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Background: Peripheral vascular interventions (PVIs) for lower extremity peripheral artery disease have been increasing, particularly in the office-based setting. Our goal was to evaluate practice patterns for PVI by site of service using a contemporary real-world dataset., Methods: The Vascular Quality Initiative PVI registry was queried from 2010-2021. Site of service was classified as hospital/inpatient, hospital/outpatient, and ambulatory/office-based center. Patient demographics, comorbidities, procedural details, and periprocedural outcomes were analyzed., Results: There were 54,897 hospital/inpatient (43.2%), 64,105 hospital/outpatient (50.4%), and 8,179 ambulatory/office-based center (6.4%) PVI. When comparing the 2 outpatient settings, ambulatory/office-based center patients were older than hospital/outpatient (mean age 70.7 vs. 68.7 years), more often female sex (41.4% vs. 39.1%), never smokers (27.5% vs. 18.5%), primary Medicare (61.6% vs. 55.9%), nonambulatory (6.5% vs. 4.7%), less often with coronary artery disease (30.2% vs. 34.1%), chronic obstructive pulmonary disease (18.1% vs. 26.9%), congestive heart failure (13% vs. 17.2%), obesity (30.9% vs. 33.6%), and less often on a statin (71.4% vs. 76.1%) (P < 0.001). Ambulatory/office-based center procedures were more likely for claudication (60.1% vs. 55.8%), more often involved femoro-popliteal (73.1% vs. 64.6%) and infrapopliteal (36.7% vs. 24.3%), and less often iliac interventions (24.1% vs. 33.6%) (P < 0.001).Overall, atherectomy was used in 14.2% of hospital/inpatient, 19.4% of hospital/outpatient, and 63.4% of ambulatory/office-based center procedures. Stents were used in 41.8% of hospital/inpatient, 45.1% of hospital/outpatient, and 48.8% of ambulatory/office-based center procedures. However, stent grafts were used in 12.5% of hospital/inpatient, 8.8% of hospital/outpatient, and only 1.3% of ambulatory/office-based center procedures. On multivariable analysis, compared with hospital/inpatient, atherectomy use was associated with ambulatory/office-based center setting (Odds ratio 10.9, 95% confidence interval 10.3-11.5, P < 0.001) and hospital/outpatient setting (Odds ratio 1.57, 95% confidence interval 1.51-1.62, P < 0.001). Periprocedure complications including hematoma requiring intervention (0.3%), any stenosis/occlusion (0.2%), and distal embolization (0.6%) were quite low across all settings., Conclusions: There are substantial variations in patient populations, procedural indications, and types of interventions undertaken during PVI across different locations. Ambulatory/office-based procedures more commonly treat claudicants, use atherectomy, and less often use stent grafts. Further research is warranted to investigate long-term trends in practice patterns and long-term outcomes, for PVI in the ever-expanding ambulatory/office-based setting., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Length of stay (LOS) and readmissions are common measures to evaluate quality of health care. The objective of this study was to evaluate factors related to hospital LOS and readmission within 90 days following carotid endarterectomy (CEA) in patients who have not had a stroke., Methods: Using a single institution database, patients who underwent CEA for carotid stenosis between 2014 and 2019 were identified. Asymptomatic carotid stenosis (no history of any stroke or transient ischemic attack (TIA) within 6 months prior to CEA), and patients who had a TIA without stroke were included. Demographic and perioperative factors were collected. Primary outcomes analyzed were increased LOS (>1 day) and readmission within 90 days after surgery., Results: There were 125 patients identified who underwent CEA for 133 carotid stenosis, and 8 patients had bilateral CEA; of which 36.8% were asymptomatic carotid stenosis with the remaining being operated on for TIA without any stroke. The mean age was 68 years old and 36.1% of cases were female. The median postoperative LOS was 2 days. Increased LOS occurred in 81 cases (60.9%). Increased LOS, compared to no increased LOS, occurred more often in patients with diabetes (48.1% vs. 30.8%, P = 0.047), in those with operations starting after 12:00 pm (45.7% vs. 21.2%, P = 0.004) and those with any minor complications such as neck swelling, neck pain, and urinary retention (30.9% vs. 15.4%, P = 0.044). Readmission within 90 days after CEA occurred in 24 (18%) of cases. Readmission within 90 days, compared to no readmission within 90 days, occurred more often in patients with a history of coronary artery disease (58.3% vs. 27.5%, P = 0.004), congestive heart failure (37.5% vs. 11%, P = 0.001), and atrial fibrillation (29.2% vs. 8.3%, P = 0.004)., Conclusions: More than half of patients undergoing CEA for carotid stenosis were discharged after postoperative day 1. Interventions on modifiable clinical risk factors, such as morning CEA scheduling and management of comorbidities, may decrease LOS and 90-day readmission rates., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: The Society of Vascular Surgery and the American Venous Forum recommend duplex ultrasound (DUS) following endovenous ablation. However, this screening may not be cost-effective or clinically indicated. The most common abnormal finding, endovenous heat-induced thrombosis (EHIT level 1-2), represents extension of thrombus from the saphenous <50% across the femoral or popliteal vein, which is thought to have a benign course regardless of intervention. The likelihood of venous thromboembolism (VTE) after thermal and non-thermal ablations was explored to determine the utility of routine postoperative DUS., Methods: This is an updated and expanded systematic review including data from randomized trials and large observational studies (≥150 patients) of thermal and non-thermal ablations, examining the incidence of VTE. Using PubMed and EMBASE, 4584 publications were screened from 2000 through 2020. After applying inclusion and exclusion criteria, 72 studies were included. Random effects DerSimonian-Laird method was conducted to obtain the pooled incidence. We calculated the number of tests needed to detect one VTE, and the cost was derived from Center for Medicare Services tables., Results: A total of 31,663 patients were included. The pooled incidence of EHIT II-IV, deep venous thrombosis (DVT), and pulmonary embolism (PE) was 1.32% (95% confidence interval [CI], 0.75%-2.02%); DVT (excluding EHIT), 0.20% (95% CI, 0.0%-0.2%); EHIT (I-IV), 2.51% (95% CI, 1.54%-3.68%); and EHIT (II-IV), 1.00% (95% CI, 0.51%-1.61%). There was no mortality. There was a lower DVT rate in thermal vs non-thermal ablations (0.23% vs 0.43%; P = .02); however, for all VTE (EHIT I-IV + DVT + PE), thermal techniques had more thrombosis (2.5% vs 0.5%; P <.001). When clinical significance is defined as DVT + EHIT (II-IV), 175 studies are needed to identify one VTE, costing $21,813 per "significant VTE." Patients receiving pharmacological prophylaxis had less EHIT I-IV compared with those who did not (3.04% vs 1.63%; P < .001); those who received DUS during the first post-op week had three times higher EHIT incidence compared with those whose first DUS was >7 days postoperative (6.6% vs 2.4%; P < .001)., Conclusions: For thermal and non-thermal endovenous ablations, the incidence of VTE diagnosed with routine DUS is small and without clear clinical significance but caries a high cost. The Society of Vascular Surgery and the American Venous Forum recommendation to perform DUS within 72 hours is not justified by these data. We recommend a more targeted post-ablation scanning protocol including symptomatic patients and those at high risk., (Copyright © 2022. Published by Elsevier Inc.)

Background: Shunting during eversion carotid endarterectomy (eCEA) may be technically challenging. Whether shunting practice patterns modify perioperative stroke risk after eCEA is unclear. We aimed to compare eCEA outcomes based on shunting practice., Methods: The Vascular Quality Initiative (2011-2019) was queried for eCEAs performed for symptomatic and asymptomatic carotid stenosis. Univariable and multivariable analyses compared outcomes based on whether shunting was routine practice, preoperatively-indicated, intraoperatively-indicated, or not performed., Results: There were 13,207 eCEAs identified. Average age was 71.4 years and 59.4% of patients were male sex. Ipsilateral carotid stenosis was >80% in 45.6% and there was severe contralateral carotid stenosis in 8.6%. Early ipsilateral symptoms within 14 days of eCEA were transient ischemic attack in 5.6% and stroke in 7%. The majority of cases were performed under general anesthesia (82.7%). Electroencephalogram monitoring and stump pressures were utilized in 30.9% and 14.7%, respectively. Shunting was routine (25.4%), preoperatively-indicated (1.9%), intraoperatively-indicated (4.7%), or not implemented (68%). Preoperatively-indicated shunting was more often performed in patients with early symptomatic carotid stenosis or severe contralateral carotid stenosis. After routine shunting, preoperatively-indicated shunting, intraoperatively-indicated shunting, and no shunting, median operative duration was 110, 101, 112, and 97 min, respectively (P < 0.001), and ipsilateral perioperative stroke prevalence was 0.6%, 1.2%, 1.9%, and 0.7%, respectively (P = 0.004). On multivariable analysis, longer operative time was associated with routine shunting (MR 1.17, 95% CI 1.15-1.19, P < 0.001), preoperatively-indicated shunting (MR 1.09, 95% CI 1.04-1.15, P < 0.001), and intraoperatively-indicated shunting (MR 1.12, 95% CI 1.09-1.16, P < 0.001) compared with no shunting. Compared with no shunting, routine shunting (OR 0.91, 95% CI 0.54-1.54, P = 0.74) and preoperatively-indicated shunting (OR 1.53, 95% CI 0.47-4.99, P = 0.48) were not associated with stroke; however, intraoperatively-indicated shunting was associated with increased stroke (OR 2.74, 95% CI 1.41-5.3, P = 0.003). Shunting type was not associated with perioperative mortality., Conclusions: Intraoperatively-indicated shunting during eCEA was associated with longest operative duration and increased perioperative stroke risk. Surgeon familiarity with shunting and planning to shunt in advance may permit more expeditious shunting and prevent stroke., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Intermittent claudication (IC) is a commonly treated vascular condition. Patient sex has been shown to influence outcomes of interventions for other vascular disorders; however, whether outcomes of interventions for IC vary by sex is unclear. We sought to assess the association of patient sex with outcomes after IC interventions., Methods: The Vascular Quality Initiative was queried from 2010-2020 for all peripheral endovascular interventions (PVI), infra-inguinal bypasses (IIB), and supra-inguinal bypasses (SIB) for any degree IC. Univariable and multivariable analyses compared peri-operative and long-term outcomes by patient sex., Results: There were 24,701 female and 40,051 male patients undergoing PVI, 2,789 female and 6,525 male patients undergoing IIB, and 1,695 female and 2,370 male patients undergoing SIB for IC. Guideline-recommended pre-operative medical therapy differed with female patients less often prescribed aspirin for PVI (73.4% vs. 77.3%), IIB (71.5% vs. 74.8%), and SIB (70.9% vs. 74.3%) or statins for PVI (71.8% vs. 76.7%) and IIB (73.1% vs. 76.0%) (all P < 0.05). Female compared with male patients had lower 1-year reintervention-free survival after PVI (84.4% ± 0.3% vs. 86.3% ± 0.2%, P < 0.001), IIB (79.0% ± 0.9% vs. 81.2% ± 0.6%, P = 0.04), and SIB (89.4% ± 0.9% vs. 92.6% ± 0.7%, P = 0.005), but similar amputation-free survival and survival across all procedures. Multivariable analysis confirmed that female sex was associated with increased 1-year reintervention for PVI (HR 1.16, 95% CI 1.09-1.24, P < 0.001), IIB, (HR 1.16, 95% CI 1.03-1.31, P = 0.02), and SIB (HR 1.60, 95% CI 1.20-2.13, P = 0.001)., Conclusions: Female patients undergoing interventions for IC were less often pre-operatively medically optimized than male patients, though the difference was small. Furthermore, female sex was associated with more reinterventions after interventions. Interventionists treating female patients should increase their efforts to maximize medical therapy. Future research should clarify reasons for poorer intervention durability in female patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Acute limb ischemia (ALI) is a vascular emergency associated with high rates of limb loss and mortality. Management of these patients is challenging given the severe systemic illness resulting from tissue ischemia and the high incidence of preexisting comorbid conditions and underlying peripheral arterial disease. Expeditious diagnosis, anticoagulation, and revascularization are of utmost importance in reducing morbidity. Revascularization may be accomplished using open, endovascular, or hybrid techniques. Approach to revascularization depends on the severity of ischemia, location of occlusion, cause, chance of recovery, comorbidities, and available resources., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Plant growth, development, and nutritional quality depends upon amino acid homeostasis, especially in seeds. However, our understanding of the underlying genetics influencing amino acid content and composition remains limited, with only a few candidate genes and quantitative trait loci identified to date. Improved knowledge of the genetics and biological processes that determine amino acid levels will enable researchers to use this information for plant breeding and biological discovery. Toward this goal, we used genomic prediction to identify biological processes that are associated with, and therefore potentially influence, free amino acid (FAA) composition in seeds of the model plant Arabidopsis thaliana Markers were split into categories based on metabolic pathway annotations and fit using a genomic partitioning model to evaluate the influence of each pathway on heritability explained, model fit, and predictive ability. Selected pathways included processes known to influence FAA composition, albeit to an unknown degree, and spanned four categories: amino acid, core, specialized, and protein metabolism. Using this approach, we identified associations for pathways containing known variants for FAA traits, in addition to finding new trait-pathway associations. Markers related to amino acid metabolism, which are directly involved in FAA regulation, improved predictive ability for branched chain amino acids and histidine. The use of genomic partitioning also revealed patterns across biochemical families, in which serine-derived FAAs were associated with protein related annotations and aromatic FAAs were associated with specialized metabolic pathways. Taken together, these findings provide evidence that genomic partitioning is a viable strategy to uncover the relative contributions of biological processes to FAA traits in seeds, offering a promising framework to guide hypothesis testing and narrow the search space for candidate genes., (Copyright © 2020 Turner-Hissong et al.)

The nutritional conditions experienced by a population have a major role in shaping trait evolution in many taxa. Constraints exerted by nutrient limitation or nutrient imbalance can influence the maximal value that fitness components such as reproduction and lifespan attains, and organisms may shift how resources are allocated to different structures and functions in response to changes in nutrition. Whether the phenotypic changes associated with changes in nutrition represent an adaptive response is largely unknown. Further, it is unclear whether the response of fitness components to diet even has the potential to evolve in most systems. In this study, we use an admixed multi-parental population of Drosophila melanogaster reared in three different diet conditions to estimate quantitative genetic parameters for lifespan and fecundity. We find significant genetic variation for both traits in our population and show that lifespan has moderate to high heritabilities within diets. Genetic correlations for lifespan between diets were significantly less than one, demonstrating a strong genotype by diet interaction. These findings demonstrate substantial standing genetic variation in our population that is comparable to natural populations and highlights the potential for adaptation to changing nutritional environments.

Background: Retractions of scientific articles represent attempts to correct the literature. Our goal was to examine retracted surgical papers., Methods: NCBI PubMed database was queried using the search terms "surgery," "surg," or "surgical" and "retracted" or "retraction." Article details were recorded., Results: There were 184 retracted surgical articles identified from 1991 through 2015. Average retraction time was 3.6 years. General (26%), Cardiac (22%), and Orthopedic (10%) surgery were most common. Reasons for retraction were duplication (35.3%), Institutional Review Board violations (18.5%), falsified data (14.7%), data errors (9.8%), author dispute (8.2%), plagiarism (7.6%), copyright violations (2.2%), financial disclosure violations (0.5%), and consent (0.5%). No reason for retraction was given in 8.7% of cases. Median IF was higher for administrative than content-related retraction reasons (3.0 vs. 2.0, P < 0.01). A paywall, requiring a subscription to read, restricted access to 23.4% of retraction notices., Conclusions: Article retractions occur across all fields of surgery for various reasons, both administrative and content-related. The majority of surgical retraction notices have a reason for retraction listed and do not require payment to read., (Copyright © 2017 Elsevier Inc. All rights reserved.)

All organisms use resources to grow, survive and reproduce. The supply of these resources varies widely across landscapes and time, imposing ultimate constraints on the maximal trait values for allocation-related traits. In this review, we address three key questions fundamental to our understanding of the evolution of allocation strategies and their underlying mechanisms. First, we ask: how diverse are flexible resource allocation strategies among different organisms? We find there are many, varied, examples of flexible strategies that depend on nutrition. However, this diversity is often ignored in some of the best-known cases of resource allocation shifts, such as the commonly observed pattern of lifespan extension under nutrient limitation. A greater appreciation of the wide variety of flexible allocation strategies leads directly to our second major question: what conditions select for different plastic allocation strategies? Here, we highlight the need for additional models that explicitly consider the evolution of phenotypically plastic allocation strategies and empirical tests of the predictions of those models in natural populations. Finally, we consider the question: what are the underlying mechanisms determining resource allocation strategies? Although evolutionary biologists assume differential allocation of resources is a major factor limiting trait evolution, few proximate mechanisms are known that specifically support the model. We argue that an integrated framework can reconcile evolutionary models with proximate mechanisms that appear at first glance to be in conflict with these models. Overall, we encourage future studies to: (i) mimic ecological conditions in which those patterns evolve, and (ii) take advantage of the 'omic' opportunities to produce multi-level data and analytical models that effectively integrate across physiological and evolutionary theory., (© 2017 The Author(s).)

A major goal in the analysis of complex traits is to partition the observed genetic variation in a trait into components due to individual loci and perhaps variants within those loci. However, in both QTL mapping and genetic association studies, the estimated percent variation attributable to a QTL is upwardly biased conditional on it being discovered. This bias was first described in two-way QTL mapping experiments by William Beavis, and has been referred to extensively as "the Beavis effect." The Beavis effect is likely to occur in multiparent population (MPP) panels as well as collections of sequenced lines used for genome-wide association studies (GWAS). However, the strength of the Beavis effect is unknown-and often implicitly assumed to be negligible-when "hits" are obtained from an association panel consisting of hundreds of inbred lines tested across millions of SNPs, or in multiparent mapping populations where mapping involves fitting a complex statistical model with several d.f. at thousands of genetic intervals. To estimate the size of the effect in more complex panels, we performed simulations of both biallelic and multiallelic QTL in two major Drosophila melanogaster mapping panels, the GWAS-based Drosophila Genetic Reference Panel (DGRP), and the MPP the Drosophila Synthetic Population Resource (DSPR). Our results show that overestimation is determined most strongly by sample size and is only minimally impacted by the mapping design. When < 100, 200, 500, and 1000 lines are employed, the variance attributable to hits is inflated by factors of 6, 3, 1.5, and 1.1, respectively, for a QTL that truly contributes 5% to the variation in the trait. This overestimation indicates that QTL could be difficult to validate in follow-up replication experiments where additional individuals are examined. Further, QTL could be difficult to cross-validate between the two Drosophila resources. We provide guidelines for: (1) the sample sizes necessary to accurately estimate the percent variance to an identified QTL, (2) the conditions under which one is likely to replicate a mapped QTL in a second study using the same mapping population, and (3) the conditions under which a QTL mapped in one mapping panel is likely to replicate in the other (DGRP and DSPR)., (Copyright © 2017 King et al.)

Natural populations exhibit a great deal of interindividual genetic variation in the response to toxins, exemplified by the variable clinical efficacy of pharmaceutical drugs in humans, and the evolution of pesticide resistant insects. Such variation can result from several phenomena, including variable metabolic detoxification of the xenobiotic, and differential sensitivity of the molecular target of the toxin. Our goal is to genetically dissect variation in the response to xenobiotics, and characterize naturally-segregating polymorphisms that modulate toxicity. Here, we use the Drosophila Synthetic Population Resource (DSPR), a multiparent advanced intercross panel of recombinant inbred lines, to identify QTL (Quantitative Trait Loci) underlying xenobiotic resistance, and employ caffeine as a model toxic compound. Phenotyping over 1,700 genotypes led to the identification of ten QTL, each explaining 4.5-14.4% of the broad-sense heritability for caffeine resistance. Four QTL harbor members of the cytochrome P450 family of detoxification enzymes, which represent strong a priori candidate genes. The case is especially strong for Cyp12d1, with multiple lines of evidence indicating the gene causally impacts caffeine resistance. Cyp12d1 is implicated by QTL mapped in both panels of DSPR RILs, is significantly upregulated in the presence of caffeine, and RNAi knockdown robustly decreases caffeine tolerance. Furthermore, copy number variation at Cyp12d1 is strongly associated with phenotype in the DSPR, with a trend in the same direction observed in the DGRP (Drosophila Genetic Reference Panel). No additional plausible causative polymorphisms were observed in a full genomewide association study in the DGRP, or in analyses restricted to QTL regions mapped in the DSPR. Just as in human populations, replicating modest-effect, naturally-segregating causative variants in an association study framework in flies will likely require very large sample sizes.

For most complex traits we have a poor understanding of the positions, phenotypic effects, and population frequencies of the underlying genetic variants contributing to their variation. Recently, several groups have developed multi-parent advanced intercross mapping panels in different model organisms in an attempt to improve our ability to characterize causative genetic variants. These panels are powerful and are particularly well suited to the dissection of phenotypic variation generated by rare alleles and loci segregating multiple functional alleles. We describe studies using one such panel, the Drosophila Synthetic Population Resource (DSPR), and the implications for our understanding of the genetic basis of complex traits. In particular, we note that many loci of large effect appear to be multiallelic. If multiallelism is a general rule, analytical approaches designed to identify multiallelic variants should be a priority for both genome-wide association studies (GWASs) and multi-parental panels., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Animals in nature are frequently challenged by toxic compounds, from those that occur naturally in plants as a defense against herbivory, to pesticides used to protect crops. On exposure to such xenobiotic substances, animals mount a transcriptional response, generating detoxification enzymes and transporters that metabolize and remove the toxin. Genetic variation in this response can lead to variation in the susceptibility of different genotypes to the toxic effects of a given xenobiotic. Here we use Drosophila melanogaster to dissect the genetic basis of larval resistance to nicotine, a common plant defense chemical and widely used addictive drug in humans. We identified quantitative trait loci (QTL) for the trait using the DSPR (Drosophila Synthetic Population Resource), a panel of multiparental advanced intercross lines. Mapped QTL collectively explain 68.4% of the broad-sense heritability for nicotine resistance. The two largest-effect loci-contributing 50.3 and 8.5% to the genetic variation-map to short regions encompassing members of classic detoxification gene families. The largest QTL resides over a cluster of ten UDP-glucuronosyltransferase (UGT) genes, while the next largest QTL harbors a pair of cytochrome P450 genes. Using RNAseq we measured gene expression in a pair of DSPR founders predicted to harbor different alleles at both QTL and showed that Ugt86Dd, Cyp28d1, and Cyp28d2 had significantly higher expression in the founder carrying the allele conferring greater resistance. These genes are very strong candidates to harbor causative, regulatory polymorphisms that explain a large fraction of the genetic variation in larval nicotine resistance in the DSPR., (Copyright © 2014 by the Genetics Society of America.)

The severity of the toxic side effects of chemotherapy shows a great deal of interindividual variability, and much of this variation is likely genetically based. Simple DNA tests predictive of toxic side effects could revolutionize the way chemotherapy is carried out. Due to the challenges in identifying polymorphisms that affect toxicity in humans, we use Drosophila fecundity following oral exposure to carboplatin, gemcitabine and mitomycin C as a model system to identify naturally occurring DNA variants predictive of toxicity. We use the Drosophila Synthetic Population Resource (DSPR), a panel of recombinant inbred lines derived from a multiparent advanced intercross, to map quantitative trait loci affecting chemotoxicity. We identify two QTL each for carboplatin and gemcitabine toxicity and none for mitomycin. One QTL is associated with fly orthologs of a priori human carboplatin candidate genes ABCC2 and MSH2, and a second QTL is associated with fly orthologs of human gemcitabine candidate genes RRM2 and RRM2B. The third, a carboplatin QTL, is associated with a posteriori human orthologs from solute carrier family 7A, INPP4A&B, and NALCN. The fourth, a gemcitabine QTL that also affects methotrexate toxicity, is associated with human ortholog GPx4. Mapped QTL each explain a significant fraction of variation in toxicity, yet individual SNPs and transposable elements in the candidate gene regions fail to singly explain QTL peaks. Furthermore, estimates of founder haplotype effects are consistent with genes harboring several segregating functional alleles. We find little evidence for nonsynonymous SNPs explaining mapped QTL; thus it seems likely that standing variation in toxicity is due to regulatory alleles., (Copyright © 2014 by the Genetics Society of America.)

Modern genetic mapping is plagued by the "missing heritability" problem, which refers to the discordance between the estimated heritabilities of quantitative traits and the variance accounted for by mapped causative variants. One major potential explanation for the missing heritability is allelic heterogeneity, in which there are multiple causative variants at each causative gene with only a fraction having been identified. The majority of genome-wide association studies (GWAS) implicitly assume that a single SNP can explain all the variance for a causative locus. However, if allelic heterogeneity is prevalent, a substantial amount of genetic variance will remain unexplained. In this paper, we take a haplotype-based mapping approach and quantify the number of alleles segregating at each locus using a large set of 7922 eQTL contributing to regulatory variation in the Drosophila melanogaster female head. Not only does this study provide a comprehensive eQTL map for a major community genetic resource, the Drosophila Synthetic Population Resource, but it also provides a direct test of the allelic heterogeneity hypothesis. We find that 95% of cis-eQTLs and 78% of trans-eQTLs are due to multiple alleles, demonstrating that allelic heterogeneity is widespread in Drosophila eQTL. Allelic heterogeneity likely contributes significantly to the missing heritability problem common in GWAS studies.

The severity of the toxic side effects of chemotherapy varies among patients, and much of this variation is likely genetically based. Here, we use the model system Drosophila melanogaster to genetically dissect the toxicity of methotrexate (MTX), a drug used primarily to treat childhood acute lymphoblastic leukemia and rheumatoid arthritis. We use the Drosophila Synthetic Population Resource, a panel of recombinant inbred lines derived from a multiparent advanced intercross, and quantify MTX toxicity as a reduction in female fecundity. We identify three quantitative trait loci (QTL) affecting MTX toxicity; two colocalize with the fly orthologs of human genes believed to mediate MTX toxicity and one is a novel MTX toxicity gene with a human ortholog. A fourth suggestive QTL spans a centromere. Local single-marker association scans of candidate gene exons fail to implicate amino acid variants as the causative single-nucleotide polymorphisms, and we therefore hypothesize the causative variation is regulatory. In addition, the effects at our mapped QTL do not conform to a simple biallelic pattern, suggesting multiple causative factors underlie the QTL mapping results. Consistent with this observation, no single single-nucleotide polymorphism located in or near a candidate gene can explain the QTL mapping signal. Overall, our results validate D. melanogaster as a model for uncovering the genetic basis of chemotoxicity and suggest the genetic basis of MTX toxicity is due to a handful of genes each harboring multiple segregating regulatory factors.