Institute of Cell, Animal and Population Biology, University of Edinburgh, Edinburgh, Scotland
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Abstract |
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Introduction |
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In D. melanogaster, comparisons of African and non-African levels of nucleotide diversity have focused primarily on the X chromosome (e.g., Begun and Aquadro 1993, 1995
; Langley et al. 2000
). Patterns of polymorphism at these loci suggest a bottleneck in non-African populations. Curiously, the handful of autosomal loci that have been studied (Clark and Wang 1997
; Aguadé 1998, 1999
; Tsaur, Ting, and Wu 1998
; Begun et al. 1999
; Andolfatto and Kreitman 2000
) do not support this hypothesis. The data are more scarce for D. simulans, for which African and non-African single-nucleotide variation has been compared at only two-single copy nuclear loci (Begun and Aquadro 1995
; Hamblin and Veuille 1999
). Here, I reexamine the bottleneck hypothesis for D. melanogaster and D. simulans using single-nucleotide polymorphisms for a large number of loci scattered throughout the genome. While nucleotide variation in these two species has been summarized before (Moriyama and Powell 1996
), a very different picture emerges when African and non-African populations are considered separately.
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Materials and Methods |
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Sign tests (Sokal and Rohlf 1998
, p. 444) were performed with the null hypothesis that nucleotide diversity levels are equal in non-African and African populations (i.e., that there was no bottleneck). The tests were one-tailed, since, under both the null and alternative (i.e., a bottleneck) hypotheses, we do not expect more variation outside of Africa.
The sign test assumes that loci are independent. It is unclear whether this is strictly true in the case of loci at the tip of the X chromosome in D. melanogaster (i.e., cytological positions 1A to 2B), which are believed to experience little crossing over (reviewed in Langley et al. 2000
). This said, recombination events (cf. Hudson and Kaplan 1985
) could be detected within the su(s) and su(wa) loci. In addition, linkage disequilibrium has been shown to decay with distance at su(s) and su(wa) on the same scale as loci in regions with higher rates of crossing over (Langley et al. 2000
). Evidence for considerable recombination (perhaps gene conversion) in these data suggests that collapsing these loci into a single data point is overly conservative. Nonetheless, if the average of all six loci (weighted equally) was used as a single data point, the qualitative conclusions were unchanged.
Levels of Nucleotide Diversity by Chromosome and Geographic Locality
I compared diversities at loci in African and non-African populations of D. melanogaster and D. simulans. Average X and autosome synonymous site diversities (W and
) included only synonymous sites of coding regions (i.e., all noncoding sites and loci were excluded). I report mean synonymous site diversities over all loci, weighting each of the loci equally. This weighting was not entirely appropriate, since sequenced loci varied in length and sample size, and population samples were not drawn identically. Unfortunately, this problem is inherent in analyses that combine data from many sources. I excluded the data of Teeter et al. (2000)
from calculations of nucleotide diversity, since many of the loci are very short (i.e., less than several hundred base pairs) and original sequences were not available for the assignment of coding regions. DnaSPv3.0 (Rozas and Rozas 1999
) was used for polymorphism analyses.
In comparisons of averages of nonhomologous loci, I wished to minimize the effects that the recombinational landscape of each chromosome may have on levels of nucleotide variation (Aquadro, Begun, and Kindahl 1994
; Charlesworth 1996
). To this end, I excluded anon1E9, asense, and Dras1 from diversity calculations for D. melanogaster. Synonymous variation at these loci was more likely to be affected by selection at linked sites, as the crossing-over rate for these loci was estimated to be less than 5 x 10-9 per base pair per generation (cf. Comeron, Kreitman, and Aguadé [1999
] and True, Mercer, and Laurie [1996] for estimated rates of crossing over).
Patterns of Synonymous and Replacement Variation
For between-species comparisons of synonymous and replacement polymorphism, I restricted the analysis to homologous loci sequenced in both species. In addition to loci referenced above, I included Adh and Adh-dup (D. simulans; Sumner 1991
), ci (Berry et al. 1991), cta (Wayne and Kreitman 1996
), Est-6 (Cooke and Oakeshott 1989
; Karotam, Delves, and Oakeshott 1993
; Hasson and Eanes 1996
), Gld (Hamblin and Aquadro 1996, 1997), janus (Kliman et al. 2000
; F. Depaulis, personal communication), Mlc1 (Leicht et al. 1995
), Pgd (Begun and Aquadro 1994
; Begun and Whitley 2000
), prune (Simmons et al. 1994
), runt (Labate, Biermann, and Eanes 1999
), and white (Kirby and Stephan 1995
; Kliman et al. 2000
). For African versus non-African comparisons of synonymous and replacement polymorphism, I considered all loci with both African and non-African samples. In this part of the analysis, I included all available Adh and Adh-dup alleles for D. melanogaster.
Sampling Locations
This study combined data from many sources. For the majority of loci in D. melanogaster, African samples had a mixed sampling scheme that included one or more lines from Botswana, Kenya, Madagascar, South Africa, or Zimbabwe. Exceptions were Boss, Ref(2)P, and Rh3, for which only two West African lines were sampled. Acp29AB, Adh, eve, Pgi, and Tpi were sampled in both East and West Africa. Non-African samples were generally a mix from diverse geographic localities, with a bias toward North America. The data of Teeter et al. (2000)
had a consistent sampling scheme for all loci: African populations were composed of one South African line and one (or two) Kenyan lines, and non-African lines were drawn from a worldwide sample. Generally, samples for D. simulans included one or more lines from East Africa. G6pd, Boss, Pgi, and Rh3 were sampled in both East and West Africa; vermilion included only West Africa. Non-African samples were generally a mix from diverse geographic localities, with a bias toward North America. Additional details can be found in the original sources (see references above).
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Results and Discussion |
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Demographic events such as a bottleneck are expected to affect the whole genome similarly (i.e., they are expected to result in lower levels of variation outside Africa). While genomes with a smaller effective population size will recover faster from changes in population size (e.g., Fay and Wu 1999
), it is unclear how relevant this will be to the interpretation of X-autosome comparisons (see arguments below). The discrepancy between the X chromosome and the autosomes is therefore difficult to explain with a simple bottleneck in the history of non-African populations. In order to reconcile all the data with the bottleneck hypothesis, we would have to invoke post hoc differences between non-African and African populations of D. melanogaster.
X-Chromosome Versus Autosome Nucleotide Diversity in D. melanogaster
Table 3
summarizes mean synonymous site diversity levels in African and non-African samples for X-linked and autosomal loci in D. melanogaster and D. simulans. Comparisons of X and autosome levels of diversity were complicated by possible differences in their effective population sizes. Assuming equal sex ratios and no selection, a simple correction is to multiply X diversities by 4/3 (based on relative numbers of X chromosomes and autosomes). However, if sexual selection on males is prevalent in natural populations of Drosophila (cf. Andersson 1994
), then the ratio of effective sizes of the X chromosome and autosomes may be closer to unity (Caballero 1995
). Sex-specific life history traits (e.g., mortality rates) in the wild may further complicate the appropriate scaling of levels of variation on the X chromosome and the autosomes (B. Charlesworth, personal communication). Unfortunately, we remain virtually ignorant of the relative importance of sexual selection and sex-specific life history traits in natural populations of D. melanogaster and D. simulans. Laboratory measurements have suggested that the effective population size of females is greater than that of males (Crow and Morton 1954
). Thus, the appropriate correction for X-chromosome diversity may be less than 4/3.
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In summary, the chromosome-specific differences between African and non-African populations of D. melanogaster (tables 2 and 3 ) make a simple demographic explanation, such as a bottleneck, improbable. Additional factors must be invoked to explain the discordant geographic patterns for the X chromosome versus the autosomes. Regardless of whether or not a bottleneck occurred in the history of non-African populations, we are left to explain why X-chromosome diversity appears to be elevated above that of autosomes in African populations.
A Role for Autosomal Inversions?
A possible explanation for the unexpectedly low levels of diversity for African D. melanogaster autosomes is the presence of common autosomal inversion polymorphisms. Based on the geographic distribution of inversions in this species (Lemeunier and Aulard 1992
), it is likely that autosomal inversions are more often present in our African samples than in non-African samples. Inversions suppress crossing over within the inverted region when heterozygous. Linked neutral diversity on autosomes polymorphic for inversions may therefore be more susceptible to variation-reducing selection (and thus harbor reduced variability) than are X-linked loci (cf. Begun 1996
). This explanation probably requires the persistence of inversions at appreciable frequencies. Even if this scenario explains the reduced variability on African autosomes, careful timing of inversion and bottleneck effects would be required to explain why a bottleneck pattern was not apparent in the autosomal data. Recent studies of two common inversions have suggested that they are not old and have had low historical frequencies (Wesley and Eanes 1994
; Andolfatto, Wall, and Kreitman 1999
). Thus, an alternative explanation is a recent change in inversion frequencies in Africa. This hypothesis predicts that nucleotide diversity of inverted chromosomes will be less than that of standard chromosomes (cf. Navarro, Barbadilla, and Ruiz 2000
). However, direct comparisons of inverted and standard chromosomes (Hasson and Eanes 1996
; Aguadé 1998, 1999
; Andolfatto, Wall, and Kreitman 1999
; Benassi et al. 1999
; Depaulis, Brazier, and Veuille 1999
) do not suggest markedly reduced levels of variation in inverted chromosomes (with the exception of loci very close to inversion breakpoints).
The impact of inversions in African populations can be assessed indirectly by comparing D. melanogaster/D. simulans ratios of nucleotide diversities for the X chromosome and the autosomes. Inversions are rare in D. simulans (Lemeunier and Aulard 1992
), so this species should not show the same pattern if inversions account for the reduced autosomal diversity in African D. melanogaster samples. The African D. melanogaster/D. simulans ratios of
W were 0.9 for the X chromosome and 0.5 for the autosomes (table 3 ); non-African populations had more equal ratios (0.5 and 0.6, respectively). These ratios and the estimates of mean diversities on which they were based had large standard errors. In addition, we must assume that no other factors affect X-linked and autosomal variation in D. simulans. This said, the pattern was consistent with the hypothesis that inversions have decreased diversity levels on the autosomes in African populations of D. melanogaster.
Evidence for a Bottleneck in the History of D. simulans
As shown in table 1
, there are few data for D. simulans for which African/non-African comparisons of single-nucleotide polymorphisms can be made. Combining all chromosomes, a sign test (table 2
) revealed significantly lower diversity in non-African populations relative to African populations (11:2; P = 0.013). While this finding is consistent with the microsatellite survey of Irvin et al. (1998)
, a caveat in making African/non-African comparisons is the possibility of African/non-African differences in population structure. The diversity measure
W is sensitive to the degree of population subdivision. In particular, when populations are subdivided and both demes are sampled,
W will be larger than predicted for a panmictic population of the same total size (Tajima 1989a
). Recent data from the G6pd locus (Hamblin and Veuille 1999
) are consistent with considerable population differentiation within Africa. As an illustration, total variability at the G6pd locus in Africa is about twofold higher than total non-African diversity (table 1
). A measure which is less sensitive to population subdivision than total diversity is the average of within-population diversities (Tajima 1989a
). When average within-population diversities at G6pd were compared, African populations (
W within = 0.0033 per site) were more similar to non-African populations (
W within = 0.0036 per site). Similarly, the vermilion locus showed considerable between-populations differentiation within Africa (Hamblin and Veuille 1999
). In summary, while the available data for D. simulans show a trend toward higher levels of total nucleotide diversity in Africa than outside of Africa (tables 13 ), within-population diversities are not necessarily higher in Africa. Thus, it remains unclear whether the nucleotide data support a simple bottleneck model.
Patterns of Synonymous and Replacement Polymorphism
Table 4
lists the numbers of synonymous and replacement polymorphisms and their ratios (S/R) in D. melanogaster and D. simulans for all available pairs of homologous loci. The S/R ratio for the autosomes of D. melanogaster was significantly lower than that for D. simulans autosomes (two-tailed Fisher's exact test; P = 0.01). In contrast, S/R ratios were surprisingly similar in the two species for the X chromosome (two-tailed Fisher's exact test; P = 1.00). These findings are consistent with the X-autosome contrast first noted by Begun (1996)
. There appears to be an excess of replacement polymorphisms and/or a deficiency of synonymous polymorphisms on D. melanogaster autosomes relative to D. simulans autosomes. Also of interest is the pattern of within-species variability (table 4
). In populations of D. melanogaster, the within-species S/R ratios on the X chromosome were higher than those of the autosomes. This trend was somewhat less marked in D. simulans. Since nonhomologous loci were compared, little can be said with certainty in X-autosome comparisons. A Fisher's exact test was performed on S/R ratios under the assumption that the mean numbers of synonymous and replacement sites do not differ between the X-linked and autosomal loci. This test revealed a significantly smaller S/R ratio on autosomes relative to the X chromosome in both species (two-tailed P < 10-6 and P < 0.003 for D. melanogaster and D. simulans, respectively).
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Models of Synonymous and Replacement Site Evolution
How can the above patterns of synonymous and replacement polymorphism be explained? One possibility is that the majority of amino acid replacement changes are deleterious and partially recessive (McVean and Charlesworth 1999
). Allow, for the moment, the three following assumptions: (1) sites evolve independently, (2) most amino acid replacement mutations are deleterious and partially recessive, and (3) selection is stronger in D. simulans than in D. melanogaster (proportional to Nes, where Ne is the effective population size and s is the mean deleterious selection coefficient). This last assumption is supported by patterns of polymorphism and divergence in these two species (Akashi 1995, 1996
). Figure 1
is a schematic diagram based on figures 2 and 4 of McVean and Charlesworth (1999)
. The key feature is that the slope of the line relating diversity to the strength of selection is less steep on autosomes than on the X chromosome due to the recessiveness of deleterious mutations. This model neatly accounts for three features of the synonymous and replacement polymorphism data: (1) the within-species S/R ratio is greater on the X chromosome than on the autosomes; (2) the X-autosome S/R discrepancy is more marked in D. melanogaster than in D. simulans; and (3) as first noted by Begun (1996)
, the D. melanogaster and D. simulans S/R ratios are more discrepant on the autosomes than on the X chromosome.
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Both D. melanogaster and D. simulans are thought to have recently colonized Europe and the Americas. Thus, possible targets for recent transient or geographically localized selection are loci involved in adaptation to temperate habitats. If transient selection is shaping patterns of variability at a large number of loci, we may expect S/R ratios to be lower outside of than within Africa. As seen in table 5 , S/R ratios in African and non-African populations are remarkably similar. The trend on the X toward a lower S/R ratio in non-African D. simulans is not significant (two-tailed Fisher's exact test; P = 0.347). Note that this test may lack power, since African and non-African samples share part of their genealogical histories. Nonetheless, it appears that the relatively recent range expansion from Africa, possibly accompanied by changes in effective population size, selection pressures, and changes in inversion frequencies in D. melanogaster, has not had a large effect on the dynamics of synonymous and replacement polymorphism in these two species.
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Conclusions |
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Drosophila melanogaster autosomes harbor an excess of amino acid replacement polymorphisms (and/or a deficiency of synonymous polymorphisms) relative to D. simulans autosomes, while the X chromosome shows no such pattern. Here, I have argued that several features of within- and between-species patterns of synonymous and replacement polymorphism might be explained by assuming that replacement polymorphisms are deleterious and partially recessive and that purifying selection is more efficient in D. simulans than in D. melanogaster. Generally lower recombination rates on D. melanogaster autosomes may also contribute to this pattern if transient selection on amino acid variants is common.
This study highlights problems encountered in comparisons of X-linked and autosomal loci. Many factors, both selective and demographic, can contribute to sex-autosome differences in levels of nucleotide diversity (Aquadro, Begun, and Kindahl 1994
; Caballero 1995
; Charlesworth 1996
; Fay and Wu 1999
). It has been proposed that X-autosome comparisons may provide a way to distinguish between background selection and positive selection in the genome (Aquadro, Begun, and Kindahl 1994
). For example, if most advantageous alleles are recessive, hitchhiking models (Maynard-Smith and Haigh 1974
) predict reduced diversity on the X chromosome relative to autosomes, whereas the background selection hypothesis (Charlesworth, Morgan, and Charlesworth 1993
) predicts the opposite pattern (Aquadro, Begun, and Kindahl 1994
). Thus, adaptation to temperate habitats may explain the larger diversity reductions on the X chromosome relative to autosomes in non-African populations of both D. melanogaster and D. simulans (tables 13
; see also Begun and Whitley 2000
). However, we still have a poor understanding of how ancient population structure and recent demographic perturbations may have affected levels of nucleotide variation (in addition to the unknown impact of inversion polymorphisms in D. melanogaster). Comparisons of X and autosome nucleotide diversities may not be informative about the mode of selection as long as a panmictic population model remains the null hypothesis.
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Acknowledgements |
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Footnotes |
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1 Keywords: bottleneck
selection
deleterious mutations
polymorphism
inversion
synonymous
nonsynonymous
dominance
2 Address for correspondence and reprints: Institute of Cell, Animal and Population Biology, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom. peter.andolfatto{at}ed.ac.uk
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