Biology subjects

Evers, B.

Publications and source records attributed to Evers, B..

8 recordsLinked to original sources

bioRxiv2024

Amyloid fibril polymorphism in the heart of an ATTR amyloidosis patient with polyneuropathy attributed to the V122Δ variant

ATTR amyloidosis is a phenotypically heterogeneous disease characterized by the pathological deposition of transthyretin in the form of amyloid fibrils into various organs. ATTR amyloidosis may result from mutations in variant (ATTRv) amyloidosis, or aging in wild-type (ATTRwt) amyloidosis. ATTRwt generally manifests as cardiomyopathy, whereas ATTRv may present as polyneuropathy, cardiomyopathy, or mixed, in combination with many other symptoms deriving from multisystem organ involvement. Over 220 different mutational variants of transthyretin have been identified, many of them being linked to specific disease symptoms. Yet, the role of these mutations in explaining differential disease manifestations remains unclear. Using cryo-electron microscopy, here we structurally characterized fibrils from the heart and the liver of an ATTRv patient carrying the V122{Delta} mutation, which is predominantly associated with polyneuropathy. Our results show that these fibrils are polymorphic, presenting as both single and double filaments. Our study alludes to a structural connection contributing to phenotypic variation in ATTR amyloidosis, as polymorphism in ATTR fibrils may manifest in patients with predominantly polyneuropathic phenotypes. SignificanceATTR amyloidosis is a systemic, clinically diverse disease that results in organ failure due to the accumulation of transthyretin amyloid fibrils. ATTR patients present with varied symptoms, yet the root of this phenotypic heterogeneity remains unclear. Previous studies suggest an association between phenotype and fibril structure polymorphism. Here we describe the cryo-electron microscopy structure of variant transthyretin amyloid fibrils associated with a predominantly polyneuropathy phenotype. We have found polymorphism within these fibrils, a phenomenon we have thus far only observed in polyneuropathic associated transthyretin mutations. Our results signify an association between fibril structure and phenotype in ATTR amyloidosis.

molecular biology↗

bioRxiv2023

A fluorescence-based sensor screen identifies MED12 as a potential microsatellite instability regulator in colon cancer

Inactivation of the DNA mismatch repair (MMR) system, due to (epi)genetic alterations of MMR genes, increases the frequency of mutations across the genome, creating a phenotype known as microsatellite instability (MSI). Cancers with this phenotype have been associated with a better prognosis for some time, but only since recently it has been recognised as a predictive biomarker of response to immunotherapy. Because MSI tumours accumulate more insertions and/or deletions in coding regions of the genome containing microsatellites, there is an increase in neoantigens resulting from reading frame shifts, which promotes immunogenicity. To investigate if additional genes exist that can cause an MSI phenotype, we developed a fluorescence-based sensor to identify genes whose inactivation increases the rate of frameshift mutations on microsatellite sequences in cancer cells. Using genome-scale CRISPR/Cas9 screens, we identified MED12 as a potential new regulator of microsatellite instability. Consistent with this, we found that MED12 mutant colon cancers that lack mutations in the known MMR genes are more likely to be of the MSI phenotype.

cancer biology↗

bioRxiv2022

Applied phenomics and genomics for improving barley yellow dwarf resistance in winter wheat

Barley yellow dwarf (BYD) is one of the major viral diseases of cereals. Phenotyping BYD in wheat is extremely challenging due to similarities to other biotic and abiotic stresses. Breeding for resistance is additionally challenging as the wheat primary germplasm pool lacks genetic resistance, with most of the few resistance genes named to date originating from a wild relative species. The objectives of this study were to, i) evaluate the use of high-throughput phenotyping (HTP) from unmanned aerial systems to improve BYD assessment and selection, ii) identify genomic regions associated with BYD resistance, and iii) evaluate genomic prediction models ability to predict BYD resistance. Up to 107 wheat lines were phenotyped during each of five field seasons under both insecticide treated and untreated plots. Across all seasons, BYD severity was lower with the insecticide treatment and plant height (PTHTM) and grain yield (GY) showed increased values relative to untreated entries. Only 9.2% of the lines were positive for the presence of the translocated segment carrying resistance gene Bdv2 on chromosome 7DL. Despite the low frequency, this region was identified through association mapping. Furthermore, we mapped a potentially novel genomic region for resistance on chromosome 5AS. Given the variable heritability of the trait (0.211 - 0.806), we obtained relatively good predictive ability for BYD severity ranging between 0.06 - 0.26. Including Bdv2 on the predictive model had a large effect for predicting BYD but almost no effect for PTHTM and GY. This study was the first attempt to characterize BYD using field-HTP and apply GS to predict the disease severity. These methods have the potential to improve BYD characterization and identifying new sources of resistance will be crucial for delivering BYD resistant germplasm.

genetics↗

bioRxiv2021

Genetic Characterization and Curation of Diploid A-Genome Wheat Species

The A-genome diploid wheats represent the earliest domesticated and cultivated wheat species in the Fertile Crescent and the donor of the wheat A sub-genome. The A-genome species encompass the cultivated einkorn (Triticum. monococcum L. subsp. monococcum), wild einkorn (T. monococcum L. subsp. aegilopoides (Link) Thell.) and T. urartu. We evaluated the collection of 930 accessions in the Wheat Genetics Resource Center (WGRC), using genotyping-by-sequencing (GBS) and identified 13,089 curated SNPs. Genomic analysis detected misclassified and duplicated accessions with most duplicates originated from the same or a nearby locations. About 56% (n = 520) of the WGRC A-genome species collections were duplicates supporting the need for genomic characterization for effective curation and maintenance of these collections. Population structure analysis confirmed the morphology-based classifications of the accessions and reflected the species geographic distributions. We also showed that the T. urartu as the closest A-genome diploid to wheat through phylogenetic analysis. Population analysis within the wild einkorn group showed three genetically distinct clusters, which corresponded with wild einkorn races , {beta}, and {gamma} described previously. The T. monococcum genome-wide FST scan identified candidate genomic regions harboring domestication selection signature (Btr1) on the short arm of chromosome 3Am at ~ 70 Mb. We established A-genome core set (79 accessions) based on allelic diversity, geographical distribution, and available phenotypic data. The individual species core set maintained at least 80% of allelic variants in the A-genome collection and constitute a valuable genetic resource to improve wheat and domesticated einkorn in breeding programs. One-sentence summaryGenotyping of gene bank collections of diploid A-genome relatives of wheat uncovered relatively higher genetic diversity and unique evolutionary relationships which gives insight to the effective use of these germplasm for wheat improvement.

genetics↗

bioRxiv2021

Elongation factor ELOF1 drives transcription-coupled repair and prevents genome instability

Correct transcription is crucial for life. However, DNA damage severely impedes elongating RNA Polymerase II (Pol II), causing transcription inhibition and transcription-replication conflicts. Cells are equipped with intricate mechanisms to counteract the severe consequence of these transcription-blocking lesions (TBLs). However, the exact mechanism and factors involved remain largely unknown. Here, using a genome-wide CRISPR/cas9 screen, we identified elongation factor ELOF1 as an important new factor in the transcription stress response upon DNA damage. We show that ELOF1 has an evolutionary conserved role in Transcription-Coupled Nucleotide Excision Repair (TC-NER), where it promotes recruitment of the TC-NER factors UVSSA and TFIIH to efficiently repair TBLs and resume transcription. Additionally, ELOF1 modulates transcription to protect cells from transcription-mediated replication stress, thereby preserving genome stability. Thus, ELOF1 protects the transcription machinery from DNA damage by two distinct mechanisms.

cell biology↗

bioRxiv2020

Breeding Program Optimization for Genomic Selection in Winter Wheat

Developing methodologies in the fields of phenomics and genomic prediction have the potential to increase the production of crop species by accelerating germplasm improvement. The integration of these technologies into germplasm improvement and breeding programs requires evidence that there will be a direct economic benefit to the program. We determined a basic set of parameters, such as prediction accuracy greater than 0.3, the ability to genotype over 7 lines for the cost of one phenotypic evaluation, and heritability levels below 0.4, at which the use of genomic selection would be of economic benefit in terms of genetic gain and operational costs to the Kansas State University (KSU) winter wheat breeding program. The breeding program was then examined to determine whether the parameters benefitting genomic selection were observed or achievable in a practical sense. Our results show that the KSU winter wheat breeding program is at a decision point with regards to their primary means of selection. A few operational changes to increase prediction accuracy would place the program in the parameter space where genomic selection is expected to outpace the current phenotypic selection methodology at a parity of the operation cost and would be of greatest benefit to the program.

genomics↗

bioRxiv2019

High-throughput phenotyping with deep learning gives insight into the genetic architecture of flowering time in wheat

BackgroundPrecise measurement of plant traits with precision and speed on large populations has emerged as a critical bottleneck in connecting genotype to phenotype in genetics and breeding. This bottleneck limits advancements in understanding plant genomes and the development of improved, high-yielding crop varieties. ResultsHere we demonstrate the application of deep learning on proximal imaging from a mobile field vehicle to directly score plant morphology and developmental stages in wheat under field conditions. We developed and trained a convolutional neural network with image datasets labeled from expert visual scores and used this breeder-trained network to directly score wheat morphology and developmental stages. For both morphological (awned) and phenological (flowering time) traits, we demonstrate high heritability and extremely high accuracy against the ground-truth values from visual scoring. Using the traits scored by the network, we tested genotype-to-phenotype association using the deep learning phenotypes and uncovered novel epistatic interactions for flowering time. Enabled by the time-series high-throughput phenotyping, we describe a new phenotype as the rate of flowering and show heritable genetic control. ConclusionsWe demonstrated a field-based high-throughput phenotyping approach using deep learning that can directly score morphological and developmental phenotypes in genetic populations. Most powerfully, the deep learning approach presented here gives a conceptual advancement in high-throughput plant phenotyping as it can potentially score any trait in any plant species through leveraging expert knowledge from breeders, geneticist, pathologists and physiologists.

genetics↗

bioRxiv2018

phospho-ERK is a response biomarker to a combination of sorafenib and MEK inhibition in liver cancer

Treatment of liver cancer remains challenging, due to a paucity of drugs that target critical dependencies. Sorafenib is a multikinase inhibitor that is approved as the standard therapy for advanced hepatocellular carcinoma patients, but it can only provide limited survival benefit for patients. To investigate the cause of this limited therapeutic effect, we performed a CRISPR-Cas9 based synthetic lethality screen to search for kinases whose knockout synergize with sorafenib. We find that suppression of ERK2 sensitizes several liver cancer cell lines to sorafenib. Drugs inhibiting the MEK or ERK kinases reverse unresponsiveness to sorafenib in vitro and in vivo in a subset of liver cancer cell lines characterized by high levels of active phospho-ERK levels through synergistic inhibition of ERK kinase activity. Our data provide a combination strategy for treating liver cancer and suggest that tumors with activation of p-ERK, which is seen in some 30% of liver cancers, are most likely to benefit from such combinatorial treatment.

cancer biology↗