Biomedical subjects

T F Mackay

Publications and source records attributed to T F Mackay.

At least 37 records · Page 2Linked to original sources

PubMed1998

Candidate quantitative trait loci and naturally occurring phenotypic variation for bristle number in Drosophila melanogaster: the Delta-Hairless gene region.

Delta (Dl) and Hairless (H) are two chromosome 3 candidate neurogenic loci that might contribute to naturally occurring quantitative variation for sensory bristle number. To evaluate this hypothesis, we assessed quantitative genetic variation in abdominal and sternopleural bristle numbers among homozygous isogenic third chromosomes sampled from nature and substituted into the Samarkand (Sam) inbred chromosome 1 and 2 background; among homozygous lines in which the wild-derived Dl-H gene region was introgressed into the Sam chromosome 3 background; and among Dl-H region introgression lines as heterozygotes against the Sam wild-type strain and derivatives of Sam into which mutant Dl and H alleles had been introgressed. Variation among the Dl-H region introgression lines accounted for 36% (8.3%) of the total chromosome 3 among line variance in abdominal (sternopleural) bristle number and for 53% of the chromosome 3 sex x line variance in abdominal bristle number. Naturally occurring alleles in the Dl-H region failed to complement a Dl mutant allele for female abdominal bristle number and sternopleural bristle number in both sexes, and an H mutant allele for both bristle traits in males and females. These results are consistent with the hypothesis that naturally occurring alleles at Dl and H contribute to quantitative genetic variation in sensory bristle number.

Analysis of Variance↗

PubMed1998

Two sites in the Delta gene region contribute to naturally occurring variation in bristle number in Drosophila melanogaster.

A restriction enzyme survey of a 57-kb region including the gene Delta uncovered 53 polymorphic molecular markers in a sample of 55 naturally occurring chromosomes. A permutation test, which assesses the significance of the molecular marker with the largest effect on bristle variation in four genetic backgrounds relative to permuted data-sets, found two sites that were independently associated with variation in bristle number. A common site in the second intron of Delta affected only sternopleural bristle number, and another common site in the fifth intron affected only abdominal bristle number in females. Under an additive genetic model, the polymorphism in the second intron may account for 12% of the total genetic variation in sternopleural bristle number due to third chromosomes, and the site in the fifth intron may account for 6% of the total variation in female abdominal bristle number due to the third chromosomes. These results suggest the following: (1) models that incorporate balancing selection are more consistent with observations than deleterious mutation-selection equilibrium models, (2) mapped quantitative trait loci of large effect may not represent a single variable site at a genetic locus, and (3) linkage disequilibrium can be used as a tool for understanding the molecular basis of quantitative variation.

Animals↗

PubMed1998

Genotype-environment interaction at quantitative trait loci affecting sensory bristle number in Drosophila melanogaster.

The magnitude of segregating variation for bristle number in Drosophila melanogaster exceeds that predicted from models of mutation-selection balance. To evaluate the hypothesis that genotype-environment interaction (GEI) maintains variation for bristle number in nature, we quantified the extent of GEI for abdominal and sternopleural bristles among 98 recombinant inbred lines, derived from two homozygous laboratory strains, in three temperature environments. There was considerable GEI for both bristle traits, which was mainly attributable to changes in rank order of line means. We conducted a genome-wide screen for quantitative trait loci (QTLs) affecting bristle number in each sex and temperature environment, using a dense (3.2-cM) marker map of polymorphic insertion sites of roo transposable elements. Nine sternopleural and 11 abdominal bristle number QTLs were detected. Significant GEI was exhibited by 14 QTLs, but there was heterogeneity among QTLs in their sensitivity to thermal and sexual environments. To further evaluate the hypothesis that GEI maintains variation for bristle number, we require estimates of allelic effects across environments at genetic loci affecting the traits. This level of resolution may be achievable for Drosophila bristle number because candidate loci affecting bristle development often map to the same location as bristle number QTLs.

Animals↗

PubMed1998

The mutation rates of di-, tri- and tetranucleotide repeats in Drosophila melanogaster.

In a recent study, we reported that the combined average mutation rate of 10 di-, 6 tri-, and 8 tetranucleotide repeats in Drosophila melanogaster was 6.3 x 10(-6) mutations per locus per generation, a rate substantially below that of microsatellite repeat units in mammals studied to date (range = 10(-2)-10(-5) per locus per generation). To obtain a more precise estimate of mutation rate for dinucleotide repeat motifs alone, we assayed 39 new dinucleotide repeat microsatellite loci in the mutation accumulation lines from our earlier study. Our estimate of mutation rate for a total of 49 dinucleotide repeats is 9.3 x 10(-6) per locus per generation, only slightly higher than the estimate from our earlier study. We also estimated the relative difference in microsatellite mutation rate among di-, tri-, and tetranucleotide repeats in the genome of D. melanogaster using a method based on population variation, and we found that tri- and tetranucleotide repeats mutate at rates 6.4 and 8.4 times slower than that of dinucleotide repeats, respectively. The slower mutation rates of tri- and tetranucleotide repeats appear to be associated with a relatively short repeat unit length of these repeat motifs in the genome of D. melanogaster. A positive correlation between repeat unit length and allelic variation suggests that mutation rate increases as the repeat unit lengths of microsatellites increase.

Africa↗

PubMed1998

Polygenic mutation in Drosophila melanogaster: genotype x environment interaction for spontaneous mutations affecting bristle number.

A highly inbred line of Drosophila melanogaster was subdivided into replicate sublines that were subsequently maintained independently with 10 pairs of parents per generation. The parents were randomly sampled for 19 'unselected' sublines and artificially selected for high or low abdominal or sternopleural bristle number for 12 'selected' sublines (with 3 replicate selection lines/trait/direction of selection). Divergence in mean bristle number among the unselected sublines, and response of the selected sublines to selection, are attributable to the accumulation of new mutations affecting bristle number. The input of mutational variance per generation, VM, can be estimated from the magnitude of response or divergence, assuming neutrality of mutations affecting the bristle traits. We reared unselected lines at generations 222 and 224, and selected lines at generations 182-184 of mutation accumulation at each of three temperatures (18 degrees C, 25 degrees C, 28 degrees C), and estimated the mutational variance common to all environments and the mutational variance from genotype x environment interaction. For sternopleural bristle number, the mutational interaction variance was 26% of the mutational variance common to all temperatures, and the interaction variance was due to temperature x line interaction. For abdominal bristle number, the mutational interaction variance was 142% of the mutational variance common to all temperatures, and the interaction variance was due to interactions of temperature x line, sex x line, and temperature x sex x line. It is possible that segregating variation for bristle number is maintained partly by genotype x environment interaction, but information on the fitness profiles of mutations affecting bristle number in each environment will be necessary to evaluate this hypothesis quantitatively.

Abdomen↗

PubMed1997

Sex-specific quantitative trait loci affecting longevity in Drosophila melanogaster.

Senescence, the decline in survivorship and fertility with increasing age, is a near-universal property of organisms. Senescence and limited lifespan are thought to arise because weak natural selection late in life allows the accumulation of mutations with deleterious late-age effects that are either neutral (the mutation accumulation hypothesis) or beneficial (the antagonistic pleiotropy hypothesis) early in life. Analyses of Drosophila spontaneous mutations, patterns of segregating variation and covariation, and lines selected for late-age fertility have implicated both classes of mutation in the evolution of aging, but neither their relative contributions nor the properties of individual loci that cause aging in nature are known. To begin to dissect the multiple genetic causes of quantitative variation in lifespan, we have conducted a genome-wide screen for quantitative trait loci (QTLs) affecting lifespan that segregate among a panel of recombinant inbred lines using a dense molecular marker map. Five autosomal QTLs were mapped by composite interval mapping and by sequential multiple marker analysis. The QTLs had large sex-specific effects on lifespan and age-specific effects on survivorship and mortality and mapped to the same regions as candidate genes with fertility, cellular aging, stress resistance and male-specific effects. Late age-of-onset QTL effects are consistent with the mutation accumulation hypothesis for the evolution of senescence, and sex-specific QTL effects suggest a novel mechanism for maintaining genetic variation for lifespan.

Animals↗

PubMed1997

Low mutation rates of microsatellite loci in Drosophila melanogaster.

Analysis of variation at microsatellite DNA loci is widely used in studies of parentage, linkage and evolutionary history. The utility of microsatellites is primarily due to high levels of allelic diversity, believed to reflect mutation rates orders of magnitude higher than base pair substitutions at single-copy genes. For humans, mice, rats and pigs, microsatellite mutation rates have been estimated at 10(-3)-10(-5). However, a recent study comparing microsatellite variation in humans with non-human primates suggests that microsatellite mutation rates may vary considerably across taxa. We measured mutation rates of 24 microsatellite loci in mutation accumulation lines of Drosophila melanogaster. Surprisingly, only a single mutation was detected after screening 157,680 allele-generations, yielding an estimated average mutation rate per locus of 6.3 x 10(-6), a mutation rate considerably lower than reported for various mammals. We propose that the comparatively low mutation rate is primarily a function of short microsatellite repeat lengths in the D. melanogaster genome.

Animals↗

PubMed1997

Genetic and molecular analysis of smooth, a quantitative trait locus affecting bristle number in Drosophila melanogaster.

A semi-lethal, sterile allele of the smooth locus (2-91.5), sm3, was discovered in an artificial selection line for low abdominal bristle number that had been started from a P-M dysgenic cross. The fitness effects and extremely low bristle number phenotype of the allele could not be separated by recombination from a P-element insertion at cytological location 56E, and precise excision of the P-element at this site was associated with reversion to wild type. The smooth gene was cloned using the P-element insertion as a tag. The gene encodes a 2.6-kb transcript derived from 10 exons and covers a genomic region of at least 80 kb. The Drosophila smooth gene shares substantial sequence identity with a group of RNA binding proteins, with the closest relationship being to the human heterogeneous nuclear ribonucleoprotein L gene. The smooth gene is by definition an abdominal bristle number quantitative trait locus, but further work is required to discern whether naturally occurring allelic variation at this locus is a source of genetic variation for abdominal bristle number in natural populations.

Abdomen↗

PubMed1997

Accumulation of transposable elements in laboratory lines of Drosophila melanogaster.

It is recognized that a stable number of transposable element (TE) copies per genome is maintained in natural populations of D. melanogaster as a result of the dynamic equilibrium between transposition to new sites and natural selection eliminating copies. The force of natural selection opposing TE multiplication is partly relaxed in inbred laboratory lines of flies. The average rate of TE transposition is from 2.6 x 10(-4) to 5.0 x 10(-4) per copy per generation, and the average rate of excision is at least two orders of magnitude lower; therefore inbred lines accumulate increasing numbers of copies with time. Correlations between the rate of transposition and TE copy number have been determined for copia, Doc, roo, and 412 and found to be either zero or positive. Because the rate of transposition is not a decreasing function of TE copy number, TE accumulation in inbred lines is self-accelerating. Transpositions cause a substantial fraction of mutations in D. melanogaster, therefore the mutation rate should increase with time in laboratory lines of this species. Inferences about the properties of spontaneous mutations from studies of mutation accumulation in laboratory lines should be reevaluated, because they are based on the assumption of a constant mutation rate.

Animals↗

PubMed1996

Positive association between copia transposition rate and copy number in Drosophila melanogaster.

Rates of copia transposition were determined directly, by cytological in situ hybridization analysis of sites of copia insertion in progeny of males from sublines of an inbred strain with different genomic copia copy numbers. Copia transposition rate was positively and nonlinearly associated with copia copy number. This relation cannot be simply explained by mutations in a single host factor that normally suppresses transposition, or by mutations in copia elements themselves. We postulate that the number of copia virus-like particles, necessary for copia transposition, could depend nonlinearly on copia copy number. Deleterious side-effects of the transposition process may be an important force controlling copia copy number in natural populations.

Analysis of Variance↗

PubMed1996

The nature of quantitative genetic variation revisited: lessons from Drosophila bristles.

Most characters that distinguish one individual from another, like height or weight, vary continuously in populations. Continuous variation of these 'quantitative' traits is due to the simultaneous segregation of multiple quantitative trait loci (QTLs) as well as environmental influences. A major challenge in human medicine, animal and plant breeding and evolutionary genetics is to identify QTLs and determine their genetic properties. Studies of the classic quantitative traits, abdominal and sternopleural bristle numbers of Drosophila, have shown that: (1) many loci have small effects on bristle number, but a few have large effects and cause most of the genetic variation; (2) 'candidate' loci involved in bristle development often have large quantitative effects on bristle number; and (3) alleles at QTLs affecting bristle number have variable degrees of dominance, interact with each other, and affect other quantitative traits, including fitness. Lessons learned from this model system will be applicable to studies of the genetic basis of quantitative variation in other species.

Animals↗

PubMed1996

Effects of single P-element insertions on bristle number and viability in Drosophila melanogaster.

Single P-element mutagenesis was used to construct 1094 lines with P[lArB] inserts on all three major chromosomes in an isogenic background previously free of P elements. The effects of insertions on bristle number and on viability were assessed by comparison to 392 control lines. The variance and effects of P-element inserts on bristle number and viability were larger than those inferred from spontaneous mutations. The distributions of effects on bristle number were symmetrical and highly leptokurtic, such that a few inserts with large effects caused most of the increase in variance. The distribution of effects on viability were negatively skewed and platykurtic. On average, the effects of P-element insertions on bristle number were partly recessive and on viability were completely recessive. P-element inserts with large effects on bristle number tended to have reduced viability, but the correlation between the absolute value of the effects on bristle number and on viability was not strong. Fifty P-element inserts tagging quantitative trait loci (QTLs) with large effects on bristle number were mapped cytogenetically. Two P-element-induced scabrous alleles and five extramacrochaetae alleles were generated. Single P-element mutagenesis is a powerful method for identifying QTLs at the level of genetic locus.

Analysis of Variance↗

PubMed1996

Effects of single P-element insertions on olfactory behavior in Drosophila melanogaster.

Single P-element (P[lArB]) insertional mutagenesis of an isogenic strain was used to identify autosomal loci affecting odor-guided behavior of Drosophila melanogaster. The avoidance response to benzaldehyde of 379 homozygous P[lArB] element-containing insert lines was evaluated quantitatively. Fourteen smell impaired (smi) lines were identified in which P[lArB] element insertion caused different degrees of hyposmia in one or both sexes. The smi loci map to different cytological locations and probably are novel olfactory genes. Enhancer trap analysis of the smi lines indicates that expression of at least 10 smi genes is controlled by olfactory tissue-specific promoter/enhancer elements.

Animals↗

PubMed1996

Polygenic mutation in Drosophila melanogaster: genetic interactions between selection lines and candidate quantitative trait loci.

We have investigated genetic interactions between spontaneous mutations affecting abdominal and sternopleural bristle number that have accumulated in 12 long-term selection lines derived from an inbred strain, and mutations at 14 candidate bristle number quantitative trait loci. The quantitative test for complementation was to cross the selection lines to an inbred wild-type strain (the control cross) and to a derivative of the control strain into which the mutant allele at the candidate locus to be tested was substituted (the tester strain). Genetic interactions between spontaneous mutations affecting bristle number and the candidate locus mutations were common, and in several cases the interaction effects were different in males and females. Analyses of variance of the (tester- control) differences among and within groups of replicate lines selected in the same direction for the same trait showed significant group effects for several candidate loci. Genetically, the interactions could be caused by allelism of, and/ or epistasis between, spontaneous mutations in the selection lines and the candidate locus mutations. It is possible that much of the response to selection was from new mutations at candidate bristle number quantitative trait loci, and that for some of these loci, mutation rates were high.

Analysis of Variance↗

PubMed1996

Quantitative genetic variation of odor-guided behavior in a natural population of Drosophila melanogaster.

Quantitative genetic variation in behavioral response to the odorant, benzaldehyde, was assessed among a sample of 43 X and 35 third chromosomes extracted from a natural population and substituted into a common inbred background. Significant genetic variation among chromosome lines was detected. Heritability estimates for olfactory response, however, were low, as is typical for traits under natural selection. Furthermore, the loci affecting naturally occurring variation in olfactory response to benzaldehyde were not the same in males and females, since the genetic correlation between the sexes was low and not significantly different from zero for the chromosome 3 lines. Competitive fitness, viability and fertility of the chromosome 3 lines were estimated using the balancer equilibrium technique. Genetic correlations between fitness and odor-guided behavior were not significantly different from zero, suggesting the number of loci causing variation in olfactory response is small relative to the number of loci causing variation in fitness. Since different genes affect variation in olfactory response in males and females, genetic variation for olfactory response could be maintained by genotype x sex environment interaction. This unusual genetic architecture implies that divergent evolutionary trajectories for olfactory behavior may occur in males and females.

Animals↗

PubMed1996

Genetic interactions between naturally occurring alleles at quantitative trait loci and mutant alleles at candidate loci affecting bristle number in Drosophila melanogaster.

Previously, we mapped quantitative trait loci (QTL) affecting response to short-term selection for abdominal bristle number to seven suggestive regions that contain loci involved in bristle development and/or that have adult bristle number mutant phenotypes, and are thus candidates for bristle number QTL in natural populations. To test the hypothesis that the factors contributing to selection response genetically interact with these candidate loci, high and low chromosomes from selection lines were crossed to chromosomes containing wild-type or mutant alleles at the candidate loci, and the numbers of bristles were recorded in trans heterozygotes. Quantitative failure to complement, detected as a significant selection line*cross effect by analysis of variance, can be interpreted as evidence for allelism or epistasis between the factors on selected chromosomes and the candidate loci. Mutations at some candidate loci (bb, emc, h, Dl, Hairless) showed strong interactions with selected chromosomes, whereas others interacted weakly (ASC, abd, Scr) or not at all (N, mab, E(spl)). These results support the hypothesis that some candidate loci, initially identified through mutations of large effect on bristle number, either harbor or are close members in the same genetic pathway as variants that contribute to standing variation in bristle number.

Alleles↗

PubMed1995

The genetic basis of quantitative variation: numbers of sensory bristles of Drosophila melanogaster as a model system.

The numbers of sensory hairs of Drosophila melanogaster present an ideal model system to elucidate the genetic basis of morphological quantitative variation. Loci affecting bristle number can be identified and their properties studied by accumulating spontaneous mutations, by P element mutagenesis, by mapping factors causing divergence between selection lines and by the association of phenotype variation with molecular variation at candidate neurogenic loci. The consensus emerging from the application of all approaches is that much of the mutational and segregating variation affecting bristle number is attributable to alleles with large phenotype effects at a small number of candidate loci.

Animals↗

PubMed1995

Polygenic mutation in Drosophila melanogaster: non-linear divergence among unselected strains.

A highly inbred strain of Drosophila melanogaster was subdivided into 20 replicate sublines that were maintained independently with 10 pairs of randomly sampled parents per generation for 180 generations. The variance between lines in abdominal and sternopleural bristle number increased little after 100 generations, in contrast to the neutral expectation of a linear increase; and the covariances of line means between different generations declined with increasing number of generations apart, in contrast to the neutral expectation of constant covariance. Thus, under a neutral model, the estimates of mutational variance were lower than for previous estimates from the first 100 generations of subline divergence. An autoregressive model was fitted to the variance of line means that indicated strong natural selection. There is no single unequivocal explanation for the results. Possible and nonexclusive alternatives include stabilizing selection on bristle number and deleterious effects on fitness of bristle mutations. The inferred strengths of selection on both traits are too high for stabilizing selection alone, and the between-line variance did not continue to increase sufficiently for pleiotropy alone to account for the observations. A third potential explanation that does not invoke selection is duplicate epistasis between mutations affecting bristle number.

Analysis of Variance↗