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 compositelikelihood-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.

No abstract

DNA diversity in two segments of the Notch locus was surveyed in four populations of Drosophila melanogaster and two of D. simulans. In both species we observed evidence of non-steady-state evolution. In D. simulans we observed a significant excess of intermediate frequency variants in a non-African population. In D. melanogaster we observed a disparity between levels of sequence polymorphism and divergence between one of the Notch regions sequenced and other neutral X chromosome loci. The striking feature of the data is the high level of synonymous site divergence at Notch, which is the highest reported to date. To more thoroughly investigate the pattern of synonymous site evolution between these species, we developed a method for calibrating preferred, unpreferred, and equal synonymous substitutions by the effective (potential) number of such changes. In D. simulans, we find that preferred changes per "site" are evolving significantly faster than unpreferred changes at Notch. In contrast we observe a significantly faster per site substitution rate of unpreferred changes in D. melanogaster at this locus. These results suggest that positive selection, and not simply relaxation of constraint on codon bias, has contributed to the higher levels of unpreferred divergence along the D. melanogaster lineage at Notch.

Drosophila melanogaster originated in tropical Africa but has achieved a cosmopolitan distribution in association with human habitation. Cosmopolitan populations of D. melanogaster are known to have reduced genetic variation, particularly on the X chromosome. However, the relative importance of population bottlenecks and selective sweeps in explaining this reduction is uncertain. We surveyed variation at 31 microsatellites across a 330-kb section of the X chromosome located between the white and kirre genes. Two linked clusters of loci were observed with reduced variation and a skew toward rare alleles in both an Ecuador and a Zimbabwe population sample. Examining Zimbabwe DNA sequence polymorphism within one of these regions allowed us to localize a selective sweep to a 361-bp window within the 59 regulatory region of the roughest gene, with one nucleotide substitution representing the best candidate for the target of selection. Estimates of sweep age suggested that this fixation event occurred prior to the expansion of D. melanogaster from sub-Saharan Africa. For both putative sweep regions in our data set, cosmopolitan populations showed wider footprints of selection compared to those in Zimbabwe. This pattern appears consistent with the demographic amplification of preexisting sweep signals due to one or more population bottlenecks.

To identify genomic regions affected by the rapid fixation of beneficial mutations (selective sweeps), we performed a scan of microsatellite variability across the Notch locus region of Drosophila melanogaster. Nine microsatellites spanning 60 kb of the X chromosome were surveyed for variation in one African and three non-African populations of this species. The microsatellites identified an 14-kb window for which we observed relatively low levels of variability and/or a skew in the frequency spectrum toward rare alleles, patterns predicted at regions linked to a selective sweep. DNA sequence polymorphism data were subsequently collected within this 14-kb region for three of the D. melanogaster populations. The sequence data strongly support the initial microsatellite findings; in the non-African populations there is evidence of a recent selective sweep downstream of the Notch locus near or within the open reading frames CG18508 and Fcp3C. In addition, we observe a significant McDonald-Kreitman test result suggesting too many amino acid fixations species wide, presumably due to positive selection, at the unannotated open reading frame CG18508. Thus, we observe within this small genomic region evidence for both recent (skew toward rare alleles in nonAfrican populations) and recurring (amino acid evolution at CG18508) episodes of positive selection.