X-linked Quantitative Trait Loci Research Articles

Patterns of longevity and fecundity at two temperatures in a set of heat-selected recombinant inbred lines of Drosophila melanogaster.

Quantitative trait loci (QTL) were mapped for longevity and fecundity at two temperatures, 20 and 30 °C, in two sets of recombinant inbred lines (RIL) highly differing in thermotolerance. Early fecundity (EF) and longevity showed a negative association between temperatures. For instance, longevity was higher and fecundity was lower in the RIL panel showing higher life span at 30 °C. One X-linked QTL (7B3-12E) co-localized for longevity and EF at 20 °C, with one QTL allele showing a positive additive effect on longevity and a negative effect on EF. The across-RIL genetic correlation between longevity and EF was not significant within each temperature, and most QTL that affect life span have no effect on EF at each temperature. EF and longevity can mostly be genetically uncoupled in the thermotolerance-divergent RIL within each temperature as opposed to between temperatures. QTL were mostly temperature specific, although some trait-specific QTL showed possible antagonistic effects between temperatures.

The genetic architecture of coordinately evolving male wing pigmentation and courtship behavior in Drosophila elegans and Drosophila gunungcola.

Many adaptive phenotypes consist of combinations of simpler traits that act synergistically, such as morphological traits and the behaviors that use those traits. Genetic correlations between components of such combinatorial traits, in the form of pleiotropic or tightly linked genes, can in principle promote the evolution and maintenance of these traits. In the Oriental Drosophila melanogaster species group, male wing pigmentation shows phylogenetic correlations with male courtship behavior; species with male-specific apical wing melanin spots also exhibit male visual wing displays, whereas species lacking these spots generally lack the displays. In this study, we investigated the quantitative genetic basis of divergence in male wing spots and displays between D. elegans, which possesses both traits, and its sibling species D. gunungcola, which lacks them. We found that divergence in wing spot size is determined by at least three quantitative trait loci (QTL) and divergence in courtship score is determined by at least four QTL. On the autosomes, QTL locations for pigmentation and behavior were generally separate, but on the X chromosome two clusters of QTL were found affecting both wing pigmentation and courtship behavior. We also examined the genetic basis of divergence in three components of male courtship, wing display, circling, and body shaking. Each of these showed a distinct genetic architecture, with some QTL mapping to similar positions as QTL for overall courtship score. Pairwise tests for interactions between marker loci revealed evidence of epistasis between putative QTL for wing pigmentation but not those for courtship behavior. The clustering of X-linked QTL for male pigmentation and behavior is consistent with the concerted evolution of these traits and motivates fine-scale mapping studies to elucidate the nature of the contributing genetic factors in these intervals.

Quantitative trait loci for energy balance traits in an advanced intercross line derived from mice divergently selected for heat loss.

Obesity in human populations, currently a serious health concern, is considered to be the consequence of an energy imbalance in which more energy in calories is consumed than is expended. We used interval mapping techniques to investigate the genetic basis of a number of energy balance traits in an F11 advanced intercross population of mice created from an original intercross of lines selected for increased and decreased heat loss. We uncovered a total of 137 quantitative trait loci (QTLs) for these traits at 41 unique sites on 18 of the 20 chromosomes in the mouse genome, with X-linked QTLs being most prevalent. Two QTLs were found for the selection target of heat loss, one on distal chromosome 1 and another on proximal chromosome 2. The number of QTLs affecting the various traits generally was consistent with previous estimates of heritabilities in the same population, with the most found for two bone mineral traits and the least for feed intake and several body composition traits. QTLs were generally additive in their effects, and some, especially those affecting the body weight traits, were sex-specific. Pleiotropy was extensive within trait groups (body weights, adiposity and organ weight traits, bone traits) and especially between body composition traits adjusted and not adjusted for body weight at sacrifice. Nine QTLs were found for one or more of the adiposity traits, five of which appeared to be unique. The confidence intervals among all QTLs averaged 13.3 Mb, much smaller than usually observed in an F2 cross, and in some cases this allowed us to make reasonable inferences about candidate genes underlying these QTLs. This study combined QTL mapping with genetic parameter analysis in a large segregating population, and has advanced our understanding of the genetic architecture of complex traits related to obesity.

Identification of X-linked quantitative trait loci affecting cold tolerance in Drosophila melanogaster and fine mapping by selective sweep analysis

Drosophila melanogaster is a cosmopolitan species that colonizes a great variety of environments. One trait that shows abundant evidence for naturally segregating genetic variance in different populations of D.melanogaster is cold tolerance. Previous work has found quantitative trait loci (QTL) exclusively on the second and the third chromosomes. To gain insight into the genetic architecture of cold tolerance on the X chromosome and to compare the results with our analyses of selective sweeps, a mapping population was derived from a cross between substitution lines that solely differed in the origin of their X chromosome: one originates from a European inbred line and the other one from an African inbred line. We found a total of six QTL for cold tolerance factors on the X chromosome of D.melanogaster. Although the composite interval mapping revealed slightly different QTL profiles between sexes, a coherent model suggests that most QTL overlapped between sexes, and each explained around 5-14% of the genetic variance (which may be slightly overestimated). The allelic effects were largely additive, but we also detected two significant interactions. Taken together, this provides evidence for multiple QTL that are spread along the entire X chromosome and whose effects range from low to intermediate. One detected transgressive QTL influences cold tolerance in different ways for the two sexes. While females benefit from the European allele increasing their cold tolerance, males tend to do better with the African allele. Finally, using selective sweep mapping, the candidate gene CG16700 for cold tolerance colocalizing with a QTL was identified.

THREE SELECTIONS ARE BETTER THAN ONE: CLINAL VARIATION OF THERMAL QTL FROM INDEPENDENT SELECTION EXPERIMENTS IN DROSOPHILA

We report the results of two independent selection experiments that have exposed distinct populations of Drosophila melanogaster to different forms of thermal selection. A recombinant population derived from Arvin California and Zimbabwe isofemale lines was exposed to laboratory natural selection at two temperatures (T(AZ): 18°C and 28°C). Microsatellite mapping identified quantitative trait loci (QTL) on the X-chromosome between the replicate "Hot" and "Cold" populations. In a separate experiment, disruptive selection was imposed on an outbred California population for the "knockdown" temperature (T(KD)) in a thermal column. Microsatellite mapping of the "High" and "Low" populations also uncovered primarily X-linked QTL. Notably, a marker in the shaggy locus at band 3A was significantly differentiated in both experiments. Finer scale mapping of the 3A region has narrowed the QTL to the shaggy gene region, which contains several candidate genes that function in circadian rhythms. The same allele that was increased in frequency in the High T(KD) populations is significantly clinal in North America and is more common at the warm end of the cline (Florida vs. Maine; however, the cline was not apparent in Australia). Together, these studies show that independent selection experiments can uncover the same target of selection and that evolution in the laboratory can recapitulate putatively adaptive clinal variation in nature.

Combined expression patterns of QTL-linked candidate genes best predict thermotolerance in Drosophila melanogaster

Knockdown resistance to high temperature (KRHT) is a thermal adaptation trait in Drosophila melanogaster. Here we used quantitative real-time PCR (qRT-PCR) to test for possible associations between KRHT and the expression of candidate genes within quantitative trait loci (QTL) in eight recombinant inbred lines (RIL). hsp60 and hsc70-3 map within an X-linked QTL, while CG10383, catsup, ddc, trap1, and cyp6a13 are linked in a KRHT-QTL on chromosome 2. hsc70-3 expression increased by heat-hardening. Principal Components analysis revealed that catsup, ddc and trap1 were either co-expressed or combined in their expression levels. This composite expression variable (e-PC1) was positively associated to KRHT in non-hardened RIL. In heat-hardened flies, hsp60 was negatively related to hsc70-3 on e-PC2, with effects on KRHT. These results are consistent with the notion that QTL can be shaped by expression variation in combined candidate loci. We found composite variables of gene expression (e-PCs) that best correlated to KRHT. Network effects with other untested linked loci are apparent because, in spite of their associations with KRHT phenotypes, e-PCs were sometimes uncorrelated with their QTL genotype.

Association Test for X-Linked QTL in Family-Based Designs

Family-based association methods for detecting quantitative trait loci (QTL) have been developed primarily for autosomes, and comparable methods for X-linked QTL have received less attention. We have developed a family-based association test for quantitative traits, named XQTL, which uses X-linked markers in a nuclear family design. XQTL adopts the framework of the orthogonal model implemented in the QTDT program, modifying the sex-specific score for X-linked genotypes. XQTL also takes into account the dosage effect due to female X chromosome inactivation. Restricted maximum likelihood (REML) and Fisher's scoring method are used to estimate variance components of random effects. Fixed effects, derived from the phenotypic differences among and within families, are estimated by the least-squares method. Our proposed XQTL can perform allelic and two-locus haplotypic association tests and can provide estimates of additive genetic effects and variance components. Simulation studies show correct type I error rates under the null hypothesis and robust statistical power under alternative scenarios. The loss of power observed when parental genotypes are missing can be compensated by an increase of offspring number. By treating age at onset of Parkinson disease as a quantitative trait, we illustrate our method, using MAO polymorphisms in 780 families.

A Dominant X-Linked QTL Regulating Pubertal Timing in Mice Found by Whole Genome Scanning and Modified Interval-Specific Congenic Strain Analysis

BackgroundPubertal timing in mammals is triggered by reactivation of the hypothalamic-pituitary-gonadal (HPG) axis and modulated by both genetic and environmental factors. Strain-dependent differences in vaginal opening among inbred mouse strains suggest that genetic background contribute significantly to the puberty timing, although the exact mechanism remains unknown.Methodology/Principal FindingsWe performed a genome-wide scanning for linkage in reciprocal crosses between two strains, C3H/HeJ (C3H) and C57BL6/J (B6), which differed significantly in the pubertal timing. Vaginal opening (VO) was used to characterize pubertal timing in female mice, and the age at VO of all female mice (two parental strains, F1 and F2 progeny) was recorded. A genome-wide search was performed in 260 phenotypically extreme F2 mice out of 464 female progeny of the F1 intercrosses to identify quantitative trait loci (QTLs) controlling this trait. A QTL significantly associated was mapped to the DXMit166 marker (15.5 cM, LOD = 3.86, p<0.01) in the reciprocal cross population (C3HB6F2). This QTL contributed 2.1 days to the timing of VO, which accounted for 32.31% of the difference between the original strains. Further study showed that the QTL was B6-dominant and explained 10.5% of variation to this trait with a power of 99.4% at an alpha level of 0.05.The location of the significant ChrX QTL found by genome scanning was then fine-mapped to a region of ∼2.5 cM between marker DXMit68 and rs29053133 by generating and phenotyping a panel of 10 modified interval-specific congenic strains (mISCSs).Conclusions/SignificanceSuch findings in our study lay a foundation for positional cloning of genes regulating the timing of puberty, and also reveal the fact that chromosome X (the sex chromosome) does carry gene(s) which take part in the regulative pathway of the pubertal timing in mice.

X-linked QTL for knockdown resistance to high temperature in Drosophila melanogaster

Knockdown Resistance to High Temperature (KRHT) is an adaptive trait of thermotolerance in insects. An interval mapping was performed on chromosome X of Drosophila melanogaster to search for quantitative trait loci (QTL) affecting KRHT. A backcross population was obtained from two lines that dramatically differ for KRHT. Microsatellites were used as markers. Composite interval mapping identified a large-effect QTL in the region of band 10 where putative candidate genes map. To further test for this QTL a set of recombinant (but non-inbred) lines was obtained from backcrosses between the parental lines used for the interval mapping. Recombinant line analysis confirmed that one QTL is targeted by band 10. We identify and discuss candidate loci contained within our QTL region.

X chromosome influences sperm length in the stalk-eyed fly Cyrtodiopsis dalmanni

Whether sexually selected traits are sex linked can have profound effects on their evolution. In the diopsid stalk-eyed fly, Cyrtodiopsis dalmanni, sperm length and female reproductive tract morphology have coevolved across species, postcopulatory sexual selection is known to occur, and X-linked genes affect female ventral sperm receptacle size. Here, we estimate the location of quantitative trait loci (QTL) for spermatocyst tail length by using F2 progeny segregating for an X-linked factor that causes sex-ratio meiotic drive. We found two QTL, including a major X-linked QTL responsible for 25% of the variation in spermatocyst tail length 2.1 cM from the sex-ratio element and 0.8 cM from a major eye span QTL. Sex-ratio males produce shorter spermatocyst tails and shorter eye spans. Thus, X-linked factors affect both pre- and postcopulatory traits, and linkage between the alleles for short eye span and short spermatocyst tail length allow pre- and postcopulatory sexual selection to potentially act in concert against the transmission bias caused by the sex-ratio chromosome.

Localization of two new X‐linked quantitative trait loci controlling corpus callosum size in the mouse

Corpus callosum (CC) size is a complex trait, characterized by a gradation of values within a normal range, as well as abnormalities that include a small or totally absent CC. Among inbred mouse strains with defects of the CC, BTBR T(+)tf/J (BTBR) mice have the most extreme phenotype; all animals show total absence of the CC and severe reduction of the hippocampal commissure (HC). In contrast, the BALB/cByJ (BALB) strain has a low frequency of small CC and consistently normal HC. Reciprocal F(1) crosses between BTBR and BALB suggest the presence of X-linked quantitative trait loci (QTLs) affecting CC size. Through linkage analysis of backcross male progeny, we have localized two regions on the X chromosome, having peaks at 68.5 Mb (approximately 29.5 cM) and at 134.5 Mb (approximately 60.5 cM) that are largely responsible for the reciprocal differences, with the BTBR allele showing X-linked dominant inheritance associated with CC defects.

Variance component models for X‐linked QTLs

This paper discusses the theory and implementation of a model for mapping X-linked quantitative trait loci (QTL). As a result of X inactivation, a female's body is subdivided into a number of patches. In each patch one of her two X chromosomes is randomly switched off. This smooths the allelic contributions in a heterozygote and implies that females should show less trait variation than males for an X-linked trait. The latest version of the genetic analysis program Mendel incorporates a simple variance component version of this model. An application to head circumference in autistic children illustrates Mendel in action.

The genetic basis of postzygotic reproductive isolation between Drosophila santomea and D. yakuba due to hybrid male sterility.

A major unresolved challenge of evolutionary biology is to determine the nature of the allelic variants of "speciation genes": those alleles whose interaction produces inviable or infertile interspecific hybrids but does not reduce fitness in pure species. Here we map quantitative trait loci (QTL) affecting fertility of male hybrids between D. yakuba and its recently discovered sibling species, D. santomea. We mapped three to four X chromosome QTL and two autosomal QTL with large effects on the reduced fertility of D. yakuba and D. santomea backcross males. We observed epistasis between the X-linked QTL and also between the X and autosomal QTL. The X chromosome had a disproportionately large effect on hybrid sterility in both reciprocal backcross hybrids. However, the genetics of hybrid sterility differ between D. yakuba and D. santomea backcross males, both in terms of the magnitude of main effects and in the epistatic interactions. The QTL affecting hybrid fertility did not colocalize with QTL affecting sexual isolation in this species pair, but did colocalize with QTL affecting the marked difference in pigmentation between D. yakuba and D. santomea. These results provide the basis for future high-resolution mapping and ultimately, molecular cloning, of the interacting genes that contribute to hybrid sterility.

Quantitative trait loci affecting knockdown resistance to high temperature in Drosophila melanogaster.

Knockdown resistance to high temperature is an ecologically important trait in small insects. A composite interval mapping was performed on the two major autosomes of Drosophila melanogaster to search for quantitative trait loci (QTL) affecting knockdown resistance to high temperature (KRHT). Two dramatically divergent lines from geographically different thermal environments were artificially selected on KRHT. These lines were crossed to produce two backcross (BC) populations. Each BC was analysed for 200 males with 18 marker loci on chromosomes 2 and 3. Three X-linked markers were used to test for X-linked QTL in an exploratory way. The largest estimate of autosome additive effects was found in the pericentromeric region of chromosome 2, accounting for 19.26% (BC to the low line) and 29.15% (BC to the high line) of the phenotypic variance in BC populations, but it could represent multiple closely linked QTL. Complete dominance was apparent for three QTL on chromosome 3, where heat-shock genes are concentrated. Exploratory analysis of chromosome X indicated a substantial contribution of this chromosome to KRHT. The results show that a large-effect QTL with dominant gene action maps on the right arm of chromosome 3. Further, the results confirm that QTL for heat resistance are not limited to chromosome 3.

Exploring alternative models for sex-linked quantitative trait loci in outbred populations: application to an iberian x landrace pig intercross.

We present a very flexible method that allows us to analyze X-linked quantitative trait loci (QTL) in crosses between outbred lines. The dosage compensation phenomenon is modeled explicitly in an identity-by-descent approach. A variety of models can be fitted, ranging from considering alternative fixed alleles within the founder breeds to a model where the only genetic variation is within breeds, as well as mixed models. Different genetic variances within each founder breed can be estimated. We illustrate the method with data from an F(2) cross between Iberian x Landrace pigs for intramuscular fat content and meat color component a*. The Iberian allele exhibited a strong overdominant effect for intramuscular fat in females. There was also limited evidence of one or more regions affecting color component a*. The analysis suggested that the QTL alleles were fixed in the Iberian founders, whereas there was some evidence of segregation in Landrace for the QTL affecting a* color component.

Local properties of the genome can bias QTL analyses

Given the ever-increasing availability of molecular markers, the explosive growth of quantitative trait loci (QTL) mapping studies is not surprising. For the difficult-to-study but important quantitative traits, QTL mapping assists in our understanding of their genetic architecture: the numbers of loci that contribute to the trait, their locations, their relative effect sizes, and the interactions among these genes. QTL mapping studies are also the first step towards the cloning and molecular characterization of the genes that underlie variation in quantitative traits. In recent years, the genetics community has become more aware of caveats and limitations of QTL analyses. For instance, they tend to overestimate the effect sizes of those QTLs with the largest effects, particularly when the sample size is modest (<1000 genotypes assayed). However, most of the known biases are ones of methodology and not of biology. Now, Noor et al.1xSee all References1 argue that properties of the genome can bias QTL analysis. Specifically, they warn that variation in recombination rates and gene density among different regions of the genome can bias substantially the results of mapping studies.This warning is based upon simulations they performed to assess the ability of QTL mapping programs to detect QTLs placed at random in Drosophila melanogaster. They placed QTLs in two different ways. In one, they placed QTLs at random with respect to recombination position (RR). This reflects the assumption that the density of QTLs per recombination unit is constant across the genome. They also placed QTLs at random with respect to the 14 000 coding sequences identified in the complete genome of D. melanogaster (RC). This placement reflects the assumption that the probability that a QTL exists is constant across coding regions, a more reasonable assumption than that reflected in RR. Yet, the tacit assumption of most simulated QTL mapping studies is that QTLs are distributed randomly based on the recombination map. Using single-marker linear regression and composite interval mapping, Noor et al. detect fewer QTLs in RC simulations than in RR simulations. They also find that in the RC simulations, QTLs are detected most often in regions where the ratio of gene density to recombination is high. These results show that, at least for D. melanogaster, the variation in the distribution of the number of coding regions per recombination unit is sufficient to distort the detection of QTLs significantly. These results are robust to changes in several parameters including marker density, heritability and QTL effect sizes.One possible example of this biasing effect is the ‘small X effect’ seen in genetic studies of behavioral isolation between different species of the D. melanogaster group. Differential selection pressures affecting the two sexes has been invoked as a possible explanation for this phenomenon. Noor et al. argue that this phenomenon might just be an artifact of the X chromosome having a lower density of genes per recombination unit than the autosomes. Supporting their contention, they find substantially more X-linked QTLs are detected in the RR than in the RC simulations.This bias can easily be corrected in D. melanogaster studies and the bias seen in D. melanogaster could be a ‘worst case scenario’, because this species has only three major pairs of chromosomes. Biases can be lower in species where the ratio of chromosomes to genes is higher. Still, this study should caution researchers in their interpretations of QTL analyses. As the authors state, ‘results of QTL mapping should be taken as hypotheses to be tested by additional genetic methods, particularly in species for which detailed genetic and physical genome maps are not available’. These results also highlight the continuing importance studying the natural history of genomes.

Detection of quantitative trait loci for body weight at 10 weeks from Philippine wild mice.

A genome-wide scan for quantitative trait loci (QTLs) controlling body weight at 10 weeks after birth was carried out in a population of 387 intersubspecific backcross mice derived from a cross between C57BL/6J inbred mice (Mus musculus domesticus) and wild mice (M. m. castaneus) captured in the Philippines, in order to discover novel QTLs from the wild mice that have about 60% lower body weight than C57BL/6J. By interval mapping, we detected four QTLs: a highly significant QTL on Chromosome (Chr) 2, which was common in both sexes; two significant QTLs on Chr 13, one male-specific and the other female-specific; and a suggestive male-specific QTL on X Chr. By composite interval mapping, we confirmed the presence of the three QTLs on Chrs 2 and 13, but not of the male-specific X-linked QTL. The composite interval mapping analysis newly identified three QTLs: a significant male-specific QTL on Chr 11 and two highly significant female-specific QTLs on Chrs 9 and X. Individual QTLs explained 3.8-11.6% of the phenotypic variance, and all the QTL alleles derived from the wild mice decreased body weight. A two-way analysis of variance revealed a significant epistatic interaction between the Chr 2 QTL and the background marker locus D12Mit4 on Chr 12 only in males. The interaction effect unexpectedly increased body weight. The chromosomal region containing the Chr 2 QTL did not coincide with those of growth or fatness QTLs mapped in previous studies. These results suggest that a population of wild mice may play an important role as new sources of valuable QTLs.

Mapping quantitative trait loci for body weight on the X chromosome in mice. I. Analysis of a reciprocal F2 population

Evidence of a large sex-linked effect accounting for 25% of the divergence between mouse lines selected for body weight has been described previously. A marker-based study was undertaken to determine the number and map positions of the putative X-linked quantitative trait loci (QTLs). An F2 population was generated from a reciprocal F1 between an inbred low line derived from the low selection line and the high selection line. To enable inference of marker-associated QTL effects on the X chromosome, an analytical technique was developed based on the multiple regression method of Haley and Knott. The analysis of data on 10 week weight indicated a single QTL of large effect situated at about 23 cM from the proximal end of the chromosome, with a peak LOD score of 24.4. The likelihood curve showed a single well-defined peak, and gave a 95% confidence interval for the QTL location of 8 cM. The estimates for the additive genotypic effects in males and females (half the differences between hemizygous males and between homozygous females) were 2.6 g in both cases, or 17% and 20% of the 10 week body weight in males and females respectively. Dominance effects in the females were found to be non-significant. No significant X-linked effect on carcass fat percentage was detected, but a single X-linked QTL appears to explain almost the entire X-linked body weight effect.