A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer

Funder: Fundación Científica Asociación Española Contra el Cáncer (ES)Funder: Cancer Focus Northern Ireland and Department for Employment and LearningFunder: Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, USAAbstract: Background: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. Methods: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. Results: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E−06 in 1D approach and a Local Moran’s Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8—a lncRNA associated with pancreatic carcinogenesis—with a lowest p value = 6.91E−05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1—a major regulator of the ER stress and unfolded protein responses in acinar cells—identified by 3D; all of them with a strong in silico functional support. Conclusions: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases

Data from: Size-dependent ejaculation strategies and reproductive success in the yellow dung fly, Scathophaga stercoraria

Theory predicts that sperm competition will favour the production of larger ejaculates. However, because the benefits of greater reproductive investment are balanced by the costs of spermatogenesis, expenditure should depend on male physiology, mating rate and the relationship between additional investment and fertilization gains. In the yellow dung fly, Scathophagastercoraria, males adopt size-dependent alternative mating tactics that are associated with discrete ecological resources (foraging and oviposition substrates), although males switch between these environments throughout their lives. By copulating on foraging substrate (fruit or flowers), males can bypass intense mate competition that occurs at oviposition sites (cow dung), but as a consequence, must occupy a disfavoured mating role (i.e. face a greater risk that their ejaculate will be displaced from storage prior to fertilization). Small males often mate on foraging substrate, whereas large males mate in this environment only during feeding bouts. Optimal ejaculate expenditure should therefore depend on male size and their current mating role. By measuring copula duration (i.e. ejaculate expenditure) of natural matings and assigning paternity to resulting offspring, we confirmed that copulations on dung sire approximately three times as many offspring as those on foraging substrate. Furthermore, large males reduced copula duration on fruit, as predicted, since this strategy enables greater investment into high-payoff matings on dung. Conversely, small males copulated for shorter durations on dung than on foraging substrate, perhaps to minimize the risk of being displaced from copula by a rival. These patterns of ejaculate expenditure translated into greater offspring production for large males on dung and for small males on fruit. We discuss the possible proximate factors driving these size- and context-dependent patterns of ejaculate allocation by yellow dung fly males. Together, our findings shed light on the allocation strategies and reproductive consequences of alternative mating tactics

Development and validation of a larval bioassay and selection protocol for insecticide resistance in Drosophila suzukii.

The rapid invasion of Drosophila suzukii (Matsumura) throughout Europe and the Americas has led to an increased reliance on calendar-based broad-spectrum insecticide programs among berry and cherry growers. Relatively few active ingredients (AIs) are currently available for effective D. suzukii management, and studies from multiple growing regions indicate that susceptibility to at least some of these materials is declining. Greater effort is needed to understand the status of susceptibility across field populations and the potential for increased resistance to develop, as well as the possible fitness costs incurred by resistant individuals. However, current bioassay protocols used for resistance monitoring and selection studies (i.e. resistance risk assessments) are labor-intensive and costly, making large-scale studies difficult to conduct. Here, we first present a novel bioassay protocol using larvae that requires little effort or cost to implement beyond what is needed for basic D. suzukii laboratory colony maintenance. We then perform dose-response bioassays using this protocol to identify larval lethal concentrations for three commonly used insecticides (malathion, spinosad and zeta-cypermethrin) in a susceptible population. Finally, resistance risk assessments were conducted using a population of D. suzukii from commercial caneberry fields near Watsonville, CA. We find that five generations of larval selection with a discriminating dose is sufficient to significantly increase both larval (malathion and spinosad) and adult (spinosad) resistance to the target AIs. This approach provides a simple, cost-effective tool for assaying susceptibility of D. suzukii populations to insecticides and for selecting resistant insect lines for resistance management research

Gress.Pitnick.AB.data

Raw copula durations for pomace males (m1.cop.dur) and dung males (m2.cop.dur) were recorded in the field, as was ambient temperature (temp1 = temperature during pomace mating, temp2 = temperature during dung mating); Portion of offspring sired by male 1 and 2 (P1 and P2); m1.progeny and m2.progeny represent the absolute number of offspring sired by male 1 and 2 in the subsequent female clutch; male hind tibia length was measured in the lab (m1.ru and m2.ru raw values, m1.htl.mm and m2.htl.mm are divided by 32 to convert to mm); sperm1 and sperm2 are estimates of the number of sperm transferred per ejaculate using known relationships between male htl and sperm transfer rate (0.0018 (htl^3) - 0.003) * 826.8

Alternative mating tactics in the yellow dung fly: resolving mechanisms of small-male advantage off pasture

Recent work suggests that the yellow dung fly mating system may include alternative patroller-competitor mating tactics in which large males compete for gravid females on dung, whereas small, non-competitive males search for females at foraging sites. Small males obtain most matings off pasture, yet the behavioural mechanism(s) giving rise to this pattern are unknown. We investigated the male and female behaviours that determine mating success in this environment by conducting field mating experiments and found small males to benefit from several attributes specific to the off-pasture mating environment. First, small males from foraging sites exhibited higher mating propensity, indicating that large males away from dung may be depleted of energy and/or sperm. Second, small males were more discriminating, being significantly less likely to attempt with non-gravid females, which are absent on dung but common off pasture. Third, non-gravid females were generally more likely to actively struggle and reject mating attempts; however, such behaviours occurred disproportionately more often with large males. Female Scathophaga stercoraria thus appear to preferentially mate with small males when off pasture. These findings challenge assumptions about male-female interactions in systems with alternative mating tactics and reveal hidden processes that may influence selection patterns in the field

all data

These data were obtained using experimental matings conducted in Plexiglas chambers in the field. Male mating attempts were recorded (Attempt/No attempt), latency to attempt (min), outcome of attempt (Copulation/Rejection), capture success (Yes/No), female resistance (Yes/No), female resistance duration (sec), and male displacement when faced with resistance (Yes/No). Raw measures of body size are also included in reticle units (at 32x mag). Finally, female egg development was recorded as either nongravid or gravid (meaning female clutch visually appeared mature)

Data from: Alternative mating tactics in the yellow dung fly: resolving mechanisms of small-male advantage off pasture

Recent work suggests the yellow dung fly mating system may include alternative patroller-competitor mating tactics in which large males compete for gravid females on dung, whereas small, non-competitive males search for females at foraging sites. Small males obtain most matings off pasture, yet the behavioural mechanism(s) giving rise to this pattern are unknown. We investigated the male and female behaviours that determine mating success in this environment by conducting field mating experiments and found small males to benefit from several attributes specific to the off-pasture mating environment. First, small males from foraging sites exhibited higher mating propensity, indicating that large males away from dung may be depleted of energy and/or sperm. Second, small males were more discriminating, being significantly less likely to attempt with non-gravid females, which are absent on dung but common off pasture. Third, non-gravid females were generally more likely to actively struggle and reject mating attempts; however, such behaviours occurred disproportionately more often with large males. Female Scathophaga stercoraria thus appear to preferentially mate with small males when off pasture. These findings challenge assumptions about male-female interactions in systems with alternative mating tactics and reveal hidden processes that may influence selection patterns in the field

Chromosome 17q12-21 Variants Are Associated with Multiple Wheezing Phenotypes in Childhood

Rationale: Birth cohort studies have identified several temporal patterns of wheezing, only some of which are associated with asthma. Whether 17q12-21 genetic variants, which are closely associated with asthma, are also associated with childhood wheezing phenotypes remains poorly explored.Objectives: To determine whether wheezing phenotypes, defined by latent class analysis (LCA), are associated with nine 17q12-21 SNPs and if so, whether these relationships differ by race/ancestry.Methods: Data from seven U.S. birth cohorts (n = 3,786) from the CREW (Children's Respiratory Research and Environment Workgroup) were harmonized to represent whether subjects wheezed in each year of life from birth until age 11 years. LCA was then performed to identify wheeze phenotypes. Genetic associations between SNPs and wheeze phenotypes were assessed separately in European American (EA) (n = 1,308) and, for the first time, in African American (AA) (n = 620) children.Measurements and Main Results: The LCA best supported four latent classes of wheeze: infrequent, transient, late-onset, and persistent. Odds of belonging to any of the three wheezing classes (vs. infrequent) increased with the risk alleles for multiple SNPs in EA children. Only one SNP, rs2305480, showed increased odds of belonging to any wheezing class in both AA and EA children.Conclusions: These results indicate that 17q12-21 is a "wheezing locus," and this association may reflect an early life susceptibility to respiratory viruses common to all wheezing children. Which children will have their symptoms remit or reoccur during childhood may be independent of the influence of rs2305480.12 month embargo; published 03 February 2021This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]