Linkage disequilibrium in the white locus region of Drosophila melanogaster

SummaryLinkage disequilibrium between molecular polymorphisms in a 10 kb region in the white locus of Drosophila melanogaster, revealed with a battery of four-cutter restriction enzymes, was investigated in 266 lines sampled from seven natural populations around the world. A total of 73 (35 restriction site, 37 insertion/deletion and 1 inversion) polymorphisms were detected, of which 55 non-unique polymorphisms were analysed for linkage disequilibrium. Clustering of significant linkage disequilibrium was observed in the transcriptional unit of the white locus as in Miyashita & Langley (1988). It was shown that about two thirds of the 2-locus combinations showing significant linkage disequilibrium have similar degree and direction of association over different populations. Despite lower divergence in allelic frequencies of molecular polymorphisms among populations, an increase in the proportion of 2-locus pairs showing significant linkage disequilibrium is observed in the transcriptional unit. Large values of Ohta's D measure ratio (1982 a, b) cluster in the transcriptional unit, and correspond to significant linkage disequilibria. Although the exact molecular mechanism is not clear, these results suggest that epistatic selection is responsible for significant linkage disequilibrium in the transcriptional unit of this locus

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THE GENETIC STRUCTURE OF NATURAL POPULATIONS OF DROSOPHILA MELANOGASTER XIII. FURTHER STUDIES ON LINKAGE DISEQUILIBRIUM

Genetics ◽

10.1093/genetics/86.1.175 ◽

1977 ◽

Vol 86 (1) ◽

pp. 175-185

Author(s):

Terumi Mukai ◽

Robert A Voelker

Keyword(s):

Drosophila Melanogaster ◽

Linkage Disequilibrium ◽

Natural Populations ◽

Linkage Disequilibria ◽

Two Factors ◽

Carolina Population ◽

Recombination Value ◽

Significant Linkage ◽

Octanol Dehydrogenase ◽

Double Crossovers

ABSTRACT 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. αglycerol-3-phosphate dehydrogenase-1 (αGpdh-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malate dehydrogenase-1 (Mdh-1), alcohol dehydrogenase (Adh), and hexokinase-C (Hex-C, tentative name, F. M. Johnson, unpublished; position determined by the present authors to be 2-74.5) were assayed for 617 second chromosomes, and esterase-C (Est-C) and octanol dehydrogenase (Odh) were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 αGpdh-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 αGpdh-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 (χ2 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.

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Selection Intensity Against Deleterious Mutations in RNA Secondary Structures and Rate of Compensatory Nucleotide Substitutions

Genetics ◽

10.1093/genetics/159.1.389 ◽

2001 ◽

Vol 159 (1) ◽

pp. 389-399 ◽

Cited By ~ 1

Author(s):

Hideki Innan ◽

Wolfgang Stephan

Keyword(s):

Linkage Disequilibrium ◽

Natural Populations ◽

Selection Intensity ◽

Deleterious Mutations ◽

Significant Linkage Disequilibrium ◽

Nucleotide Substitutions ◽

Diploid Population ◽

Locus Model ◽

Tight Linkage ◽

Significant Linkage

Abstract A two-locus model of reversible mutations with compensatory fitness interactions is presented; single mutations are assumed to be deleterious but neutral in appropriate combinations. The expectation of the time of compensatory nucleotide substitutions is calculated analytically for the case of tight linkage between sites. It is shown that selection increases the substitution time dramatically when selection intensity Ns > 1, where N is the diploid population size and s the selection coefficient. Computer simulations demonstrate that recombination increases the substitution time, but the effect of recombination is small when selection is weak. The amount of linkage disequilibrium generated in the process of compensatory substitution is also investigated. It is shown that significant linkage disequilibrium is expected to be rare in natural populations. The model is applied to the mRNA secondary structure of the bicoid 3′ untranslated region of Drosophila. It is concluded that average selection intensity Ns against single deleterious mutations is not likely to be much larger than 1.

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Molecular Evolution of Two Linked Genes, Est-6 and Sod, in Drosophila melanogaster

Genetics ◽

10.1093/genetics/153.3.1357 ◽

1999 ◽

Vol 153 (3) ◽

pp. 1357-1369 ◽

Cited By ~ 3

Author(s):

Evgeniy S Balakirev ◽

Elena I Balakirev ◽

Francisco Rodríguez-Trelles ◽

Francisco J Ayala

Keyword(s):

Drosophila Melanogaster ◽

Linkage Disequilibrium ◽

Early Experiment ◽

Amino Acid Replacement ◽

Allozyme Polymorphism ◽

Nucleotide Polymorphism ◽

Significant Linkage Disequilibrium ◽

Nucleotide Level ◽

S Alleles ◽

Significant Linkage

Abstract We have obtained 15 sequences of Est-6 from a natural population of Drosophila melanogaster to test whether linkage disequilibrium exists between Est-6 and the closely linked Sod, and whether natural selection may be involved. An early experiment with allozymes had shown linkage disequilibrium between these two loci, while none was detected between other gene pairs. The Sod sequences for the same 15 haplotypes were obtained previously. The two genes exhibit similar levels of nucleotide polymorphism, but the patterns are different. In Est-6, there are nine amino acid replacement polymorphisms, one of which accounts for the S-F allozyme polymorphism. In Sod, there is only one replacement polymorphism, which corresponds to the S-F allozyme polymorphism. The transversion/transition ratio is more than five times larger in Sod than in Est-6. At the nucleotide level, the S and F alleles of Est-6 make up two allele families that are quite different from each other, while there is relatively little variation within each of them. There are also two families of alleles in Sod, one consisting of a subset of F alleles, and the other consisting of another subset of F alleles, designed F(A), plus all the S alleles. The Sod F(A) and S alleles are completely or nearly identical in nucleotide sequence, except for the replacement mutation that accounts for the allozyme difference. The two allele families have independent evolutionary histories in the two genes. There are traces of statistically significant linkage disequilibrium between the two genes that, we suggest, may have arisen as a consequence of selection favoring one particular sequence at each locus.

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Molecular and phenotypic variation of the white locus region in Drosophila melanogaster.

Genetics ◽

10.1093/genetics/120.1.199 ◽

1988 ◽

Vol 120 (1) ◽

pp. 199-212

Author(s):

N Miyashita ◽

C H Langley

Keyword(s):

Drosophila Melanogaster ◽

X Chromosome ◽

Restriction Site ◽

Restriction Enzymes ◽

Transcriptional Unit ◽

X Chromosomes ◽

Linkage Disequilibria ◽

Restriction Sites ◽

White Locus ◽

Shock Locus

Abstract Restriction site and insertion/deletion polymorphism in a 45-kb region of the white locus on the X chromosome in Drosophila melanogaster was investigated for 64 X chromosome lines with six 6-cutter and ten 4-cutter restriction enzymes. A total of 109 polymorphisms were detected (54 restriction sites and 55 insertions/deletions). Estimated heterozygosity per nucleotide for this region (0.004-0.008) was similar to those of the Adh and 87A heat-shock locus regions located on the autosomes in D. melanogaster. This is contrary to a simple prediction based on the theory of mutation selection-balance of partially recessive deleterious mutants which predicts less variation on X chromosomes. Large linkage disequilibria between pairs of polymorphisms (including insertions and deletions) within the transcriptional unit (especially the 3' end of the 1st intron) were observed. As expected from population genetics theory, linkage disequilibria between these polymorphisms were greater for those pairs that are physically closer on the restriction map. Linkage equilibrium was typically observed when the pairs of sites were separated by 2 kb or more. Although significant between-line variation in eye pigment was observed (P less than 0.05), there is little evidence for strong associations between this phenotype and the polymorphisms at the DNA level.

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Linkage disequilibrium, natural selection, and epistatic gene interaction in Drosophila nasuta

Genome ◽

10.1139/g88-082 ◽

1988 ◽

Vol 30 (4) ◽

pp. 495-498 ◽

Cited By ~ 2

Author(s):

Arun Kumar ◽

J. P. Gupta

Keyword(s):

Linkage Disequilibrium ◽

Natural Selection ◽

Natural Populations ◽

Gene Interaction ◽

Significant Linkage Disequilibrium ◽

Linked Gene ◽

Significant Linkage ◽

Drosophila Nasuta ◽

Main Factor

The data of linkage disequilibrium between III-2 and 111-35 gene arrangements in natural populations of Drosophila nasuta is presented. The results demonstrated that there was significant linkage disequilibrium between the above gene arrangements in natural populations. Among all nine possible karyotypic combinations, only four combinations were seen. The absence of some combinations might be because of sublethal combinations of genes that reduced the viabilities of their carriers. The frequency of double inversion heterozygotes was always in excess and only 1.29% single hetrozygotes were observed. Based on these findings, we suggest that natural selection acting through the suppression of recombination and epistatic gene interaction providing fitness are the main factor for the maintenance of linkage disequilibrium between the above linked gene arrangements in natural populations of D. nasuta.Key words: linkage disequilibrium, selection, epistasis, Drosophila nasuta.

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Protein Variation in ADH and ADH-RELATED in Drosophila pseudoobscura: Linkage Disequilibrium Between Single Nucleotide Polymorphisms and Protein Alleles

Genetics ◽

10.1093/genetics/159.2.673 ◽

2001 ◽

Vol 159 (2) ◽

pp. 673-687

Author(s):

Stephen W Schaeffer ◽

C Scott Walthour ◽

Donna M Toleno ◽

Anna T Olek ◽

Ellen L Miller

Keyword(s):

Linkage Disequilibrium ◽

Single Nucleotide Polymorphisms ◽

Drosophila Pseudoobscura ◽

Linkage Disequilibrium Mapping ◽

Nucleotide Polymorphisms ◽

Neutral Model ◽

Significant Linkage Disequilibrium ◽

Single Nucleotide ◽

Synonymous Sites ◽

Significant Linkage

Abstract 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%.

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Estimates of linkage disequilibrium and the recombination parameter determined from segregating nucleotide sites in the alcohol dehydrogenase region of Drosophila pseudoobscura.

Genetics ◽

10.1093/genetics/135.2.541 ◽

1993 ◽

Vol 135 (2) ◽

pp. 541-552 ◽

Cited By ~ 5

Author(s):

S W Schaeffer ◽

E L Miller

Keyword(s):

Linkage Disequilibrium ◽

Alcohol Dehydrogenase ◽

Distance Effect ◽

Theoretical Distribution ◽

Drosophila Pseudoobscura ◽

Significant Linkage Disequilibrium ◽

Effective Population ◽

Nucleotide Distance ◽

Significant Linkage ◽

Recombination Parameter

Abstract The alcohol dehydrogenase (Adh) region of Drosophila pseudoobscura, which includes the two genes Adh and Adh-Dup, was used to examine the pattern and organization of linkage disequilibrium among pairs of segregating nucleotide sites. A collection of 99 strains from the geographic range of D. pseudoobscura were nucleotide-sequenced with polymerase chain reaction-mediated techniques. All pairs of the 359 polymorphic sites in the 3.5-kb Adh region were tested for significant linkage disequilibrium with Fisher's exact test. Of the 74,278 pairwise comparisons of segregating sites, 127 were in significant linkage disequilibrium at the 5% level. The distribution of five linkage disequilibrium estimators D(ij), D2, r(ij), r2 and D(ij) were compared to theoretical distributions. The observed distributions of D(ij), D2, r(ij) and r2 were consistent with the theoretical distribution given an infinite sites model. The observed distribution of D(ij) differed from the theoretical distribution because of an excess of values at -1 and 1. No spatial pattern was observed in the linkage disequilibrium pattern in the Adh region except for two clusters of sites nonrandomly associated in the adult intron and intron 2 of Adh. The magnitude of linkage disequilibrium decreases significantly as nucleotide distance increases, or a distance effect. Adh-Dup had a larger estimate of the recombination parameter, 4Nc, than Adh, where N is the effective population size and c is the recombination rate. A comparison of the mutation and recombination parameters shows that 7-17 recombination events occur for each mutation event. The heterogeneous estimates of the recombination parameter and the inverse relationship between linkage disequilibrium and nucleotide distance are no longer significant when the two clusters of Adh intron sites are excluded from analyses. The most likely explanation for the two clusters of linkage disequilibria is epistatic selection between sites in the cluster to maintain pre-mRNA secondary structure.

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Linkage disequilibrium in growing and stable populations.

Genetics ◽

10.1093/genetics/137.1.331 ◽

1994 ◽

Vol 137 (1) ◽

pp. 331-336 ◽

Cited By ~ 9

Author(s):

M Slatkin

Keyword(s):

Linkage Disequilibrium ◽

Sequence Data ◽

Significant Linkage Disequilibrium ◽

Rapid Population Growth ◽

Exact Test ◽

Dna Sequence Data ◽

Constant Size ◽

Significant Linkage ◽

Stable Populations ◽

Growing Population

Abstract Nonrandom associations between alleles at different loci can be tested for using Fisher's exact test. Extensive simulations show that there is a substantial probability of obtaining significant nonrandom associations between closely or completely linked polymorphic neutral loci in a population of constant size at equilibrium under mutation and genetic drift. In a rapidly growing population, however, there will be little chance of finding significant nonrandom associations even between completely linked loci if the growth has been sufficiently rapid. This result is illustrated by the analysis of mitochondrial DNA sequence data from humans. In comparing all pairs of informative sites, fewer than 5% of the pairs show significant disequilibrium in Sardinians, which have apparently undergone rapid population growth, while 20% to 30% in !Kung and Pygmies, which apparently have not undergone rapid growth, show significance. The extent of linkage disequilibrium in a population is closely related to the gene genealogies of the loci examined, with "star-like" genealogies making significant linkage disequilibrium unlikely.

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