Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
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Abstract |
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Introduction |
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Nucleotide polymorphism in the y-achaete-scute (y-ac-sc) gene region has been extensively analyzed in natural populations of D. melanogaster and Drosophila simulans (Aguadé, Miyashita, and Langley 1989
; Beech and Leigh Brown 1989
; Eanes, Labate, and Ajioka 1989
; Macpherson, Weir, and Leigh Brown 1990
; Begun and Aquadro 1991, 1993, 1995
; Martín-Campos et al. 1992
). In most of these studies, a very strong reduction in the level of DNA variation was detected. Surveys of other genes and/or Drosophila species also revealed low levels of nucleotide variation in genomic regions with a strong reduction in recombination rate (see, e.g., Stephan and Langley 1989
; Berry, Ajioka, and Kreitman 1991
; Stephan and Mitchell 1992
; Langley et al. 1993
). As the low levels of polymorphism detected in regions with no (or reduced) recombination could not be explained by a lower mutation rate in these regions, two selective models have been proposed to explain the extremely low variation in these regions: the hitchhiking model and the background selection model. According to the hitchhiking model (Maynard Smith and Haigh 1974
), a particular variant increasing in frequency due to positive selection will carry adjacent sites along, which will cause removal of variation at neutral linked sites when the selected variant is fixed. In contrast, the background selection model (Charlesworth, Morgan, and Charlesworth 1993
) proposes negative selection acting against recessive deleterious mutations as the cause of reduced neutral variation. Assuming the same intensity of selection, the effect predicted by both models in reducing levels of neutral linked variation should be larger the lower the recombination rate.
In Drosophila subobscura, the y gene maps at section 2B of the X (=A) chromosome (Segarra et al. 1995
). It is therefore separated from the centromere by more than one euchromatic section in standard chromosomes. Unlike in D. melanogaster and D. simulans, the recombination rate at the y gene region of D. subobscura should not be extremely reduced. The pattern of synonymous divergence between D. melanogaster and D. subobscura (Munté, Aguadé, and Segarra 1997
), which is characterized by a high number of synonymous substitutions per synonymous site and by a much higher codon bias in the latter species, would support this difference in the recombination rate. This change in the recombinational environment of the y gene is also expected to cause a drastic difference in the level of nucleotide polymorphism between both species. In fact, an effect on nucleotide diversity has already been reported for other gene regions that differ in recombination rate in different species (Stephan et al. 1994
; Schmid et al. 1999
).
However, the y region maps very close to the proximal breakpoints of four inversions described in segment I (sections 17) of the A chromosome of D. subobscura: A1, A5, A6, and A7. The adaptive character of inversion polymorphism in Drosophila is well documented (reviewed by Powell 1997
, pp. 102114). Thus, selective forces may contribute to the establishment of a newly arisen inversion. In this case, the increase in frequency of a new inversion may be a rapid process that can be envisaged as a partial selective sweep. As a consequence, nucleotide variation at loci associated with a particular inversion (as, for instance, those located near the breakpoints) may be null or very low even after the new inversion has reached its equilibrium frequency. Thereafter, these loci accumulate variation both by mutation and by genetic exchange with the preexisting arrangement. This period can be considered a transient phase that persists until nucleotide variation in the new arrangement reaches equilibrium. Therefore, the level of variation at the y gene region of D. subobscura will depend not only on its recombinational environment, but also on the age of the chromosomal lineages, and thus may be strongly affected by the history of the different polymorphic inversions in segment I.
To further investigate how the change in the recombinational environment and the presence of inversion polymorphism affect the level and pattern of variation in a particular gene region, nucleotide polymorphism at the y gene region was analyzed in a sample of two different chromosomal classes segregating for segment I of the A chromosome of D. subobscura and in the closely related species Drosophila madeirensis and Drosophila guanche. No reduction in the level of nucleotide polymorphism was detected in the y gene region compared with variation at other genomic regions analyzed in this species (Rozas and Aguadé 1994
; Cirera and Aguadé 1998
; Navarro-Sabaté, Aguadé, and Segarra 1999
). Nucleotide variation was, however, affected by chromosomal polymorphism, as the two chromosomal classes were strongly differentiated. In addition, their pattern of variation seemed to reflect the strong bottleneck produced in the origin of the arrangements. According to this result, some inferences about the history and age of the chromosomal lineages have been made.
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Materials and Methods |
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In Situ Hybridization
Salivary glands of third-instar larvae grown in uncrowded cultures were dissected and polytene chromosome slides were obtained according to Montgomery, Charlesworth, and Langley (1987)
. The recombinant phage
D.subRA4.1 (Munté, Aguadé, and Segarra 1997
) that includes the second exon of the y gene of D. subobscura was used as probe. The probe was labeled by nick translation with biotin-16-dUTP. Prehybridization, hybridization, and detection conditions were as described in Segarra et al. (1995)
.
DNA Sequencing
Genomic DNA from individual males was purified according to Ashburner (1989
, pp. 106107). The y gene region was subsequently amplified by the polymerase chain reaction (PCR). Amplification primers were designed on the available D. subobscura DNA sequence (Munté, Aguadé, and Segarra 1997
). Although in some cases the complete region was amplified in one fragment or in three overlapping fragments, in most lines, the y gene region was PCR-amplified in two overlapping fragments using primers 5'-AACCACACGAACCACTCAACG-3' and 5'-CAAAAGTGGCCATTAGCTTGC-3' for one of the fragments and 5'-GTCATAAACCGTTCCACATGC-3' and 5'-GTGGTGTGGCTTTAAGAATTCC-3' for the other one. The optimal PCR conditions were as follows: 34 cycles of 94°C for 45 s, 5758°C for 30 s, and 72°C for 3 min.
The amplified DNA was purified with the QIAquick PCR purification kit (Qiagen) and used as template for direct sequencing. Primers designed approximately every 300 nt on both strands of the sequence were used for this purpose. Sequencing reactions were performed with the ABI PRISM Dye Terminator Cycle Sequencing kit (Perkin Elmer) following the manufacturer's instructions. Sequences were run on an ABI PRISM 377 (Perkin Elmer) automated sequencer.
Sequences were assembled with Staden's (1982)
programs. Complete sequences were aligned manually or by using the CLUSTAL W program (Thompson, Higgins, and Gibson 1994
) and edited with the MacClade program (Maddison and Maddison 1992
). The DNA sequences obtained in this study were deposited in the EMBL database library with the accession numbers AJ289787AJ289813.
Data Analysis
Nucleotide polymorphism was estimated as the number of segregating sites (S), the average number of pairwise differences (k), the average number of pairwise differences per site (or nucleotide diversity) (), and the heterozygosity per site expected in a population in mutation-drift equilibrium given the observed S value (
, or Watterson's estimator; Watterson 1975
). Under the neutral model,
and
have equal expectations in a stationary population.
Genetic differentiation between arrangements was estimated as the average number of nucleotide differences per site between arrangements (dxy) and as the number of net nucleotide differences per site (da) (eqs. 10.20 and 10.21 in Nei 1987
). Putative genetic differentiation between gene arrangements was contrasted by the permutation test proposed by Hudson, Boos, and Kaplan (1992)
using the Ks estimator as a measure of differentiation. The statistical significance of the observed Ks value was determined by Monte Carlo simulations.
The number of shared polymorphic sites between arrangements (sites that segregate for the same variants in both arrangements) expected to have arisen independently in each arrangement by parallel mutation was estimated from the hypergeometric distribution, as proposed by Rozas and Aguadé (1994)
, under the assumption of no variation in mutation rate among sites. If the number of observed shared polymorphic sites is significantly higher than that expected, the existence of genetic exchange between arrangements can be inferred. This genetic exchange has to be explained mainly by gene conversion in regions like those located near the breakpoints of polymorphic inversions, where double crossover between arrangements is highly suppressed. Gene conversion tracts between arrangements were identified by the algorithm proposed by Betrán et al. (1997)
.
Linkage disequilibrium was analyzed between pairs of informative sites (sites where the less frequent variant is present at least twice in the sample). The 2 test was used to detect significant linkage disequilibrium between pairs of informative sites. The minimum number of recombination events within each chromosomal class was inferred by the four-gamete test proposed by Hudson and Kaplan (1985)
.
The tests of neutrality proposed by Tajima (1989)
and Fu and Li (1993)
were applied to determine whether the pattern of polymorphism detected in the y gene region was concordant with neutral predictions. Tajima's test is based on the normalized difference between the observed average number of pairwise nucleotide differences (k) and its expectation (
per sequence) in a population in mutation-drift equilibrium according to predictions of the neutral model. Fu and Li's F and F* statistics have the same basis, but for these statistics, the predicted
per sequence is estimated from the number of mutations in the external branches of the gene genealogy. Fu and Li's D and D* statistics use the total number of mutations and the number of mutations in the internal branches of the gene genealogy to compare different estimates of
per sequence. In the Fu and Li tests, the number of mutations in external branches is inferred from the number of singletons in the data set (D* and F* statistics) or from the information in an outgroup species (D and F statistics). Drosophila guanche was used as the outgroup species to estimate these last two statistics. Negative values of Tajima's D statistic indicate an excess of low-frequency variants in the data set, while negative values of the different Fu and Li statistics indicate an excess of unique polymorphisms.
The test proposed by Hudson, Kreitman, and Aguadé (1987)
was used to determine whether the levels of silent polymorphism relative to silent divergence present in the y gene region differed significantly from those detected at other genomic regions previously studied in D. subobscura. McDonald and Kreitman's (1991)
and McDonald's (1996)
tests were also applied (using D. guanche in the interspecific comparisons) to determine whether the y gene region was evolving according to neutral expectations. McDonald and Kreitman's (1991)
test examines whether the ratio of synonymous to nonsynonymous polymorphic sites in one species is equal to the ratio of synonymous to nonsynonymous fixed differences between species as expected under neutrality. McDonald's (1996)
test is based on the number of runs detected in a sample. A run is defined as a stretch of polymorphic (or fixed) sites limited at each end by a fixed (or polymorphic, respectively) site. Both directional and balancing selection cause a reduction in the number of runs detected in a sample. Monte Carlo simulations are performed to determine whether the number of runs observed is lower than that predicted under neutrality.
The DnaSP, version 3.4, program (Rozas and Rozas 1999
, personal communication) was used to perform most of the described analyses: nucleotide polymorphism and genetic differentiation estimates, detection of gene conversion tracts, linkage disequilibrium and recombination analyses, neutrality tests, and application of the hypergeometric distribution. This program also implements the coalescent algorithm proposed by Hudson (1983, 1990)
to perform computer simulations. The coalescent approach was used to infer the statistical significance (after 10,000 replicates) of Tajima's D and Fu and Li's D, F, D*, and F* statistics both under no recombination and assuming intermediate levels of recombination. The empirical distribution of the minimum number of recombination events expected for a particular recombination parameter (C = 3Nec for a sex-linked gene; where Ne is the effective size and c is the recombination rate between the most distant sites) was also inferred by this coalescent approach. The permtest (Hudson, Boos, and Kaplan 1992
) and the DNAruns (McDonald 1996
) programs were used to perform Monte Carlo simulations to contrast putative genetic differentiation between arrangements and to apply the runs test, respectively. Gene genealogies were reconstructed with the MEGA program (Kumar, Tamura, and Nei 1994
).
The ages of the different gene arrangements were estimated assuming a star genealogy within the chromosomal class. This assumption considers that variation within each chromosomal class was null just after its origin and that current variation is in the phase transient to equilibrium. In this case, which can be considered a particular case of the expansion model (Slatkin and Hudson 1991
; Rogers 1995
),
= 2
t (where
is the average number of nucleotide differences per site within arrangement, t is the elapsed time since the origin of the arrangement, and
can be estimated from the rate of nucleotide substitutions per site, for instance, between D. subobscura and D. guanche). This approach may lead to an underestimate of the age of a gene arrangement if variation is at equilibrium, and to an overestimate if genetic exchange between arrangements is important.
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Results |
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Genetic differentiation estimates between gene arrangements are summarized in table 1 . No fixed differences were detected between the Ast and the A2 arrangements, which, in addition, showed the highest number of shared polymorphic sites. These data are consistent with the lower dxy and da estimates between these arrangements relative to those found in the comparisons including the A1 arrangement. Therefore, A1 exhibits a much higher genetic differentiation versus either Ast or A2 than Ast versus the A2 arrangement.
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There were 13 fixed differences (one of them nonsynonymous) between the A1 and Ast+A2 chromosomal classes. In addition, they shared 21 polymorphic sites (18 silent). The hypergeometric distribution was used to estimate the number of silent shared polymorphic sites expected to have arisen independently in each chromosomal class by parallel mutation. Eighty-one and 144 silent polymorphisms out of 3,863 silent sites were detected within the A1 and Ast+A2 chromosomal classes, respectively (table 2
). According to these data, no more than five shared polymorphic sites are expected by chance (P > 0.05). Therefore, it can be inferred that genetic exchange between arrangements has contributed to the increase in the number of shared polymorphic sites. The algorithm proposed by Betrán et al. (1997)
was used to detect gene conversion tracts between the A1 and Ast+A2 chromosomal classes (fig. 2
). The tract present in line 417RIB (from site 1261 to site 2789) was unusually long when compared to the other tracts detected in lines 211RIB (202 bp), 238RIB (107 bp), and 340RIB (13 bp). The two latter tracts included nonsynonymous variants, which caused the presence of the shared replacement polymorphic sites between arrangements (see below).
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In the coding region, nucleotide diversity at all (), synonymous (
s) and nonsynonymous (
a) sites was also estimated for both chromosomal classes independently (table 3
). In this case,
and
s values were also considerably higher in the Ast+A2 class than in A1; in contrast,
a values in both chromosomal classes were much more similar.
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Replacement Polymorphism
Twelve replacement polymorphic sites were detected in the 25 lines studied, of which 7 were singletons (fig. 3
). The first three polymorphic residues are located in the signal peptide of the preprotein and are thus not included in the mature protein. All amino acid differences that segregate as polymorphic in the mature protein are conservative except for the asparagine (N)/histidine (H) replacement at site 155 of the protein. When analyzing each chromosomal class independently, eight residues were polymorphic within Ast+A2, and six were polymorphic within A1. In addition, there was a fixed replacement substitution between chromosomal classes (at residue 451) and three amino acid polymorphisms shared by both chromosomal classes. However, the presence of a valine (V), a threonine (T), and an N at residues 163, 167, and 198, respectively, in the Ast 238RIB line can be explained by the gene conversion tract detected in this line (see above). Likewise, a gene conversion event can explain the presence in the A1 340RIB line of an I (isoleucine) and an A (alanine) at residues 163 and 167, respectively. Therefore, when taking into account gene conversion, it can be argued that the two chromosomal classes present three fixed differences and no shared amino acid polymorphisms. Among the three fixed differences between arrangements, the presence of a V at residue 163 in A1 and an A at residue 167 in Ast+A2 can be considered the derived states using parsimony criteria and the amino acid sequences of D. guanche and D. madeirensis.
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McDonald (1996)
and McDonald and Kreitman (1991)
tests were also applied to the data from each chromosomal class, with D. guanche being used in the interspecific comparison to determine whether the y gene region was evolving neutrally. No departure from neutrality was detected in any of the tests performed.
Gene Genealogy
The genealogical relationships of the studied lines were inferred from information for the whole sequenced y gene region after excluding all sites with alignment gaps and applying the Jukes and Cantor (1969)
method to correct for multiple hits. Figure 4 shows the neighbor-joining tree obtained using D. madeirensis and D. guanche as outgroups. All lines grouped in two clusters in the gene genealogy. One cluster included all Ast and A2 lines that were mixed among them. The second cluster included all A1 lines. Bootstrap values for these two clusters (after 1,000 replicates) were 98% and 96%, respectively. However, in the A1 cluster, line 417RIB shows a somewhat anomalous branching. This line presents a long gene conversion tract (fig. 2
) that may explain its position in the tree. In fact, when this line was subtracted from the data set, bootstrap values for the two chromosomal class clusters increased to 100 for Ast+A2 and 99 for A1. The clustering of the lines according to chromosomal class was also obtained using other genetic distances or when only information from the coding region was considered (results not shown).
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Discussion |
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Nucleotide diversity estimates for the y-ac-sc region of D. melanogaster were over one order of magnitude lower than estimates for the y gene region in both the Ast+A2 and the A1 chromosomal classes of D. subobscura (table 2
). The higher level of variation at the y gene region in D. subobscura could be due to a higher effective population size of this species relative to D. melanogaster and D. simulans. This factor should affect all regions of the genome. However, in D. subobscura, nucleotide diversity at y was not particularly reduced when compared with estimates for the other gene regions studied in this species (table 6
). As the y, rp49, Acp70A, and Acph-1 gene regions studied included different fractions of noncoding versus coding region, comparison of silent estimates was better than direct comparison of nucleotide diversity at all sites (
total). Nucleotide diversity estimates at y (Ast+A2) and rp49 (O3+4) were similar, and they were lower than at Acp70A and Acph-1 (O3+4). Regardless of the chromosomal class (Ast+A2 or A1), the ratio of silent polymorphism to divergence for the y region was similar to that for the rp49 (either O3+4 or Ost), Acp70A, or Acph-1 (either O3+4 or Ost) region, as indicated by the nonsignificant results of the Hudson, Kreitman, and Aguadé (1987)
tests. Unlike in D. melanogaster and D. simulans, the level of nucleotide polymorphism detected in the y gene region of D. subobscura would not be reduced relative to other genomic regions studied in this species. The location of the y gene in a region with no reduced recombination in D. subobscura would explain why this gene exhibited a normal level of variation in this species. In fact, the lack of linkage disequilibrium and the minimum number of recombination events detected within each chromosomal class indicated that recombination was important in homokaryotypes. This result further supported the idea that the low level of variation at y-ac-sc in D. melanogaster and D. simulans was due to its location in a region with a strong reduction in recombination and thus reinforced the effect of the recombination rate on neutral variation that, anyway, is rather well established and generally accepted for Drosophila (for reviews, see Begun and Aquadro 1992
; Aguadé and Langley 1994
; Aquadro, Begun, and Kindahl 1994
).
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The gene genealogy of the lines studied (fig. 4
) also supports that conclusion. All A1 lines cluster together in the gene tree, which points out that the pattern of variation in this gene region still reflects and is consistent with the monophyletic origin of the A1 inversion. In Drosophila, the study of nucleotide variation at molecular markers closely linked to the breakpoints of particular inversions or at the breakpoints themselves has confirmed the monophyletic character of these inversions, as in the case of the In(3L) Payne inversion of D. melanogaster (Wesley and Eanes 1994
), the Sex-Ratio arrangement of Drosophila pseudoobscura (Babcock and Anderson 1996
), and the Ost and O3+4 arrangements of D. subobscura (Rozas and Aguadé 1993, 1994
; Navarro-Sabaté, Aguadé, and Segarra 1999
). This monophyletic character holds even for inversions whose origin seems to be mediated by transposable elements, such as inversion 2j of Drosophila buzzatii (Cáceres et al. 1999
) or In(2L)t of D. melanogaster (Andolfatto, Wall, and Kreitman 1999
). In contrast to the clustering of the A1 lines, lines Ast and A2 are intermixed in the gene genealogy. This result is concordant with the location of y relative to the breakpoints of inversion A2. Therefore, it does not question the monophyletic character of this inversion, but it indicates that recombination has erased the reliable history of these chromosomal arrangements.
Chromosomal Phylogeny
The chromosomal phylogeny of the A chromosome inversions is not well established. Four inversions have been described in segment I of the A chromosome relative to its Ast arrangement: A1, A5, A6, and A7 (Krimbas 1992
). Figure 5a
shows the relationships among these inversions. Krimbas and Loukas (1984)
proposed that according to the centrality criteria, either Ast or A5 may be the ancestral arrangement for segment I, although they favored the former alternative. The study of the closely related species D. guanche and D. madeirensis has not helped to clarify the phylogeny. In segment I, D. madeirensis differs from the Ast arrangement of D. subobscura by a single inversion that was named Am1 (1A/B-7C/D) (Papaceit and Prevosti 1991
). On the other hand, segment I of D. guanche differs from that of D. subobscura by four overlapping inversions whose identities are not well established. Brehm and Krimbas (1990)
proposed that Am1 was one of these four inversions. If this assignment were correct, it would mean that the Am1 arrangement was present in the ancestral populations of D. subobscura before the split of the D. guanche and D. madeirensis lineages. As this arrangement has not been detected in current populations of D. subobscura, it has to be inferred that Am1 went extinct in the D. subobscura lineage after the split of D. madeirensis. Therefore, according to the different authors, either Am1 or Ast might be the ancestral arrangement for segment I of the A chromosome of D. subobscura. In addition, the putative ancestral character of A1 cannot be completely discarded a priori.
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The ancestral character of Am1 is also supported by estimates of the genetic distances between D. subobscura arrangements and between D. madeirensis and these arrangements. The silent dxy value between Ast+A2 and A1 was 0.0156. In contrast, silent divergence between D. madeirensis and these chromosomal classes was 0.0268 (for Ast+A2) and 0.0265 (for A1). The shortest distance found between the Ast+A2 and the A1 chromosomes indicates that differentiation between both chromosomal classes has accumulated over a shorter period of time than that contributing to the divergence between D. madeirensis and D. subobscura.
The gene genealogy depicted in figure 4
does not seem to reflect, however, the derived character of the A1 arrangement. If indeed the A1 arrangement arose on an Ast chromosome, one would expect a priori that all A1 lines branched from an Ast+A2 line. The observed clustering of the lines according to their arrangement for segment I indicates that both arrangements have accumulated enough fixed or nearly fixed differences to be clearly differentiated. Although this result is quite unexpected, genealogies where inverted chromosomes form a cluster highly differentiated from the ancestral standard chromosomes have also been detected for the In(3L)Payne and the In(2L)t inversions of D. melanogaster, with estimated ages of 360,000 and 160,000 years, respectively (Hasson and Eanes 1996
; Andolfatto, Wall, and Kreitman 1999
).
The proposed phylogeny in figure 5b is based on the assumption that variation in the Ast+A2 and the A1 chromosomal classes is in the phase transient to equilibrium. However, other evolutionary forces unrelated to the origin of an arrangement may cause a similar pattern of variation. For instance, a selective sweep in, or near, the y gene region within a particular chromosomal class might have erased all variation putatively accumulated in this gene region after the origin of the arrangement for segment I. In this case, the estimated age of a given inversion would correspond to the hitchhiking event. Therefore, if this pattern is caused by factors other than the origin of the arrangements, this phylogeny should be revised. Information at other loci located, for instance, near the other breakpoint of inversion A1 may provide valuable information in this respect.
Relative Effective Sizes of the Chromosomal Arrangements
Assuming that A1 arose on a standard chromosome for segment I, one would expect that the pattern of variation in this arrangement was more distant from equilibrium in A1 than in Ast+A2. In contrast, Tajima (1989)
and Fu and Li (1993)
tests indicate a stronger deviation from expectations of the neutral model in a population at equilibrium for Ast+A2 than for A1 (table 4
). This result could be explained by assuming that the effective size of A1 is smaller than that of the standard arrangement for segment I. In fact, the expected time to reach the mutation-drift equilibrium for an X-linked locus is 3Ne generations, where Ne is the effective population size. Therefore, the number of generations needed to reach equilibrium would be lower for A1 than for Ast+A2 if the former chromosomal class had a lower effective size. The frequency of the A1 arrangement in the sampled population (10%) might be consistent with a smaller effective size of A1 relative to Ast+A2. However, the frequency of the A1 arrangement shows clinal variation in the Palearctic region, as it increases gradually from western to eastern Europe (Krimbas 1992
). This increase in frequency of the A1 arrangement is accompanied by a decrease in frequency of the Ast+A2 chromosomal class. If migration between European populations were high enough, these populations would be genetically homogenous within arrangement. In this case, the effective sizes of the A1 and Ast+A2 chromosomal arrangements would depend on their overall frequencies in Europe, and thus they would be expected to be much more alike both between themselves and between populations. Therefore, the A1 arrangement might not have a lower effective size than Ast+A2 despite the lower frequency of the former arrangement in the sampled population. Only the study of nucleotide variation at the y gene region in other European populations along the established cline will help to ascertain the degree of genetic differentiation within arrangement across Europe.
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Acknowledgements |
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Footnotes |
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1 Keywords: Drosophila subobscura,
yellow gene
nucleotide polymorphism
X chromosome
inversion polymorphism
recombination rate
2 Address for correspondence and reprints: Carmen Segarra, Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Diagonal 645, 08071 Barcelona, Spain. E-mail: carme{at}porthos.bio.ub.es
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