Arlequin ver 3.0 is a software package integrating several basic and advanced methods for population genetics data analysis, like the computation of standard genetic diversity indices, the estimation of allele and haplotype frequencies, tests of departure from linkage equilibrium, departure from selective neutrality and demographic equilibrium, estimation or parameters from past population expansions, and thorough analyses of population subdivision under the AMOVA framework. Arlequin 3 introduces a completely new graphical interface written in C++, a more robust semantic analysis of input files, and two new methods: a Bayesian estimation of gametic phase from multi-locus genotypes, and an estimation of the parameters of an instantaneous spatial expansion from DNA sequence polymorphism. Arlequin can handle several data types like DNA sequences, microsatellite data, or standard multi-locus genotypes. A Windows version of the software is freely available on http://cmpg.unibe.ch/software/arlequin3.

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Arlequin (version 3.0): An integrated software package for population genetics data analysis

SUMMARY When a selectively favourable gene substitution occurs in a population, changes in gene frequencies will occur at closely linked loci. In the case of a neutral polymorphism, average heterozygosity will be reduced to an extent which varies with distance from the substituted locus. The aggregate eifect of substitution on neutral polymorphism is estimated; in populations of total size 10 6 or more (and perhaps of 10 4 or more), this eifect will be more important than that of random fixation. This may explain why the extent of polymorphism in natural populations does not vary as much as one would expect from a consideration of the equilibrium between mutation and random fixation in populations of different sizes. For a selectively maintained polymorphism at a linked locus, this process will only be important in the long run if it leads to complete fixation. If the selective coefficients at the linked locus are small compared to those at the substituted locus, it is shown that the probability of complete fixation at the linked locus is approximately exp (— Nc), where c is the recombinant fraction and N the population size. It follows that in a large population a selective substitution can occur in a cistron without eliminating a selectively maintained polymorphism in the same cistron.

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The hitch-hiking effect of a favourable gene.

A theoretical investigation has been made of the influence of population size (N) and recombination fraction (c) on linkage disequilibrium (D) between a pair of loci. Two situations were studied: (i) where both loci had no effect on fitness and (ii) where they showed heterozygote superiority, but no epistacy. If the populations are initially in linkage equilibrium, then the mean value ofD remains zero with inbreeding, but the mean ofD
2 increases to a maximum value and decreases until fixation is reached at both loci. The tighter the linkage and the greater the selection, then the later is the maximum in the mean ofD
2 reached, and the larger its value. The correlation of gene frequencies,r, in the population of gametes within segregating lines was also studied. It was found that, for a range of selection intensities and initial gene frequencies, the mean value ofr
2 was determined almost entirely byN c and time, measured proportional toN. The implication of these results on observations of linkage disequilibrium in natural populations is discussed.

Linkage disequilibrium in finite populations

(i) A computer simulation study has been made of selection on two linked loci in small populations, where both loci were assumed to have additive effects on the character under selection with no interaction between loci. If N is the effective population size, i the intensity of selection in standard units, α and β measure the effects of the two loci on the character under selection as a proportion of the pheno-typic standard deviation and c is the crossover distance between them, it was shown that the selection process can be completely specified by Ni α, Ni βand Nc and the initial gene frequencies and linkage disequilibrium coefficient. It is then easily possible to generalize from computer runs at only one population size. All computer runs assumed an initial population at linkage equilibrium between the two loci. Analysis of the results was greatly simplified by considering the influence of segregation at the second locus on the chance of fixation at the first (defined as the proportion of replicate lines in which the favoured allele was eventually fixed). (ii) The effects of linkage are sufficiently described by Nc. The relationship between chance of fixation at the limit and linkage distance (expressed as 2Nc /( 2Nc + 1)) was linear in the majority of computer runs. (iii) When gene frequency changes under independent segregation were small, linkage had no effect on the advance under selection. In general, segregation at the second locus had no detectable influence on the chance of fixation at the first if the gene effects at the second were less than one-half those at the first. With larger gene effects at the second locus, the chance of fixation passed through a minimum and then rose again. For two loci to have a mutual influence on one another, their effects on the character under selection should not differ by a factor of more than two. (iv) Under conditions of suitable relative gene effects, the influence of segregation at the second locus was very dependent on the initial frequency of the desirable allele. The chance of fixation at the first, plotted against initial frequency of the desirable allele at the second, passed through a minimum when the chance of fixation at the second locus was about 0·8. (v) A transformation was found which made the influence of segregation at the second locus on the chance of fixation at the first almost independent of initial gene frequency at the first and of gene effects at the first locus when these are small. (vi) In the population of gametes at final fixation, linkage was not at equilibrium and there was an excess of repulsion gametes. (vii) The results were extended to a consideration of the effect of linkage on the limits under artificial selection. Linkage proved only to be of importance when the two loci had roughly equal effects on the character under selection. The maximum effect on the advance under selection occurred when the chance of fixation at both of the loci was between 0·7 and 0·8. When the advance under selection is most sensitive to changes in recombination value, a doubling of the latter in no case increased the advance under selection by more than about 6%. The proportion selected to give maximum advance under individual selection (0·5 under independent segregation) was increased, but only very slightly, when linkage is important. (viii) These phenomena could be satisfactorily accounted for in terms of the time scale of the selection process and the effective size of the population within which changes of gene frequency at the locus with smaller effect must take place.

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The effect of linkage on limits to artificial selection.

A major challenge of biology is understanding the relationship between molecular genetic variation and variation in quantitative traits, including fitness. This relationship determines our ability to predict phenotypes from genotypes and to understand how evolutionary forces shape variation within and between species. Previous efforts to dissect the genotype-phenotype map were based on incomplete genotypic information. Here, we describe the Drosophila melanogaster Genetic Reference Panel (DGRP), a community resource for analysis of population genomics and quantitative traits. The DGRP consists of fully sequenced inbred lines derived from a natural population. Population genomic analyses reveal reduced polymorphism in centromeric autosomal regions and the X chromosome, evidence for positive and negative selection, and rapid evolution of the X chromosome. Many variants in novel genes, most at low frequency, are associated with quantitative traits and explain a large fraction of the phenotypic variance. The DGRP facilitates genotype-phenotype mapping using the power of Drosophila genetics.

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The Drosophila melanogaster Genetic Reference Panel

The theory of balanced polymorphism which has been elaborated by population geneticists, notably Sewall Wright and R. A. Fisher, has in the main been concerned with the effects of single loci. As theory generally goes apace with experiment, this accent on single locus polymorphisms has been due to the plethora of observational evidence relating to simple cases. It is sufficient to note the vast effort made by Dobzhansky and his co-workers in their elucidation of the inversion polymorphism of the third chromosome of Drosophila pseudoobscura. In recent years, however, a few cases have come to light of polymorphisms involving more than one Mendelian unit. Among these are the inversions on different chromosomes found in D. robustca studied by Levitan (1955 and 1958), the shell color of Cepaea nemoralis reported by Lamotte (1951) and by Cain and Sheppard (1952), the complex mimicry pattern in certain butterflies (Sheppard, 1959) and the inversions in two chromosomes of the grasshopper Moraba scurra analyzed by White (1957) and Lewontin and White (1960). The study of effects of natural selection on single locus polymorphisms must take into account only inter-allelic effects such as additivity and dominance. In multi-locus polymorphisms, however,

The evolutionary dynamics of complex polymorphisms.

The survival process of descendants of a new mutant gene can be approximated by a birth-and-death branching process in the theory of probability. Making use of probability generating functions, Fisher (1930) investigated a simple survival process for selectively advantageous mutant genes. Skellam (1949) extended Fisher's method to recurrent mutations with a selective disadvantage. More recently, Kojima and Kelleher (1962) adapted the same approach to selectively advantageous mutations occurring in a population with a more realistic specification of biological parameters than Fisher's. These specifications of parameters included the partitioning of over-all selective differential into fertility and infant-to-adult mortality, adjustment of family size distribution according to observed distribution, and fluctuations of population size. The method of probability generating functions provides the exact distributions of numbers of mutant descendants for successive generations following the occurrence of the original mutation. The ultimate survival probability of a given mutation (or

Ken-ichi Kojima

Papers

The evolutionary dynamics of complex polymorphisms.

Survival process of linked mutant genes.