Biology subjects

Hayes, C.

Publications and source records attributed to Hayes, C..

18 recordsLinked to original sources

bioRxiv2026

Sub-Chronic Chlorpyrifos Exposure Leads to Epigenetic and Sex-Specific Behavioral Changes in Adult Mice

Chlorpyrifos is a widely used organophosphate pesticide that exerts its primary toxic effect through inhibition of acetylcholinesterase (AChE). Although the acute neurotoxicity of chlorpyrifos is well characterized, the lasting biochemical, behavioral, and epigenetic consequences of sub-chronic exposure remain poorly understood, particularly when considering sex-specific differences. Therefore, we exposed male and female C57BL/6J mice to either peanut oil (n=19), low chlorpyrifos exposure (1 mg/kg/day; n=19), or high chlorpyrifos exposure (10 mg/kg/day n=10) repeatedly for 21 days via subcutaneous injection. Blood AChE activity, behavior, and hippocampal DNA methylation were measured across groups. During exposure, AChE activity decreased in both males and females but only returned to baseline after behavioral testing in females exposed to low chlorpyrifos levels. Behavioral tests also revealed a sex-specific phenotype, with females in the low exposure group exhibiting reduced forced swim test immobility and a significant time by exposure interaction in open field habituation. No significant behavioral effects were observed in males. Significant DNA methylation changes were observed at 3,538 CpG sites in male and female mice after high exposure. Sex-specific analyses revealed two female-specific differentially methylated CpGs after high exposure. Pathways enriched for differentially methylated genes included several related to synaptic remodeling, cholinergic synapse, and various endocrine systems. These findings demonstrate that repeated high chlorpyrifos exposure leads to persistent cholinergic disruption and DNA methylation changes. However, the female-specific behavioral changes seen are independent of AChE activity and widespread DNA methylation changes, suggesting additional mechanisms, present only in females, may underlie behavioral sensitivity to chlorpyrifos. New and NoteworthySub-chronic chlorpyrifos exposure in adult mice produced dose-dependent blood AChE suppression and widespread hippocampal DNA methylation changes in both sexes, with pathway enrichment including cholinergic synapse and endocrine systems. Behavioral effects were subtle, with females in the low exposure group showing reduced forced swim immobility and altered locomotor habituation. Notably, the female-specific behavioral changes seen are independent of AChE activity and DNA methylation changes, suggesting novel mechanisms may underlie female behavioral sensitivity to chlorpyrifos.

neuroscience↗

bioRxiv2026

Variation in seagrass habitat use by fishery-important nekton across the Gulf of Mexico revealed by deep transfer learning with trophic group priors

Understanding how species use habitats across environmental gradients is central to guiding fisheries management and habitat restoration, yet inference is often limited by heterogeneous data and inconsistent observations. In coastal ecosystems, variation in relationships between nekton and seagrass habitats remains unresolved, in part because habitat structure, environmental context, and sampling methods are rarely integrated in predictive models. Here, we combine multi-gear monitoring data from across the Gulf of Mexico with a transfer-learning framework that incorporates trophic priors to quantify how nekton respond to seagrass structure under varying environmental conditions. We show that environmental gradients--including temperature, salinity, and water clarity--define broad-scale distributions, while seagrass structure refines habitat use at local scales. Apparent inconsistencies in seagrass-nekton relationships are largely attributable to environmental context and differences in observational processes. By integrating observations collected using different sampling methods, our approach reveals consistent species-environment relationships across sites and improves predictive performance, particularly for data-limited species, by using trophic priors. We further show that species differ in their responses to environmental gradients, with some exhibiting consistent patterns across sites and others showing strong context dependence. These results demonstrate that combining heterogeneous datasets can strengthen ecological inference and provide a pathway for scalable, data-driven conservation and restoration in rapidly changing coastal systems.

bioinformatics↗

bioRxiv2026

The PMADS Project: A Longitudinal Multimodal Cohort Study to Understand Risk for Perinatal Mood and Anxiety Disorders

BackgroundPerinatal mood and anxiety disorders (PMADs) are among the most common and consequential complications of pregnancy. The perinatal period is also characterized by profound hormonal fluctuations and large-scale brain plasticity. However, the mechanisms linking these neurobiological changes to psychiatric risk are poorly understood. Prospective, clinically informed studies are needed to identify quantitative biomarkers and clarify pathways linking perinatal neurobiology to PMADs risk. MethodsThis report describes the design of a prospective, longitudinal cohort study integrating multimodal neuroimaging, biofluid sampling, and deep clinical phenotyping to enable precision characterization of neurobiological trajectories of PMADs risk. Twenty-five individuals at elevated risk for PMADs will be recruited prior to conception and followed across six in-person timepoints spanning the menstrual cycle, pregnancy, and early postpartum, with additional remote follow-ups through the first postpartum year. Data collection includes high-resolution structural MRI, functional brain mapping using multi-echo resting-state fMRI, diffusion MRI, arterial spin labeling, ultra-high field MR-based techniques for measuring glutamate (GluCEST and 1HMRS), biofluid sampling, and comprehensive clinical, behavioral, and cognitive assessments. Structured clinical interviews assess categorical diagnoses while dimensional symptom measures capture heterogeneity and transdiagnostic features of perinatal psychopathology. Longitudinal analyses will model nonlinear trajectories of brain and symptom change across the perinatal period as well as evaluate whether preconception network features and menstrual cycle-related brain changes are associated with subsequent perinatal symptom emergence. DiscussionThis cohort study establishes a longitudinal, multimodal framework for investigating neurobiological changes across the transition to pregnancy in individuals at elevated risk for PMADs. By anchoring pregnancy-related brain changes to preconception and menstrual cycle-related variability within the same individuals, this study is designed to evaluate associations between preconception hormone sensitivity, pregnancy-induced neuroplasticity, and PMADs risk. The resulting dataset will provide a deeply phenotyped longitudinal resource for investigating brain-behavior relationships across the perinatal period. Findings are expected to inform future larger-scale studies aimed at advancing mechanistic understanding of PMADs, improving individualized risk stratification, and supporting development of personalized preventive and neuromodulatory interventions.

neuroscience↗

bioRxiv2026

Development and evaluation of a cost-effective, mid-density SNP array as a sorghum community genotyping resource

The development of accessible and cost-effective genotyping platforms is essential to accelerate genetic gain in crop improvement. To address the U.S. sorghum communitys need for a standardized, mid-density genotyping resource, we developed and validated a targeted single-nucleotide polymorphism (SNP) array using the PlexSeq next-generation sequencing (NGS) platform. The resulting genotyping array includes 2,421 SNPs spanning all ten Sorghum bicolor chromosomes and integrates trait-linked and quality control markers selected by public and private stakeholders. Genotyping 2,726 diverse accessions, including the Sorghum Association Panel (SAP), demonstrated high call rates (>90% for most samples and markers), low missing data, and accurate resolution of population structure consistent with prior whole-genome studies. In comparative genomic prediction analyses, the mid-density array performed equivalently to high-density genotype-by-sequencing (GBS) platforms for key traits such as grain yield and plant height across multi-environment trials. Designed for broad utility in breeding pipelines, the array enables marker-assisted selection, genomic prediction, identity verification, and germplasm quality control. Moreover, its adoption by the USDA National Plant Germplasm System facilitates the curation of genebanks and the management of core collections. This community-driven genotyping platform offers a scalable, reproducible, and customizable tool to support molecular breeding in sorghum and underscores the value of targeted marker systems in resource-optimized crop improvement programs.

plant biology↗

bioRxiv2025

Increased grain weight conferred by GW2 mutations in wheat does not translate into yield gains in multi-year field trials of near-isogenic lines

Multiple studies have identified genes affecting grain morphology, yet their capacity to deliver yield gains under field conditions remains unclear. We performed a multiyear, multilocation factorial evaluation of GRAIN WIDTH2 (TaGW2) mutants in hexaploid wheat using BC4 near-isogenic lines, sowing-density treatments and semi-dwarfing RHT1 backgrounds. Loss-of-function mutations in TaGW2 increased grain size and thousand grain weight (TGW) additively; with the aaBBDD single mutant showing the most stable singlelocus effect, while the aabbdd triple mutant achieved ~20% higher TGW across twelve field trials. However, overall grain yield remained unchanged or slightly reduced, reflecting a compensatory trade-off with grain number. Spike phenotyping of both main and secondary tillers showed comparable increases in TGW and spike yield despite fewer grains per spike, indicating that limited yield gain primarily reflects reduced spike number per unit area rather than decreased spike-level productivity. Effects were stable across sowing densities, whereas interactions with semi-dwarfing alleles were allele-specific: RHT-B1b partially suppressed TGW gains and accentuated yield penalties, whereas RHT-D1b maintained the large-grain phenotype and productivity. Across experiments, the TaGW2-A1D1 double mutant increased TGW (~14%) while maintaining yield stability, identifying it as a promising genotype for breeding. We conclude that TaGW2 is a reliable modifier of grain size but not yield in isolation.

plant biology↗

bioRxiv2025

Deletion of the voltage-gated calcium channel gene, CaV1.3, reduces Purkinje cell dendritic complexity without altering cerebellar-mediated eyeblink conditioning

Genetic variation in CACNA1D, the gene that encodes the pore-forming subunit of the L-type calcium channel CaV1.3, has been associated with increased risk for neuropsychiatric disorders that display abnormalities in cerebellar structures. We sought to clarify if deletion of CaV1.3 in mice would induce abnormalities in cerebellar cortex cytoarchitecture or synapse morphology. Since CaV1.3 is highly expressed in cerebellar molecular layer interneurons (MLIs) and L-type channels appear to regulate GABA release from MLIs, we hypothesized that loss of CaV1.3 would alter GABAergic synapses between MLIs and Purkinje cells (PCs) without altering MLI numbers or PC structure. As expected, we did not observe changes in the numbers of MLIs or PCs. Surprisingly, CaV1.3 KO mice do have decreased complexity of PC dendritic arbors without differences in the number or structure of GABAergic synapses onto PCs. Loss of CaV1.3 was not associated with impaired acquisition of delay eyeblink conditioning. Therefore, our data suggest that CaV1.3 expression is important for PC structure but does not affect other measures of cerebellar cortex morphology or cerebellar function as assessed by delay eyeblink conditioning.

neuroscience↗

bioRxiv2023

16p11.2 Microduplication is Associated with Lobule-Specific Abnormalities in Cerebellar Structure and Function

The 16p11.2 microduplication (16p11.2dp/+) is associated with several neuropsychiatric disorders including schizophrenia, autism spectrum disorder, bipolar disorder, intellectual disability, and attention deficit/hyperactivity disorder (ADHD). Cerebellar abnormalities have been increasingly implicated in these neuropsychiatric disorders, including those conferred by 16p11.2 microduplication. In 16p11.2dp/+ mouse models, the cerebellum is a site of transcriptional dysregulation, and cerebellar microcephaly has been reported in humans with 16p11.2 microduplication. Despite mounting evidence indicating a role for the cerebellum in neuropsychiatric disorders associated with this CNV, cerebellar cellular structure and cerebellar-dependent behavior in mice with 16p11.2 microduplication remain uncharacterized. To address this, we histologically labeled Purkinje cells (PCs) and molecular layer interneurons (MLIs) in a mouse model of 16p11.2 microduplication. We did not find any structural differences in cerebellar lobule IV/V, nor did we observe impairments in gait or motor coordination, behaviors that are associated with lobule IV/V. In contrast, we discovered a significant increase in calbindin/parvalbumin-positive PCs mislocalized to the granule layer of cerebellar lobule VI in 16p11.2dp/+ mice compared to wild-type (WT) littermates. Additionally, we found a significant decrease in parvalbumin-positive MLIs without a decrease in total DAPI-positive cell counts in lobule VI of 16p11.2dp/+ mice compared to WT littermates. Cerebellar lobule VI is associated with delay eyeblink conditioning, and 16p11.2dp/+ mice are impaired in cerebellum-dependent associative learning on this task. Specifically, 16p11.2dp/+ mice showed deficits in both conditioned response (CR) percentage and CR onset latency relative to WT mice. These results suggest that lobule VI-specific alterations to PC localization and MLI parvalbumin expression in 16p11.2dp/+ mice impair both cerebellar learning and adaptive timing of cerebellar-driven, conditioned responses. Thus, we have identified novel structural and functional alterations in the cerebellum that are associated with 16p11.2 microduplication. Importantly, individuals with schizophrenia and ADHD also show CR acquisition deficits in delay eyeblink conditioning. Together, these data suggest that the behavioral impairments in 16p11.2dp/+ mice resemble impairments seen in neuropsychiatric disorders linked to 16p11.2 microduplication in humans. Further investigation of cerebellar cortex neurons in 16p11.2dp/+ mice may provide insights into the pathogenesis of neuropsychiatric disorders linked to this copy number variant.

neuroscience↗

bioRxiv2023

Neuronal and Astrocyte Insulin-like Growth Factor-1 Signaling Differentially Modulates Ischemic Stroke Damage

Ischemic stroke is a leading cause of death and disability, as therapeutic options for mitigating the long-term deficits precipitated by the event remain limited. Acute administration of the neuroendocrine modulator insulin-like growth factor-1 (IGF-1) attenuates ischemic stroke damage in preclinical models, and clinical studies suggest IGF-1 can reduce the risk of stroke and improve overall outcomes. The cellular mechanism by which IGF-1 exerts this protection is poorly defined, as all cells within the neurovascular unit express the IGF-1 receptor. We hypothesize that the functional regulation of both neurons and astrocytes by IGF-1 is critical in minimizing damage in ischemic stroke. To test this, we utilized inducible astrocyte-specific or neuron-specific transgenic mouse models to selectively reduce IGF-1R in the adult mouse brain prior to photothrombotic stroke. Acute changes in blood brain barrier permeability, microglial activation, systemic inflammation, and biochemical composition of the brain were assessed 3 hours following photothrombosis, and significant protection was observed in mice deficient in neuronal and astrocytic IGF-1R. When the extent of tissue damage and sensorimotor dysfunction was assessed for 3 days following stroke, only the neurological deficit score continued to show improvements, and the extent of improvement was enhanced with additional IGF-1 supplementation. Overall, results indicate that neuronal and astrocytic IGF-1 signaling influences stroke damage but IGF-1 signaling within these individual cell types is not required for minimizing tissue damage or behavioral outcome.

neuroscience↗

bioRxiv2022

Genomics and Phenomics Enabled Prebreeding Improved Early-Season Chilling Tolerance in Sorghum

In temperate climates, earlier planting of tropical-origin crops can provide longer growing seasons, reduce water loss, suppress weeds, and escape post-flowering drought stress. However, chilling sensitivity of sorghum, a tropical-origin cereal crop, limits early planting and over 50 years of conventional breeding has been stymied by coinheritance of chilling tolerance (CT) loci with undesirable tannin and dwarfing alleles. In this study, phenomics and genomics-enabled approaches were used for prebreeding of sorghum early-season CT. Uncrewed aircraft systems (UAS) high-throughput phenotyping platform tested for improving scalability showed moderate correlation between manual and UAS phenotyping. UAS normalized difference vegetation index (NDVI) values from the chilling nested association mapping population detected CT QTL that colocialized with manual phenotyping CT QTL. Two of the four first-generation KASP molecular markers, generated using the peak QTL SNPs, failed to function in an independent breeding program as the CT allele was common in diverse breeding lines. Population genomic FST analysis identified SNP CT alleles that were globally rare but common to the CT donors. Second-generation markers, generated using population genomics, were successful in tracking the donor CT allele in diverse breeding lines from two independent sorghum breeding programs. Marker-assisted breeding, effective in introgressing CT allele from Chinese sorghums into chilling-sensitive US elite sorghums, improved early-planted seedling performance ratings in lines with CT alleles by up to 13-24% compared to the negative control under natural chilling stress. These findings directly demonstrate the effectiveness of high-throughput phenotyping and population genomics in molecular breeding of complex adaptive traits.

genetics↗

bioRxiv2022

A neural substrate of sex-dependent modulation of motivation by value

While there is emerging evidence of sex differences in decision-making behavior, the neural substrates that underlie such differences remain largely unknown. Here, we demonstrate that in mice performing a value-based decision-making task, while choices are similar between the sexes, motivation to engage in the task is modulated by action value in females more strongly than in males. Inhibition of activity in anterior cingulate cortex (ACC) neurons that project to the dorsomedial striatum (DMS) disrupts this relationship between value and motivation preferentially in females, without affecting choice in either sex. In line with these effects, in females compared to males, ACC-DMS neurons have stronger representations of negative outcomes, and more neurons are active when the value of the chosen option is low. In contrast, the representation of each choice is similar between the sexes. Thus, we identify a neural substrate that contributes to sex-specific modulation of motivation by value.

neuroscience↗

bioRxiv2022

This is GlycoQL

MotivationWe have previously designed and implemented a tree-based ontology to represent glycan structures with the aim of searching these structures with a glyco-driven syntax. This resulted in creating the GlySTreeM knowledge-base as a linchpin of the matching procedure and we now introduce a query language, called GlycoQL, for the actual implementation of a glycan structure search. ResultsThe methodology is described and illustrated with a use-case focused on SARS-CoV-2 spike protein glycosylation. We show how to enhance site annotation with federated queries involving UniProt and GlyConnect, our glycoprotein database. Availabilitycurrently only available for reviewers at: https://beta.glyconnect.expasy.org/glycoql/ Contactcatherine.hayes@unige.ch; frederique.lisacek@sib.swiss Supplementary informationSupplementary data are available at https://glyconnect.expasy.org/glystreem/wiki.

bioinformatics↗

bioRxiv2021

Multi-site enzymes as a mechanism for bistability in reaction networks

Here, we focus on a common class of enzymes that have multiple substrate-binding sites (multi-site enzymes), and analyse their capacity to generate bistable dynamics in the reaction systems that they are embedded in. Using mathematical techniques, we show that the inherent binding and catalysis reactions arising from multiple substrate-enzyme complexes creates a potential for bistable dynamics in a reaction system. We construct a generic model of an enzyme with n substrate binding sites and derive an analytical solution for the steady state concentration of all enzyme-substrate complexes. By studying these expressions, we obtain a mechanistic understanding for bistability and derive parameter combinations that guarantee bistability and show how changing specific enzyme kinetic parameters and enzyme levels can lead to bistability in reaction systems involving mjulti-site enzymes. Thus, the presented findings provide a biochemical and mathematical basis for predicting and engineering bistability in multi-site enzymes.

systems biology↗

bioRxiv2021

Pan-genome Analysis in Sorghum Highlights the Extent of Genomic Variation and Sugarcane Aphid Resistance Genes

Sorghum bicolor, one of the most important grass crops around the world, harbors a high degree of genetic diversity. We constructed chromosome-level genome assemblies for two important sorghum inbred lines, Tx2783 and RTx436. The final high-quality reference assemblies consist of 19 and 18 scaffolds, respectively, with contig N50 values of 25.6 and 20.3 Mb. Genes were annotated using evidence-based and de novo gene predictors, and RAMPAGE data demonstrate that transcription start sites were effectively captured. Together with other public sorghum genomes, BTx623, RTx430, and Rio, extensive structural variations (SVs) of various sizes were characterized using Tx2783 as a reference. Genome-wide scanning for disease resistance (R) genes revealed high levels of diversity among these five sorghum accessions. To characterize sugarcane aphid (SCA) resistance in Tx2783, we mapped the resistance region on chromosome 6 using a recombinant inbred line (RIL) population and found a SV of 191 kb containing a cluster of R genes in Tx2783. Using Tx2783 as a backbone, along with the SVs, we constructed a pan-genome to support alignment of resequencing data from 62 sorghum accessions, and then identified core and dispensable genes using this population. This study provides the first overview of the extent of genomic structural variations and R genes in the sorghum population, and reveals potential targets for breeding of SCA resistance.

genomics↗

bioRxiv2020

Distinct signals in medial and lateral VTA dopamine neurons modulate fear extinction at different times

Dopamine (DA) neurons are known to encode reward prediction error (RPE), in addition to other signals, such as salience. While RPE is known to support learning, the role of salience in supporting learning remains less clear. To address this, we recorded and manipulated VTA DA neurons in mice during fear extinction, a behavior we observed to generate spatially segregated RPE and salience signals. We applied deep learning to classify mouse freezing behavior, eliminating the need for human scoring. Our fiber photometry recordings showed that DA neurons in medial and lateral VTA have distinct activity profiles during fear extinction: medial VTA activity more closely reflected RPE, while lateral VTA activity more closely reflected a salience-like signal. Optogenetic inhibition of DA neurons in either region slowed fear extinction, with the relevant time period for inhibition differing across regions. Our results indicate that salience-like signals can have similar downstream consequences to RPE-like signals, although with different temporal dependencies.

neuroscience↗

bioRxiv2019

Fertility of Pedicellate Spikelets in Sorghum is Controlled by a Jasmonic Acid Regulatory Module

As in other cereal crops, the panicles of sorghum (Sorghum bicolor (L.) Moench) comprise two types of floral spikelets (grass flowers). Only sessile spikelets (SSs) are capable of producing viable grains, whereas pedicellate spikelets (PSs) cease development after initiation and eventually abort. Consequently, grain number per panicle (GNP) is lower than the total number of flowers produced per panicle. The mechanism underlying this differential fertility is not well understood. To investigate this issue, we isolated a series of EMS-induced multiseeded (msd) mutants that result in full spikelet fertility, effectively doubling GNP. Previously, we showed that MSD1 is a TCP (Teosinte branched/Cycloidea/PCF) transcription factor that regulates jasmonic acid (JA) biosynthesis, and ultimately floral sex organ development. Here, we show that MSD2 encodes a lipoxygenase (LOX) that catalyzes the first committed step of JA biosynthesis. Further, we demonstrate that MSD1 binds to the promoters of MSD2 and other JA pathway genes. Together, these results show that a JA-induced module regulates sorghum panicle development and spikelet fertility. The findings advance our understanding of inflorescence development and could lead to new strategies for increasing GNP and grain yield in sorghum and other cereal crops.\n\nSignificanceThrough a single base pair mutation, grain number can be increased by ~200% in the globally important crop Sorghum bicolor. This mutation affects the expression of an enzyme, MSD2, that catalyzes the jasmonic acid pathway in developing floral meristems. The global gene expression profile in this enzymatic mutant is similar to that of a transcription factor mutant, msd1, indicating that disturbing any component of this regulatory module disrupts a positive feedback loop that occurs normally due to regular developmental perception of jasmonic acid. Additionally, the MSD1 transcription factor is able to regulate MSD2 in addition to other jasmonic acid pathway genes, suggesting that it is a primary transcriptional regulator of this hormone signaling pathway in floral meristems.

plant biology↗

bioRxiv2019

Genetic Architecture of Chilling Tolerance in Sorghum Dissected with a Nested Association Mapping Population

Dissecting the genetic architecture of stress tolerance in crops is critical to understand and improve adaptation. In temperate climates, early planting of chilling-tolerant varieties could provide longer growing seasons and drought escape, but chilling tolerance (<15{degrees}) is generally lacking in tropical-origin crops. Here we developed a nested association mapping (NAM) population to dissect the genetic architecture of early-season chilling tolerance in the tropical-origin cereal sorghum (Sorghum bicolor [L.] Moench). The NAM resource, developed from reference line BTx623 and three chilling-tolerant Chinese lines, is comprised of 771 recombinant inbred lines genotyped by sequencing at 43,320 single nucleotide polymorphisms. We phenotyped the NAM population for emergence, seedling vigor, and agronomic traits (>75,000 data points from [~]16,000 plots) in multi-environment field trials in Kansas under natural chilling stress (sown 30-45 days early) and normal growing conditions. Joint linkage mapping with early-planted field phenotypes revealed an oligogenic architecture, with 5-10 chilling tolerance loci explaining 20-41% of variation. Surprisingly, several of the major chilling tolerance loci co-localize precisely with the classical grain tannin (Tan1 and Tan2) and dwarfing genes (Dw1 and Dw3) that were under strong directional selection in the US during the 20th century. These findings suggest that chilling sensitivity was inadvertently selected due to coinheritance with desired nontannin and dwarfing alleles. The characterization of genetic architecture with NAM reveals why past chilling tolerance breeding was stymied and provides a path for genomics-enabled breeding of chilling tolerance.\n\nArticle SummaryChilling sensitivity limits productivity of tropical-origin crops in temperate climates, and remains poorly understood at a genetic level. We developed a nested association mapping resource in sorghum, a tropical-origin cereal, to understand the genetic architecture of chilling tolerance. Linkage mapping of growth traits from early-planted field trials revealed several major chilling tolerance loci, including some colocalized with genes that were selected in the origin of US grain sorghum. These findings suggest chilling sensitivity was inadvertently selected during 20th century breeding, but can be bypassed using a better understanding of the underlying genetic architecture.\n\nDisclaimerMention of a trademark, warranty, proprietary product, or vendor does not constitute a guarantee by the USDA and does not imply approval or recommendation of the product to the exclusion of others that may be suitable. USDA is an equal opportunity provider and employer.

genetics↗

bioRxiv2018

The effects of training population design on genomic prediction accuracy in wheat

Genomic selection offers several routes for increasing genetic gain or efficiency of plant breeding programs. In various species of livestock there is empirical evidence of increased rates of genetic gain from the use of genomic selection to target different aspects of the breeders equation. Accurate predictions of genomic breeding value are central to this and the design of training sets is in turn central to achieving sufficient levels of accuracy. In summary, small numbers of close relatives and very large numbers of distant relatives are expected to enable accurate predictions.\n\nTo quantify the effect of some of the properties of training sets on the accuracy of genomic selection in crops we performed an extensive field-based winter wheat trial. In summary, this trial involved the construction of 44 F2:4 bi- and triparental populations, from which 2992 lines were grown on four field locations and yield was measured. For each line, genotype data were generated for 25,000 segregating single nucleotide polymorphism markers. The overall heritability of yield was estimated to 0.65, and estimates within individual families ranged between 0.10 and 0.85. Within cross genomic prediction accuracies of yield BLUEs were 0.125 - 0.127 using two different cross-validation approaches, and generally increased with training set size. Using related crosses in training and validation sets generally resulted in higher prediction accuracies than using unrelated crosses. The results of this study emphasize the importance of the training set design in relation to the genetic material to which the resulting prediction model is to be applied.

genetics↗

bioRxiv2018

A molecular inversion probe and sequencing-based microsatellite instability assay for high throughput cancer diagnostics and Lynch syndrome screening

BackgroundClinical guidelines recommend microsatellite instability (MSI) and BRAF V600E testing of all colorectal cancers (CRCs) to screen for Lynch syndrome (LS), a hereditary predisposition to cancer. MSI is also associated with response to immunotherapy. However, uptake of MSI testing is poor and current assays are not suitable for high throughput diagnostics.\n\nWe aimed to develop a cheap and scalable sequencing assay for MSI classification, which is robust to variables in clinical samples and simultaneously tests for BRAF V600E to streamline the LS screening pipeline.\n\nMethods24 short (7-12bp) microsatellites and the BRAF V600E locus were amplified in multiplex using single molecule molecular inversion probes (smMIPs) and sequenced using the Illumina MiSeq platform. Reads were aligned to reference genome hg19. An MSI classifier was trained from 98 CRCs and validated in 99 independent CRCs collected in pathology laboratories in Edinburgh, Spain and Newcastle.\n\nResultsThe smMIP-based MSI assay has 100% accuracy for MSI status relative to MSI Analysis System (Promega). MSI classification is reproducible (100% concordance) and is robust to sample variables, detecting less than 5% MSI-high content in template DNA and giving reliable classification from sequencing only 75 DNA molecules per marker. BRAF V600E was detected with mutant allele frequencies down to 1.7%.\n\nConclusionsOur short microsatellite, smMIP-based, MSI assay provides a cheap and fully automatable assessment of MSI status and BRAF mutation. It is readily scalable to high throughput cancer diagnostics, and is suitable both as a companion diagnostic for immunotherapy and for streamlined LS screening.

cancer biology↗