions of allele frequencies to those generated by a simulation of the stepwise mutation model. We show that observed frequency distributions at 108 loci are consistent with the results of the model under the assumption that mutations cause an increase or decrease in repeat number by one and under the condition that the product Nu, where N is the effective population size and u is the mutation rate, is larger than one. We show that the variance of the distribution of allele sizes is a useful estimator of Nu and performs much better than previously suggested estimators for the stepwise mutation model. In the data, there is no correlation between the mean and variance in allele size at a locus or between the number of alleles and mean allele size, which suggests that the mutation rate at these loci is independent of allele size.     

Gene Genealogies within Mutant Allelic Classes

A coalescent theory of the gene genealogy within an allelic class that arises by a unique mutational event is developed and analyzed. To interpret this theory it was necessary to expand on existing theory for populations of varying size. Two features of the gene genealogy--the average pairwise distance and the total tree length--within the mutant class and within the nonmutant class are found. An index, I, is proposed that describes the extent to which a genealogy is similar to one from a population of constant size (for which I = 0) or to a star genealogy (for which I = 1). The value of I is positive in growing populations and is generally positive for the gene genealogy for the mutant class. The value of I is negative for a population decreasing in size and for the nonmutant class, if the mutant arose recently. The results are discussed in the context of the infinite sites model of mutation, which is appropriate for nucleotide sequence data, and the generalized stepwise mutation model, which is appropriate for microsatellite loci. The same genealogical methods are used to find the probability of at least one recombination event between a nucleotide that defines an allelic class and a marker at a nearby linked site.     

A Cladistic Measure of Gene Flow Inferred from the Phylogenies of Alleles

A method for estimating the average level of gene flow among populations is introduced. The method provides an estimate of Nm, where N is the size of each local population in an island model and m is the migration rate. This method depends on knowing the phylogeny of the nonrecombining segments of DNA that are sampled. Given the phylogeny, the geographic location from which each sample is drawn is treated as multistate character with one state for each geographic location. A parsimony criterion applied to the evolution of this character on the phylogeny provides the minimum number of migration events consistent with the phylogeny. Extensive simulations show that the distribution of this minimum number is a simple function of Nm. Assuming the phylogeny is accurately estimated, this method provides an estimate of Nm that is as nearly as accurate as estimates obtained using FST and other statistics when Nm is moderate. Two examples of the use of this method with mitochondrial DNA data are presented.     

Pachyovatamine,a bisbenzylisoquinoline alkaloid,and other alkaloids from Pachygone ovata

A new dibenzo-p-dioxin biphenyl bisbenzylisoquinoline alkaloid, pachyovatamine, has been isolated from an extract of the leaves and stems of Pachygone ovata from Sri Lanka. The alkaloid was characterized by a consideration of its physicochemical data and conversion to O-acetyltiliacorinine. Pachygonamine, N-methylpachygonamine and tiliamosine were also isolated from the same extract.     

Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population

Molecular techniques allow the survey of a large number of linked polymorphic loci in random samples from diploid populations. However, the gametic phase of haplotypes is usually unknown when diploid individuals are heterozygous at more than one locus. To overcome this difficulty, we implement an expectation-maximization (EM) algorithm leading to maximum-likelihood estimates of molecular haplotype frequencies under the assumption of Hardy-Weinberg proportions. The performance of the algorithm is evaluated for simulated data representing both DNA sequences and highly polymorphic loci with different levels of recombination. As expected, the EM algorithm is found to perform best for large samples, regardless of recombination rates among loci. To ensure finding the global maximum likelihood estimate, the EM algorithm should be started from several initial conditions. The present approach appears to be useful for the analysis of nuclear DNA sequences or highly variable loci. Although the algorithm, in principle, can accommodate an arbitrary number of loci, there are practical limitations because the computing time grows exponentially with the number of polymorphic loci. Although the algorithm, in principle, can accommodate an arbitrary number of loci, there are practical limitations because the computing time grows exponentially with the number of polymorphic loci.      

Spatial patterns in the distributions of polygenic characters

The spatial patterns in the mean and variance of a quantitative character that result from the interaction of spatially varying, optimizing selection and gene flow are considered. The model analyzed is an extension of those of Kimura (1965) and Lande (1976) for the distribution of a quantitative character maintained in a population by independent mutations. For weak selection, it is shown that there is only a small effect of gene flow on the variance of the character and that the mean value changes on a length scale that is large compared to the average dispersal distance. As in models of clines in allele frequencies, it is possible to define a “characteristic length” in terms of the average dispersal distance and strength of selection. The characteristic length is the smallest length scale environmental change to which the mean value of the character can significantly respond. It is also shown that, for weak selection, an asymmetry in dispersal can result in a significant shift in location of a cline. By considering an infinite linear cline in optimal values, it is shown that gene flow can increase the variance only when there is sufficient mixing in each generation of individuals from locations with different means. A model of selection in different niches is also considered. There is an increase in variance due to the effective weakening of the intensity of selection because of the differences in optimal values in different niches.The implications of the different models for maintenance of genetic polymorphism are discussed. Under some conditions gene flow can produce a significant increase in heterozygosity. It is also argued that spatial variation in selection on a polygenic character can be much more effective in increasing heterozygosity than temporal variation because of the potentially greater increase in phenotypic variance. The difference between some of the results for polygenic characters from those of similar models of one and two locus systems is accounted for by the fact that for normally distributed polygenic characters, changes in the variance are effectively decoupled from changes in the mean.     

A complete Neandertal mitochondrial genome sequence determined by high-throughput sequencing

A complete mitochondrial (mt) genome sequence was reconstructed from a 38,000 year-old Neandertal individual with 8341 mtDNA sequences identified among 4.8 Gb of DNA generated from approximately 0.3 g of bone. Analysis of the assembled sequence unequivocally establishes that the Neandertal mtDNA falls outside the variation of extant human mtDNAs, and allows an estimate of the divergence date between the two mtDNA lineages of 660,000 +/- 140,000 years. Of the 13 proteins encoded in the mtDNA, subunit 2 of cytochrome c oxidase of the mitochondrial electron transport chain has experienced the largest number of amino acid substitutions in human ancestors since the separation from Neandertals. There is evidence that purifying selection in the Neandertal mtDNA was reduced compared with other primate lineages, suggesting that the effective population size of Neandertals was small.     

Research at the European Synchrotron Radiation Facility medical beamline.

The application of synchrotron radiation in medical research has become a mature field of research at synchrotron facilities worldwide. In the relatively short time that synchrotrons have been available to the scientific community, their characteristic beams of UV and X-ray radiation have been applied to virtually all areas of medical science which use ionizing radiation. The ability to tune intense monochromatic beams over wide energy ranges differentiates these sources from standard clinical and research tools. At the European Synchrotron Radiation Facility (Grenoble, France), a major research facility is operational on an advanced wiggler radiation beamport, ID17. The beamport is designed to carry out a broad range of research ranging from cell radiation biology to in vivo human studies. Medical imaging programs at ID17 include transvenous coronary angiography, computed tomography, mammography and bronchography. In addition, a major research program on microbeam radiation therapy is progressing. This paper will present a very brief overview of the beamline and the imaging and therapy programs.     

Linkage disequilibrium--understanding the evolutionary past and mapping the medical future

Linkage disequilibrium--the nonrandom association of alleles at different loci--is a sensitive indicator of the population genetic forces that structure a genome. Because of the explosive growth of methods for assessing genetic variation at a fine scale, evolutionary biologists and human geneticists are increasingly exploiting linkage disequilibrium in order to understand past evolutionary and demographic events, to map genes that are associated with quantitative characters and inherited diseases, and to understand the joint evolution of linked sets of genes. This article introduces linkage disequilibrium, reviews the population genetic processes that affect it and describes some of its uses. At present, linkage disequilibrium is used much more extensively in the study of humans than in non-humans, but that is changing as technological advances make extensive genomic studies feasible in other species.     

Seeing ghosts: the effect of unsampled populations on migration rates estimated for sampled populations

In 2004, the term 'ghost population' was introduced to summarize the effect of unsampled subpopulations that exchange migrants with other subpopulations that have been sampled. Estimated long-term migration rates among populations sampled will be affected by ghost populations. Although it would be convenient to be able to define an apparent migration matrix among sampled populations that incorporate the exchange of migrants with ghost populations, no such matrix can be defined in a way that predicts all features of the coalescent process for the true migration matrix. This paper shows that if the underlying migration matrix is symmetric, it is possible to define an apparent migration matrix among sampled subpopulations that predicts the same within-population and between-population homozygosities among sampled populations as is predicted by the true migration matrix. Application of this method shows that there is no simple relationship between true and apparent migration rates, nor is there a way to place an upper bound on the effect of ghost populations. In general, ghost populations can create the appearance of migration between subpopulations that do not actually exchange migrants. Comparison with published results from the application of the program, MIGRATE, shows that the apparent migration rates inferred with that program in a three-subpopulation model differ from those based on pairwise homozygosities. The apparent migration matrix determined by the method described in this paper probably represents the upper bound on the effect of ghost populations.