Biomedical subjects

T F Mackay

Publications and source records attributed to T F Mackay.

At least 19 recordsLinked to original sources

PubMed2001

Quantitative trait locus mapping of fitness-related traits in Drosophila melanogaster.

We examined the genetic architecture of four fitness-related traits (reproductive success, ovariole number, body size and early fecundity) in a panel of 98 Oregon-R x 2b3 recombinant inbred lines (RILs). Highly significant genetic variation was observed in this population for female, but not male, reproductive success. The cross-sex genetic correlation for reproductive success was 0.20, which is not significantly different from zero. There was significant genetic variation segregating in this cross for ovariole number, but not for body size or early fecundity. The RILs were genotyped for cytological insertion sites of roo transposable elements, yielding 76 informative markers with an average spacing of 3.2 cM. Quantitative trait loci (QTL) affecting female reproductive success and ovariole number were mapped using a composite interval mapping procedure. QTL for female reproductive success were located at the tip of the X chromosome between markers at cytological locations 1B and 3E; and on the left arm of chromosome 2 in the 30D-38A cytological region. Ovariole number QTL mapped to cytological intervals 62D-69D and 98A-98E, both on the third chromosome. The regions harbouring QTL for female reproductive success and ovariole number were also identified as QTL for longevity in previous studies with these lines.

Analysis of Variance↗

PubMed2001

The genetic architecture of odor-guided behavior in Drosophila melanogaster.

Animals↗

PubMed2001

Quantitative trait loci in Drosophila.

Phenotypic variation for quantitative traits results from the simultaneous segregation of alleles at multiple quantitative trait loci. Understanding the genetic architecture of quantitative traits begins with mapping quantitative trait loci to broad genomic regions and ends with the molecular definition of quantitative trait loci alleles. This has been accomplished for some quantitative trait loci in Drosophila. Drosophila quantitative trait loci have sex-, environment- and genotype-specific effects, and are often associated with molecular polymorphisms in non-coding regions of candidate genes. These observations offer valuable lessons to those seeking to understand quantitative traits in other organisms, including humans.

Animals↗

PubMed2001

Functional genomics of odor-guided behavior in Drosophila melanogaster.

The avoidance response to repellent odorants in Drosophila melanogaster, a response essential for survival, provides an advantageous model for studies on the genetic architecture of olfactory behavior. Transposon tagging in a highly inbred strain of flies in combination with a rapid and simple statistical behavioral assay enables the identification of not only large phenotypic effects, but also small aberrations from wild-type avoidance behavior. The recent completion of the sequence of the Drosophila genome facilitates the molecular characterization of transposon-tagged genes and correlation between gene expression and behavior in smell-impaired (smi) mutant lines. Quantitative genetic analyses of a collection of smi lines in a co-isogenic background revealed an extensive network of epistatic interactions among genes that shape the olfactory avoidance response. Candidate genes for several of these transposon-tagged smi loci implicate genes that mediate odorant recognition, including a novel odorant binding protein; signal propagation, including a voltage-gated sodium channel; and a protein containing multiple leucine rich repeats and PDZ domains likely to be involved in postsynaptic organization in the olfactory pathway. Several novel genes of unknown function have also been implicated, including a novel tyrosine-regulated protein kinase. The discovery and characterization of novel gene products that have major, hitherto unappreciated effects on olfactory behavior will provide new insights in the generation and regulation of odor-guided behavior. The identification and functional characterization of proteins encoded by smi genes that form part of the olfactory subgenome and correlation of polymorphisms in these genes with variation in odor-guided behavior in natural populations will advance our understanding of the genetic architecture of chemosensory behavior.

Animals↗

PubMed2001

The genetic architecture of quantitative traits.

Phenotypic variation for quantitative traits results from the segregation of alleles at multiple quantitative trait loci (QTL) with effects that are sensitive to the genetic, sexual, and external environments. Major challenges for biology in the post-genome era are to map the molecular polymorphisms responsible for variation in medically, agriculturally, and evolutionarily important complex traits; and to determine their gene frequencies and their homozygous, heterozygous, epistatic, and pleiotropic effects in multiple environments. The ease with which QTL can be mapped to genomic intervals bounded by molecular markers belies the difficulty in matching the QTL to a genetic locus. The latter requires high-resolution recombination or linkage disequilibrium mapping to nominate putative candidate genes, followed by genetic and/or functional complementation and gene expression analyses. Complete genome sequences and improved technologies for polymorphism detection will greatly advance the genetic dissection of quantitative traits in model organisms, which will open avenues for exploration of homologous QTL in related taxa.

Animals↗

PubMed2000

Genotype-environment interaction for quantitative trait loci affecting life span in Drosophila melanogaster.

The nature of genetic variation for Drosophila longevity in a population of recombinant inbred lines was investigated by estimating quantitative genetic parameters and mapping quantitative trait loci (QTL) for adult life span in five environments: standard culture conditions, high and low temperature, and heat-shock and starvation stress. There was highly significant genetic variation for life span within each sex and environment. In the analysis of variance of life span pooled over sexes and environments, however, the significant genetic variation appeared in the genotype x sex and genotype x environment interaction terms. The genetic correlation of longevity across the sexes and environments was not significantly different from zero in these lines. We estimated map positions and effects of QTL affecting life span by linkage to highly polymorphic roo transposable element markers, using a multiple-trait composite interval mapping procedure. A minimum of 17 QTL were detected; all were sex and/or environment-specific. Ten of the QTL had sexually antagonistic or antagonistic pleiotropic effects in different environments. These data provide support for the pleiotropy theory of senescence and the hypothesis that variation for longevity might be maintained by opposing selection pressures in males and females and variable environments. Further work is necessary to assess the generality of these results, using different strains, to determine heterozygous effects and to map the life span QTL to the level of genetic loci.

Animals↗

PubMed2000

Both naturally occurring insertions of transposable elements and intermediate frequency polymorphisms at the achaete-scute complex are associated with variation in bristle number in Drosophila melanogaster.

A restriction enzyme survey of a 110-kb region including the achaete scute complex (ASC) examined 14 polymorphic molecular markers in a sample of 56 naturally occurring chromosomes. Large insertions as a class were associated with a reduction in both sternopleural and abdominal bristle number, supporting deleterious mutation-selection equilibrium models for the maintenance of quantitative genetic variation. Two polymorphic sites were independently associated with variation in bristle number measured in two genetic backgrounds as assessed by a permutation test. A 6-bp deletion near sc alpha is associated with sternopleural bristle number variation in both sexes and a 3.4-kb insertion between sc beta and sc gamma is associated with abdominal bristle number variation in females. Under an additive genetic model, the small deletion polymorphism near sc alpha accounts for 25% of the total X chromosome genetic variation in sternopleural bristle number, and the 3.4 kb insertion accounts for 22% of the total X chromosome variation in female abdominal bristle number. The observation of common polymorphisms associated with variation in bristle number is more parsimoniously explained by models that incorporate balancing selection or assume variants affecting bristle number are neutral, than mutation-selection equilibrium models.

Animals↗

PubMed2000

Quantitative trait loci for life span in Drosophila melanogaster: interactions with genetic background and larval density.

The genetic architecture of variation in adult life span was examined for a population of recombinant inbred lines, each of which had been crossed to both inbred parental strains from which the lines were derived, after emergence from both high and low larval density. QTL affecting life span were mapped within each sex and larval density treatment by linkage to highly polymorphic roo-transposable element markers, using a composite interval mapping method. We detected a total of six QTL affecting life span; the additive effects and degrees of dominance for all were highly sex- and larval environment-specific. There were significant epistatic interactions between five of the life span QTL, the effects of which also differed according to genetic background, sex, and larval density. Five additional QTL were identified that contributed to differences among lines in their sensitivity to variation in larval density. Further fine-scale mapping is necessary to determine whether candidate genes within the regions to which the QTL map are actually responsible for the observed variation in life span.

Analysis of Variance↗

PubMed2000

Deficiency mapping of quantitative trait loci affecting longevity in Drosophila melanogaster.

In a previous study, sex-specific quantitative trait loci (QTL) affecting adult longevity were mapped by linkage to polymorphic roo transposable element markers, in a population of recombinant inbred lines derived from the Oregon and 2b strains of Drosophila melanogaster. Two life span QTL were each located on chromosomes 2 and 3, within sections 33E-46C and 65D-85F on the cytological map, respectively. We used quantitative deficiency complementation mapping to further resolve the locations of life span QTL within these regions. The Oregon and 2b strains were each crossed to 47 deficiencies spanning cytological regions 32F-44E and 64C-76B, and quantitative failure of the QTL alleles to complement the deficiencies was assessed. We initially detected a minimum of five and four QTL in the chromosome 2 and 3 regions, respectively, illustrating that multiple linked factors contribute to each QTL detected by recombination mapping. The QTL locations inferred from deficiency mapping did not generally correspond to those of candidate genes affecting oxidative and thermal stress or glucose metabolism. The chromosome 2 QTL in the 35B-E region was further resolved to a minimum of three tightly linked QTL, containing six genetically defined loci, 24 genes, and predicted genes that are positional candidates corresponding to life span QTL. This region was also associated with quantitative variation in life span in a sample of 10 genotypes collected from nature. Quantitative deficiency complementation is an efficient method for fine-scale QTL mapping in Drosophila and can be further improved by controlling the background genotype of the strains to be tested.

Animals↗

PubMed2000

Quantitative trait loci for floral morphology in Arabidopsis thaliana.

A central question in biology is how genes control the expression of quantitative variation. We used statistical methods to estimate genetic variation in eight Arabidopsis thaliana floral characters (fresh flower mass, petal length, petal width, sepal length, sepal width, long stamen length, short stamen length, and pistil length) in a cosmopolitan sample of 15 ecotypes. In addition, we used genome-wide quantitative trait locus (QTL) mapping to evaluate the genetic basis of variation in these same traits in the Landsberg erecta x Columbia recombinant inbred line population. There was significant genetic variation for all traits in both the sample of naturally occurring ecotypes and in the Ler x Col recombinant inbred line population. In addition, broad-sense genetic correlations among the traits were positive and high. A composite interval mapping (CIM) analysis detected 18 significant QTL affecting at least one floral character. Eleven QTL were associated with several floral traits, supporting either pleiotropy or tight linkage as major determinants of flower morphological integration. We propose several candidate genes that may underlie these QTL on the basis of positional information and functional arguments. Genome-wide QTL mapping is a promising tool for the discovery of candidate genes controlling morphological development, the detection of novel phenotypic effects for known genes, and in generating a more complete understanding of the genetic basis of floral development.

Arabidopsis↗

PubMed1999

High-resolution mapping of quantitative trait loci for sternopleural bristle number in Drosophila melanogaster.

We have mapped quantitative trait loci (QTL) harboring naturally occurring allelic variation for Drosophila bristle number. Lines with high (H) and low (L) sternopleural bristle number were derived by artificial selection from a large base population. Isogenic H and L sublines were extracted from the selection lines, and populations of X and third chromosome H/L recombinant isogenic lines were constructed in the homozygous low line background. The polymorphic cytological locations of roo transposable elements provided a dense molecular marker map with an average intermarker distance of 4.5 cM. Two X chromosome and six chromosome 3 QTL affecting response to selection for sternopleural bristle number and three X chromosome and three chromosome 3 QTL affecting correlated response in abdominal bristle number were detected using a composite interval mapping method. The average effects of bristle number QTL were moderately large, and some had sex-specific effects. Epistasis between QTL affecting sternopleural bristle number was common, and interaction effects were large. Many of the intervals containing bristle number QTL coincided with those mapped in previous studies. However, resolution of bristle number QTL to the level of genetic loci is not trivial, because the genomic regions containing bristle number QTL often did not contain obvious candidate loci, and results of quantitative complementation tests to mutations at candidate loci affecting adult bristle number were ambiguous.

Alleles↗

PubMed1999

The genetic architecture of selection response. Inferences from fine-scale mapping of bristle number quantitative trait loci in Drosophila melanogaster.

Quantitative trait loci (QTL) affecting responses and correlated responses to selection for abdominal and sternopleural bristle number have been mapped with high resolution to the X and third chromosomes. Advanced intercross recombinant isogenic chromosomes were constructed from high and low selection lines in an unselected inbred background, and QTL were detected using composite interval mapping and high density transposable element marker maps. We mapped a total of 26 bristle number QTL with large effects, which were in or immediately adjacent to intervals previously inferred to contain bristle number QTL on these chromosomes. The QTL contributing to response to selection for high bristle number were not the same as those contributing to response to selection for low bristle number, suggesting that distributions of allelic effects per locus may be asymmetrical. Correlated responses were more often attributable to loose linkage than pleiotropy or close linkage. Bristle number QTL mapping to the same locations have been inferred in studies with different parental strains. Of the 26 QTL, 20 mapped to locations consistent with candidate genes affecting peripheral nervous system development and/or bristle number. This facilitates determining the molecular basis of quantitative variation and allele frequencies by associating molecular variation at the candidate genes with phenotypic variation in bristle number in samples of alleles from nature.

Alleles↗

PubMed1998

QTL mapping of genotype-environment interaction for fitness in Drosophila melanogaster.

A fundamental assumption of models for the maintenance of genetic variation by environmental heterogeneity is that selection favours alternative alleles in different environments. It is not clear, however, whether such antagonistic pleiotropy is common. We mapped quantitative trait loci (QTLs) causing variation for reproductive performance in each of three environmental treatments among a set of 98 recombinant inbred (RI) lines derived from a cross between two D. melanogaster laboratory strains. The three treatments were standard medium at 25 degrees C, ethanol-supplemented medium at 25 degrees C, and standard medium at 18 degrees C. The RI lines showed highly significant genotype-environment interaction for the fitness measure. Of six QTLs with significant effects on fitness in at least one of the environments, five had significantly different effects at the different temperatures. In each case, the QTL by temperature interaction arose because the QTL had stronger effects at one temperature than at the other. No evidence for QTLs with opposite fitness effects in different environments was found. These results, together with those of recent studies of crop plants, suggest that antagonistic pleiotropy is a relatively uncommon form of genotype-environment interaction for fitness, but additional studies of natural populations are needed to confirm this conclusion.

Animals↗

PubMed1998

Pervasive effects of P element mutagenesis on body size in Drosophila melanogaster.

A set of Drosophila melanogaster was generated, all derived from a common isogenic base stock and each with a single new P element insert on the second or third chromosome. The lines were scored for their body size, measured as thorax length. P inserts were associated with highly significant effects on body size, although the genotypes of the construct and of the control prevented deduction of the direction of mutant effects. In addition to mutant effects on the thorax length of both sexes, there were also highly significant sex-specific effects. Pleiotropic effects of inserts affecting body size on viability and bristle number, as ascertained in a separate study of these lines (Lyman et al., 1996), were weak, Insertional mutagenesis is potentially a powerful tool for investigating the genes involved in size-control in Drosophila, but the technique requires fine tuning for use on polygenic and fitness-related traits.

Animals↗

PubMed1998

Quantitative genetics of ovariole number in Drosophila melanogaster. II. Mutational variation and genotype-environment interaction.

The rare alleles model of mutation-selection balance (MSB) hypothesis for the maintenance of genetic variation was evaluated for two quantitative traits, ovariole number and body size. Mutational variances (VM) for these traits, estimated from mutation accumulation lines, were 4.75 and 1.97 x 10(-4) times the environmental variance (VE), respectively. The mutation accumulation lines were studied in three environments to test for genotype x environment interaction (GEI) of new mutations; significant mutational GEI was found for both traits. Mutations for ovariole number have a quadratic relationship with competitive fitness, suggesting stabilizing selection for the trait; there is no significant correlation between mutations for body size and competitive fitness. Under MSB, the ratio of segregating genetic variance, VG, to mutational variance, VM, estimates the inverse of the selection coefficient against a heterozygote for a new mutation. Estimates of VG/VM for ovariole number and body size were both approximately 1.1 x 10(4). Thus, MSB can explain the level of variation, if mutations affecting these traits are under very weak selection, which is inconsistent with the empirical observation of stabilizing selection, or if the estimate of VM is biased downward by two orders of magnitude. GEI is a possible alternative explanation.

Analysis of Variance↗

PubMed1998

Heterosis for viability, fecundity, and male fertility in Drosophila melanogaster: comparison of mutational and standing variation.

If genetic variation for fitness traits in natural populations ("standing" variation) is maintained by recurrent mutation, then quantitative-genetic properties of standing variation should resemble those of newly arisen mutations. One well-known property of standing variation for fitness traits is inbreeding depression, with its converse of heterosis or hybrid vigor. We measured heterosis for three fitness traits, pre-adult viability, female fecundity, and male fertility, among a set of inbred Drosophilia melanogaster lines recently derived from the wild, and also among a set of lines that had been allowed to accumulate spontaneous mutations for over 200 generations. The inbred lines but not the mutation-accumulation (MA) lines showed heterosis for pre-adult viability. Both sets of lines showed heterosis for female fecundity, but heterosis for male fertility was weak or absent. Crosses among a subset of the MA lines showed that they were strongly differentiated for male fertility, with the differences inherited in autosomal fashion; the absence of heterosis for male fertility among the MA lines was therefore not caused by an absence of mutations affecting this trait. Crosses among the inbred lines also gave some, albeit equivocal, evidence for male fertility variation. The contrast between the results for female fecundity and those for male fertility suggests that mutations affecting different fitness traits may differ in their average dominance properties, and that such differences may be reflected in properties of standing variation. The strong differentiation among the MA lines in male fertility further suggests that mutations affecting this trait occur at a high rate.

Alleles↗

PubMed1998

Epistatic interactions between smell-impaired loci in Drosophila melanogaster.

Odor-guided behavior is a polygenic trait determined by the concerted expression of multiple loci. Previously, P-element mutagenesis was used to identify single P[lArB] insertions, in a common isogenic background, with homozygous effects on olfactory behavior. Here, we have crossed 12 lines with these smell impaired (smi) mutations in a half-diallel design (excluding homozygous parental genotypes and reciprocal crosses) to produce all possible 66 doubly heterozygous hybrids with P[lArB] insertions at two distinct locations. The olfactory behavior of the transheterozygous progeny was measured using an assay that quantified the avoidance response to the repellent odorant benzaldehyde. There was significant variation in general combining abilities of avoidance scores among the smi mutants, indicating variation in heterozygous effects. Further, there was significant variation among specific combining abilities of each cross, indicating dependencies of heterozygous effects on the smi locus genotypes, i.e., epistasis. Significant epistatic interactions were identified for nine transheterozygote genotypes, involving 10 of the 12 smi loci. Eight of these loci form an interacting ensemble of genes that modulate expression of the behavioral phenotype. These observations illustrate the power of quantitative genetic analyses to detect subtle phenotypic effects and point to an extensive network of epistatic interactions among genes in the olfactory subgenome.

Animals↗

PubMed1998

quemao, a Drosophila bristle locus, encodes geranylgeranyl pyrophosphate synthase.

The quemao (qm) locus of Drosophila melanogaster is characterized by a P-element-associated mutant lacking most of the large bristles on the thorax and by several EMS-induced recessive lethals. quemao was cloned using a transposon tagging strategy. P-element-mediated transformation demonstrated that the cloned qm DNA sequence (from the 65F cytological region) rescues the mutant phenotype. A 2.3-kb qm transcript was identified by Northern blot analysis by sequencing of the isolated qm cDNA clones and by 5' rapid amplification cDNA end (RACE). The predicted amino acid sequence (338 residues) of the coding region of the qm transcript shares 42, 31, 13, 20, and 12% identical amino acid sequences with the geranylgeranyl pyrophosphate synthase (GGPPS) of fungi, yeast, plants, archaebacteria, and eubacteria, respectively. It also contains five highly conserved domains common among all known isoprenyl pyrophosphate synthases. The P element associated with the original qm mutant is inserted in the 5' untranslated region of the transcript. An EMS-induced qm nonsense mutation at the 12th codon leads to recessive lethality at the first larval instar, indicating the essential role of qm in the isoprenoid biosynthesis of insects.

Amino Acid Sequence↗