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1.
Schaeffer SW 《Genetical research》2002,80(3):163-175
Positive and negative selection on indel variation may explain the correlation between intron length and recombination levels in natural populations of Drosophila. A nucleotide sequence analysis of the 3.5 kilobase sequence of the alcohol dehydrogenase (Adh) region from 139 Drosophila pseudoobscura strains and one D. miranda strain was used to determine whether positive or negative selection acts on indel variation in a gene that experiences high levels of recombination. A total of 30 deletion and 36 insertion polymorphisms were segregating within D. pseudoobscura populations and no indels were fixed between D. pseudoobscura and its two sibling species D. miranda and D. persimilis. The ratio of Tajima's D to its theoretical minimum value (D(min)) was proposed as a metric to assess the heterogeneity in D among D. pseudoobscura loci when the number of segregating sites differs among loci. The magnitude of the D/D(min) ratio was found to increase as the rate of population expansion increases, allowing one to assess which loci have an excess of rare variants due to population expansion versus purifying selection. D. pseudoobscura populations appear to have had modest increases in size accounting for some of the observed excess of rare variants. The D/D(min) ratio rejected a neutral model for deletion polymorphisms. Linkage disequilibrium among pairs of indels was greater than between pairs of segregating nucleotides. These results suggest that purifying selection removes deletion variation from intron sequences, but not insertion polymorphisms. Genome rearrangement and size-dependent intron evolution are proposed as mechanisms that limit runaway intron expansion. 相似文献
2.
A 3.5-kb segment of the alcohol dehydrogenase (Adh) region that includes the Adh and Adh-related genes was sequenced in 139 Drosophila pseudoobscura strains collected from 13 populations. The Adh gene encodes four protein alleles and rejects a neutral model of protein evolution with the McDonald-Kreitman test, although the number of segregating synonymous sites is too high to conclude that adaptive selection has operated. The Adh-related gene encodes 18 protein haplotypes and fails to reject an equilibrium neutral model. The populations fail to show significant geographic differentiation of the Adh-related haplotypes. Eight of 404 single nucleotide polymorphisms (SNPs) in the Adh region were in significant linkage disequilibrium with three ADHR protein alleles. Coalescent simulations with and without recombination were used to derive the expected levels of significant linkage disequilibrium between SNPs and 18 protein haplotypes. Maximum levels of linkage disequilibrium are expected for protein alleles at moderate frequencies. In coalescent models without recombination, linkage disequilibrium decays between SNPs and high frequency haplotypes because common alleles mutate to haplotypes that are rare or that reach moderate frequency. The implication of this study is that linkage disequilibrium mapping has the highest probability of success with disease-causing alleles at frequencies of 10%. 相似文献
3.
4.
Inferring the Evolutionary Histories of the Adh and Adh-Dup Loci in Drosophila Melanogaster from Patterns of Polymorphism and Divergence 总被引:5,自引:0,他引:5
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The DNA sequences of 11 Drosophila melanogaster lines are compared across three contiguous regions, the Adh and Adh-dup loci and a noncoding 5' flanking region of Adh. Ninety-eight of approximately 4750 sites are segregating in the sample, 36 in the 5' flanking region, 38 in Adh and 24 in Adh-dup. Several methods are presented to test whether the patterns and levels of polymorphism are consistent with neutral molecular evolution. The analysis of within- and between-species polymorphism indicates that the region is evolving in a nonneutral and complex fashion. A graphical analysis of the data provides support for a hypothesized balanced polymorphism at or near position 1490, site of the amino acid replacement difference between Adhf and Adhs. The Adh-dup locus is less polymorphic than Adh and all 24 of its polymorphisms occur at low frequency--suggestive of a recent selective substitution in the Adh-dup region. Adhs alleles form two distinct evolutionary lineages that differ one from another at a total of nineteen sites in the Adh and Adh-dup loci. The polymorphisms are in complete linkage disequilibrium. A recombination experiment failed to find evidence for recombination suppression between the two allelic classes. Two hypotheses are presented to account for the widespread distribution of the two divergent lineages in natural populations. Natural selection appears to have played an important role in governing the overall patterns of nucleotide variation across the two-gene region. 相似文献
5.
The Duchenne muscular dystrophy (Dmd) locus lies in a region of the X chromosome that experiences a high rate of recombination and is thus expected to be relatively unaffected by the effects of selection on nearby genes. To provide a picture of nucleotide variability at a high-recombination locus in humans, we sequenced 5. 4 kb from two introns of Dmd in a worldwide sample of 41 alleles from Africa, Asia, Europe, and the Americas. These same regions were also sequenced in one common chimpanzee and one orangutan. Dramatically different patterns of genetic variation were observed at these two introns, which are separated by >500 kb of DNA. Nucleotide diversity at intron 44 pi = 0.141% was more than four times higher than nucleotide diversity at intron 7 pi = 0.034% despite similar levels of divergence for these two regions. Intron 7 exhibited significant linkage disequilibrium extending over 10 kb and also showed a significant excess of rare polymorphisms. In contrast, intron 44 exhibited little linkage disequilibrium and no skew in the frequency distribution of segregating sites. Intron 7 was much more variable in Africa than in other continents, while intron 44 displayed similar levels of variability in different geographic regions. Comparison of intraspecific polymorphism to interspecific divergence using the HKA test revealed a significant reduction in variability at intron 7 relative to intron 44, and this effect was most pronounced in the non-African samples. These results are best explained by positive directional selection acting at or near intron 7 and demonstrate that even genes in regions of high recombination may be influenced by selection at linked sites. 相似文献
6.
7.
Ohta T 《Journal of molecular evolution》2000,51(1):21-25
By means of simulations and DNA sequence analyses, standardized identity excess (a measure of linkage disequilibrium) between
segregating nucleotide sites was studied as an effort to quantify the patchwork pattern among alleles of the major histocompatibility
complex loci. It was found that the pattern under selective neutrality, and/or no intralocus recombination does not fit the
observed pattern based on DNA sequences. However, the intensity and type of selection and the rate of recombination are difficult
to estimate by comparing simulation results with the observed pattern.
Received: 10 December 1999 / Accepted: 2 March 2000 相似文献
8.
The Genetic Structure of Natural Populations of DROSOPHILA MELANOGASTER Xiii. Further Studies on Linkage Disequilibrium
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The Raleigh, North Carolina, population of Drosophila melanogaster was examined for linkage disequilibrium in 1974, several years after previous analyses in 1968, 1969, and 1970. alphaglycerol-3-phosphate dehydrogenase-1 (alphaGpdh-1), malate dehydrogenase-1 (Mdh-1), alcohol dehydrogenase (Adh), and hexokinase-C (Hex-C, tentative name, F. M. Johnson, unpublished; position determined by the present authors to be 2-74.5) were assayed for 617 second chromosomes, and esterase-C (Est-C) and octanol dehydrogenase (Odh) were assayed for 526 third chromosomes. In addition, two polymorphic inversions in the second chromosomes [In(2L)t and In(2R)NS] were examined, and the following findings were obtained: (1) No linkage disequilibrium between isozyme genes was detected. Significant linkage disequilibria were found only between the polymorphic inversions and isozyme genes [In(2L)t vs. Adh, and In(2R)NS vs. Hex-C]. Significant disequilibrium was not detected between In(2L)t and alphaGpdh-1, which is included in the inversion, but a tendency toward disequilibrium was consistently found from 1968 to 1974. The frequency of two-strand double crossovers within inversion In(2L)t involving a single crossover on each side of alphaGpdh-1 was estimated to be 0.00022. Thus, the consistent but not significant linkage disequilibrium between the two factors can be explained by recombination after the inversion occurred. (2) Previously existing linkage disequilibrium between Adh and In(2R)NS (the distance is about 30 cM, but the effective recombination value is about 1.75%) was found to have disappeared. (3) No higher-order linkage disequilibrium was detected. (4) Linkage disequilibrium between Odh and Est-C (the distance of which was estimated to be 0.0058 +/- 0.002) could not be detected (chi(2) (df=1) = 0.9).-From the above results, it was concluded that linkage disequilibria among isozyme genes are very rare in D. melanogaster, so that the Franklin-Lewontin model (Franklin and Lewontin 1970) is not applicable to these genes. The linkage disequilibria between some isozyme genes and polymorphic inversions may be explained by founder effect. 相似文献
9.
On the detection of nonrandom associations between DNA polymorphisms in natural populations of Drosophila 总被引:1,自引:0,他引:1
The capacity to detect nonrandom associations between restriction-map
variants was examined in eight gene regions of Drosophila melanogaster
(yellow-achaetescute, white, Zw, Adh, Est6, and rosy) and D. pseudoobscura
(Adh and Xdh), on the basis of published population data. The statistical
power from individual pairwise tests was both heterogeneous and generally
low across gene regions. Sample sizes larger than those currently being
used are needed to ensure any power to detect disequilibrium by individual
tests. It is found that the heterogeneity in power is mostly explained by
large differences in the intensity of sample disequilibrium among regions.
The yellow-achaete- scute, Zw, and Adh loci of D. melanogaster displayed
both the highest mean power (approximately 0.4) and a very great
disequilibrium (mean absolute values of D' were 0.8-1). By contrast, all
the other gene regions exhibited lower mean power (approximately 0.2) and
moderate levels of disequilibrium (0.4-0.6). Although the proportion of
significant pairwise associations, especially for white, Est6, and rosy in
D. melanogaster and for Adh and Xdh in D. pseudoobscura, is more or less
close to the type I error, simultaneous-inference significance tests show
that gametic disequilibrium is occurring at the eight DNA regions examined.
相似文献
10.
Estimates of Gene Flow in Drosophila Pseudoobscura Determined from Nucleotide Sequence Analysis of the Alcohol Dehydrogenase Region
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The genetic structure of Drosophila pseudoobscura populations was inferred from a nucleotide sequence analysis of a 3.4-kb segment of the alcohol dehydrogenase (Adh) region. A total of 99 isochromosomal strains collected from 13 populations in North and South America were used to determine if any population departed from a neutral model and to estimate levels of gene flow between populations. This study also included the nucleotide sequences from two sibling species, D. persimilis and D. miranda. We estimated the neutral mutation parameter, 4N mu, in synonymous and noncoding sites for 17 subregions of Adh in each of nine populations with sample sizes greater than three. The nucleotide diversity data in the nine populations was tested for departures from an equilibrium neutral model with two statistical tests. The Tajima and the Hudson, Kreitman, Aguade tests showed that each population fails to reject a neutral model. Tests for genetic differentiation between populations fail to show any population substructure among the North American populations of D. pseudoobscura. The nucleotide diversity data is consistent with direct and indirect measures of gene flow that show extensive dispersal between populations of D. pseudoobscura. 相似文献
11.
We have investigated the pattern of DNA sequence variation at the exuperantia2 locus in Drosophila pseudoobscura. This adds to the increasing dataset of genetic variation in D. pseudoobscura, a useful model species for evolutionary genetic studies. The level of silent site nucleotide diversity and the divergence from an outgroup Drosophila miranda are comparable with those for other X-linked loci. One peculiar pattern at the exu2 locus of D. pseudoobscura is a complete linkage disequilibrium between two SNPs, one of which is a replacement site. As a result, there are two distinct haplotype groups in our dataset. Based upon the comparisons with the outgroup sequences from D. miranda and Drosophila persimilis, we show that the newly derived haplotype group has lower diversity than the ancestral haplotype group. The pattern of protein evolution at exu2 shows some deviation from the neutral model. Together, these and other characteristics of the exu2 locus suggest the action of selection on the pattern of SNP variation, consistent with a partial selective sweep associated with the newly derived haplotype. 相似文献
12.
Molecular Population Genetics of an Electrophoretically Monomorphic Protein in the Alcohol Dehydrogenase Region of Drosophila Pseudoobscura
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Nucleotide sequence data from the alcohol dehydrogenase (Adh) region of 18 isochromosomal strains of Drosophila pseudoobscura were used to determine whether the lack of amino acid polymorphism in ADH results from a low neutral mutation rate or a recent directional selection event. We estimated the neutral mutation parameter, 4Nmu, in synonymous sites for 17 subregions of Adh. The nucleotide diversity data were tested for departures from an equilibrium neutral model with two statistical tests. The Tajima test and the Hudson, Kreitman and Aguade test each failed to reject a neutral model. These results suggest that the ADH enzyme of D. pseudoobscura lacks amino acid polymorphisms because the neutral mutation rate of nonsynonymous sites is low. The neutral mutation parameter for synonymous sites is heterogeneous between domains of the Adh region. These data indicate that selective constrains on synonymous sites can vary between functional domains. 相似文献
13.
The occurrence and patterns of linkage disequilibrium between an inversion and allozymic loci within it or nearby have been used in attempts to discriminate among different hypotheses for the maintenance of variability. The interpretation of the data on the best-documented case, that of the nonrandom association between In(2L)t and alpha-Gpdh or Adh in the second chromosome of Drosophila melanogaster, has been done on the basis that recombination between alpha-Gpdh and Adh is almost entirely due to the recombination between In(2L)t and the locus within it (alpha-Gpdh), the recombination between the inversion and the nearby locus (Adh) being negligible. In this paper, we show that the pattern of recombination is just the opposite. 相似文献
14.
Molecular Analysis of an Allozyme Cline: Alcohol Dehydrogenase in Drosophila Melanogaster on the East Coast of North America 总被引:6,自引:6,他引:0
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Clines may either be selectively maintained or be the by-product of nonadaptive processes related to population structure and history. Drosophila melanogaster populations on the east coast of North America show a latitudinal cline in the frequencies of two common electrophoretically distinguishable alleles at the alcohol dehydrogenase locus (Adh), designated Adh-S and Adh-F. This cline may either be adaptive or an artifact of a possible recent dual founding of North American D. melanogaster populations in which frequencies of Adh alleles differed between founder populations. By means of a high resolution restriction-mapping technique, we studied the distribution of 113 haplotypes derived from 44 polymorphic DNA markers within the Adh region in 1533 individuals from 25 populations throughout the cline. We found significant clinal differentiation at the polymorphisms determining the mobility-difference causing amino acid replacement between Adh-F and Adh-S alleles. Hitchhiking was limited, despite extensive linkage disequilibrium, and other sites did not vary clinally. Such a pattern of differentiation implies that selection is responsible for the cline. To investigate whether selection acts only on the Adh-F/S site, we performed a ``selective equivalence'''' test under the assumption that all variability within the specified allelic class is selectively neutral. This revealed selective equivalence among Adh-S-bearing haplotypes, whose frequencies showed no differentiation throughout the cline, implying high levels of frequency-homogenizing gene flow. Geographical heterogeneity among Adh-F-bearing haplotypes implied the action of selection on one or more additional variants in linkage disequilibrium with Adh-F. In a further study of a subset of the data (n = 1076 from 18 populations), we found a combined insertion/deletion polymorphism, designated &1, located in the 5'' adult intron and in linkage disequilibrium with Adh-F, to show more marked clinal variation than Adh-F/S. Although the unequivocal identification of the precise target(s) of selection requires further study, we suggest that clinal selection may be acting epistatically on the Adh-F/S and &1 polymorphisms. 相似文献
15.
We analyze patterns of nucleotide variability at 15 X-linked loci and 14 autosomal loci from a North American population of Drosophila simulans. We show that there is significantly more linkage disequilibrium on the X chromosome than on chromosome arm 3R and much more linkage disequilibrium on both chromosomes than expected from estimates of recombination rates, mutation rates, and levels of diversity. To explore what types of evolutionary models might explain this observation, we examine a model of recurrent, nonoverlapping selective sweeps and a model of a recent drastic bottleneck (e.g., founder event) in the demographic history of North American populations of D. simulans. The simple sweep model is not consistent with the observed patterns of linkage disequilibrium nor with the observed frequencies of segregating mutations. Under a restricted range of parameter values, a simple bottleneck model is consistent with multiple facets of the data. While our results do not exclude some influence of selection on X vs. autosome variability levels, they suggest that demography alone may account for patterns of linkage disequilibrium and the frequency spectrum of segregating mutations in this population of D. simulans. 相似文献
16.
RNA Folding in Drosophila Shows a Distance Effect for Compensatory Fitness Interactions 总被引:5,自引:4,他引:1
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Phylogenetic-comparative analysis was used to construct a secondary structure of Adh precursor messenger RNA (pre-mRNA) in Drosophila. The analysis revealed that the rate of coevolution of base-pairing residues decreases with their physical distance. This result is in qualitative agreement with a model of compensatory fitness interactions which assumes that mutations are individually deleterious but become harmless (neutral) in appropriate combinations. This model predicts that coupled mutations can become fixed in a population under mutation pressure and random genetic drift, when the mutations are closely linked. However, the rate of joint fixation drops as distance between sites increases and recombination breaks up favorable combinations. RNA secondary structure was also used to interpret patterns of linkage disequilibrium at Adh. 相似文献
17.
The relationship between rates of recombination and DNA sequence polymorphism was analyzed for the second chromosome of Drosophila pseudoobscura. We constructed integrated genetic and physical maps of this chromosome using molecular markers at 10 loci spanning most of its physical length. The total length of the map was 128.2 cM, almost twice that of the homologous chromosome arm (3R) in D. melanogaster. There appears to be very little centromeric suppression of recombination, and rates of recombination are quite uniform across most of the chromosome. Levels of sequence variation (theta(W), based on the number of segregating sites) at seven loci (tropomyosin 1, Rhodopsin 3, Rhodopsin 1, bicoid, Xanthine dehydrogenase, Myosin light chain 1, and ribosomal protein 49) varied from 0.0036 to 0.0167. Generally consistent with earlier studies, the average estimate of theta(W) at total sites is 1.5-fold higher than that in D. melanogaster, while average theta(W) at silent sites is almost 3-fold higher. These estimates of variation were analyzed in the context of a background selection model under the same parameters of mutation rate and selection as have been proposed for D. melanogaster. It is likely that a significant fraction of the higher level of sequence variation in D. pseudoobscura can be explained by differences in regional rates of recombination rather than a larger species-level effective population size. However, the distribution of variation among synonymous, nonsynonymous, and noncoding sites appears to be quite different between the species, making direct comparisons of neutral variation, and hence inferences about effective population size, difficult. Tajima's D statistics for 6 out of the 7 loci surveyed are negative, suggesting that D. pseudoobscura may have experienced a rapid population expansion in the recent past or, alternatively, that slightly deleterious mutations constitute an important component of standing variation in this species. 相似文献
18.
Yoshida K Miyashita NT 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2005,111(6):1215-1228
DNA variation in the alcohol dehydrogenase (Adh2) region of the wild rice Oryza rufipogon and its related species was analyzed to clarify maintenance mechanisms of the DNA variation in these species. A dimorphic pattern was detected in the Adh2 region of O. rufipogon. The silent nucleotide diversity (π) in the Adh2 region in O. rufipogon was 0.011, which was higher than that of the Adh1 region in O. rufipogon. Especially, a high nucleotide diversity was detected at synonymous sites of the catalytic domain 1. Average nucleotide diversity at silent sites within each of the dimorphic sequence types of the Adh2 region was similar to that in the Adh1 region, indicating that the high level of silent polymorphism in the Adh2 region was caused by the difference between the dimorphic sequence types. On the other hand, the level of replacement polymorphism in the Adh2 region was as low as that in the Adh1 region. The neutrality test of Fu and Li indicated significantly negative deviation from the neutral mutation model for the replacement sites of the Adh2 region. This result suggests purifying selection on the replacement sites of the Adh2 region, as detected for the Adh1 region. Significant linkage disequilibria (16.4% of the tests) were detected between the Adh1 and Adh2 regions. Even when nonrandom association was tested for the strains belonging to one of the divergent sequence types of the Adh2 region, significant interlocus linkage disequilibria were detected. The close physical distance and/or epistasis between the two Adh regions could be invoked to explain these nonrandom associations. 相似文献
19.
The Epidermal growth factor receptor is an essential gene with diverse pleiotropic roles in development throughout the animal kingdom. Analysis of sequence diversity in 10.9 kb covering the complete coding region and 6.4 kb of potential regulatory regions in a sample of 250 alleles from three populations of Drosophila melanogaster suggests that the intensity of different population genetic forces varies along the locus. A total of 238 independent common SNPs and 20 indel polymorphisms were detected, with just six common replacements affecting >1475 amino acids, four of which are in the short alternate first exon. Sequence diversity is lowest in a 2-kb portion of intron 2, which is also highly conserved in comparison with D. simulans and D. pseudoobscura. Linkage disequilibrium decays to background levels within 500 bp of most sites, so haplotypes are generally restricted to up to 5 polymorphisms. The two North American samples from North Carolina and California have diverged in allele frequency at a handful of individual SNPs, but a Kenyan sample is both more divergent and more polymorphic. The effect of sample size on inference of the roles of population structure, uneven recombination, and weak selection in patterning nucleotide variation in the locus is discussed. 相似文献
20.
We analyze nucleotide polymorphism data for a large number of loci in areas of normal to high recombination in Drosophila melanogaster and D. simulans (24 and 16 loci, respectively). We find a genome-wide, systematic departure from the neutral expectation for a panmictic population at equilibrium in natural populations of both species. The distribution of sequence-based estimates of 2Nc across loci is inconsistent with the assumptions of the standard neutral theory, given the observed levels of nucleotide diversity and accepted values for recombination and mutation rates. Under these assumptions, most estimates of 2Nc are severalfold too low; in other words, both species exhibit greater intralocus linkage disequilibrium than expected. Variation in recombination or mutation rates is not sufficient to account for the excess of linkage disequilibrium. While an equilibrium island model does not seem to account for the data, more complicated forms of population structure may. A proper test of alternative demographic models will require loci to be sampled in a more consistent fashion. 相似文献