A high tumour mutational burden (hypermutation) is observed in some gliomas
; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly ...understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.
Olive (Olea europaea ssp. europaea) is the most important oil fruit crop in temperate areas, but the origin of the cultivated olive remains unclear. The existence of one or several domestication ...events in the Mediterranean Basin (MB) is still debated. We analyzed a dataset of 387 cultivated and wild accessions that were genotyped at 25 simple‐sequence repeat (SSR) loci. The sample represented genetic diversity at the geographic extremes of the MB. We inferred relationships among samples and also applied approximate Bayesian computation to estimate the most probable demographic model of our samples. Cultivated olives clustered into three different gene pools (Q1, Q2 and Q3), corresponding loosely to the west, central and eastern MB, respectively. Q1 consisted primarily of accessions from southern Spain, retained the fingerprint of a genetic bottleneck, and was closely related to accessions from the eastern MB. Q2 showed signs of recent admixture with wild olives and may derive from a local domestication event in the central MB. Overall our results suggest that admixture shaped olive germplasm and perhaps also local domestication events.
Short tandem repeat (STR) is a component of the human genome, the number of repeats of STR is prone to change during DNA replication, and when it exceeds a certain threshold, it will lead to the ...occurrence of diseases, most of which involve the nervous system. With the rapid development and wide application of the third generation long read long sequencing technology, more and more neuromuscular diseases have been confirmed to be related to STR variation. This article reviews the clinical and mechanism research progress on STR‑related neuromuscular diseases, so as to provide guidance for clinical research.
Microsatellites are a widely-used marker system in plant genetics and forensics. The development of reliable microsatellite markers from resequencing data is challenging.
We extended MISA, a ...computational tool assisting the development of microsatellite markers, and reimplemented it as a web-based application. We improved compound microsatellite detection and added the possibility to display and export MISA results in GFF3 format for downstream analysis.
MISA-web can be accessed under http://misaweb.ipk-gatersleben.de/. The website provides tutorials, usage note as well as download links to the source code.
scholz@ipk-gatersleben.de.
Marked phenotypic variation characterizes isolates of Toxoplasma gondii, a ubiquitous zoonotic parasite that serves as an important experimental model for studying apicomplexan parasites. Progress in ...identifying the heritable basis for clinically and epidemiologically significant differences requires a robust system for describing and interpreting evolutionary subdivisions in this prevalent pathogen. To develop such a system, we have examined more than 950 isolates collected from around the world and genotyped them using three independent sets of polymorphic DNA markers, sampling 30 loci distributed across all nuclear chromosomes as well as the plastid genome. Our studies reveal a biphasic pattern consisting of regions in the Northern Hemisphere where a few, highly clonal and abundant lineages predominate; elsewhere, and especially in portions of South America are characterized by a diverse assemblage of less common genotypes that show greater evidence of recombination. Clustering methods were used to organize the marked genetic diversity of 138 unique genotypes into 15 haplogroups that collectively define six major clades. Analysis of gene flow indicates that a small number of ancestral lineages gave rise to the existing diversity through a process of limited admixture. Identification of reference strains for these major groups should facilitate future studies on comparative genomics and identification of genes that control important biological phenotypes including pathogenesis and transmission.
Genetic data often exhibit patterns broadly consistent with 'isolation by distance'-a phenomenon where genetic similarity decays with geographic distance. In a heterogeneous habitat, this may occur ...more quickly in some regions than in others: for example, barriers to gene flow can accelerate differentiation between neighboring groups. We use the concept of 'effective migration' to model the relationship between genetics and geography. In this paradigm, effective migration is low in regions where genetic similarity decays quickly. We present a method to visualize variation in effective migration across a habitat from geographically indexed genetic data. Our approach uses a population genetic model to relate effective migration rates to expected genetic dissimilarities. We illustrate its potential and limitations using simulations and data from elephant, human and Arabidopsis thaliana populations. The resulting visualizations highlight important spatial features of population structure that are difficult to discern using existing methods for summarizing genetic variation.
Inheritance of nuclear microsatellite markers (nSSR) has been proved to be a powerful tool to verify or uncover the parentage of grapevine cultivars. The aim of the present study was to undertake an ...extended parentage analysis using a large sample of Vitis vinifera cultivars held in the INRA “Domaine de Vassal” Grape Germplasm Repository (France). A dataset of 2,344 unique genotypes (i.e. cultivars without synonyms, clones or mutants) identified using 20 nSSR was analysed with FAMOZ software. Parentages showing a logarithm of odds score higher than 18 were validated in relation to the historical data available. The analysis first revealed the full parentage of 828 cultivars resulting in: (1) 315 original full parentages uncovered for traditional cultivars, (2) 100 full parentages confirming results established with molecular markers in prior papers and 32 full parentages that invalidated prior results, (3) 255 full parentages confirming pedigrees as disclosed by the breeders and (4) 126 full parentages that invalidated breeders’ data. Second, incomplete parentages were determined in 1,087 cultivars due to the absence of complementary parents in our cultivar sample. Last, a group of 276 genotypes showed no direct relationship with any other cultivar in the collection. Compiling these results from the largest set of parentage data published so far both enlarges and clarifies our knowledge of the genetic constitution of cultivated V. vinifera germplasm. It also allows the identification of the main genitors involved in varietal assortment evolution and grapevine breeding.
Pear (Pyrus spp) is an important fruit crop, grown in all temperate regions of the world, with global production ranked after grape and apples among deciduous tree crops. A high-density linkage map ...is a valuable tool for fine mapping quantitative trait loci (QTL) and map-based gene cloning. In this study, we firstly constructed a high-density linkage map of pear using SNPs integrated with SSRs, developed by the rapid and robust technology of restriction-associated DNA sequencing (RADseq). The linkage map consists of 3143 SNP markers and 98 SSRs, 3241 markers in total, spanning 2243.4 cM, with an average marker distance of 0.70 cM. Anchoring SSRs were able to anchor seventeen linkage groups to their corresponding chromosomes. Based on this high-density integrated pear linkage map and two years of fruit phenotyping, a total of 32 potential QTLs for 11 traits, including length of pedicel (LFP), single fruit weight (SFW), soluble solid content (SSC), transverse diameter (TD), vertical diameter (VD), calyx status (CS), flesh colour (FC), juice content (JC), number of seeds (NS), skin colour (SC), and skin smooth (SS), were identified and positioned on the genetic map. Among them, some important fruit-related traits have for the first time been identified, such as calyx status, length of pedicel, and flesh colour, and reliable localization of QTLs were verified repeatable. This high-density linkage map of pear is a worthy reference for mapping important fruit traits, QTL identification, and comparison and combination of different genetic maps.
A highly saturated pear genetic map was constructed using over 3000 SNP markers developed by RADseq integrated with anchored SSR markers. The reliable QTLs of several fruit traits were also identified.
Crustacea, the subphylum of Arthropoda which dominates the aquatic environment, is of major importance in ecology and fisheries. Here we report the genome sequence of the Pacific white shrimp ...Litopenaeus vannamei, covering ~1.66 Gb (scaffold N50 605.56 Kb) with 25,596 protein-coding genes and a high proportion of simple sequence repeats (>23.93%). The expansion of genes related to vision and locomotion is probably central to its benthic adaptation. Frequent molting of the shrimp may be explained by an intensified ecdysone signal pathway through gene expansion and positive selection. As an important aquaculture organism, L. vannamei has been subjected to high selection pressure during the past 30 years of breeding, and this has had a considerable impact on its genome. Decoding the L. vannamei genome not only provides an insight into the genetic underpinnings of specific biological processes, but also provides valuable information for enhancing crustacean aquaculture.
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