| 1. |
- Abalde, Samuel, et al.
(författare)
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The draft genome of the microscopic Nemertoderma westbladi sheds light on the evolution of Acoelomorpha genomes
- 2023
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Ingår i: Frontiers in Genetics. - : Frontiers Media S.A.. - 1664-8021. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: Xenacoelomorpha is a marine clade of microscopic worms that is an important model system for understanding the evolution of key bilaterian novelties, such as the excretory system. Nevertheless, Xenacoelomorpha genomics has been restricted to a few species that either can be cultured in the lab or are centimetres long. Thus far, no genomes are available for Nemertodermatida, one of the group’s main clades and whose origin has been dated more than 400 million years ago.Methods: DNA was extracted from a single specimen and sequenced with HiFi following the PacBio Ultra-Low DNA Input protocol. After genome assembly, decontamination, and annotation, the genome quality was benchmarked using two acoel genomes and one Illumina genome as reference. The gene content of three cnidarians, three acoelomorphs, four deuterostomes, and eight protostomes was clustered in orthogroups to make inferences of gene content evolution. Finally, we focused on the genes related to the ultrafiltration excretory system to compare patterns of presence/absence and gene architecture among these clades.Results: We present the first nemertodermatid genome sequenced from a single specimen of Nemertoderma westbladi. Although genome contiguity remains challenging (N50: 60 kb), it is very complete (BUSCO: 80.2%, Metazoa; 88.6%, Eukaryota) and the quality of the annotation allows fine-detail analyses of genome evolution. Acoelomorph genomes seem to be relatively conserved in terms of the percentage of repeats, number of genes, number of exons per gene and intron size. In addition, a high fraction of genes present in both protostomes and deuterostomes are absent in Acoelomorpha. Interestingly, we show that all genes related to the excretory system are present in Xenacoelomorpha except Osr, a key element in the development of these organs and whose acquisition seems to be interconnected with the origin of the specialised excretory system.Conclusion: Overall, these analyses highlight the potential of the Ultra-Low Input DNA protocol and HiFi to generate high-quality genomes from single animals, even for relatively large genomes, making it a feasible option for sequencing challenging taxa, which will be an exciting resource for comparative genomics analyses.
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| 2. |
- Abebe, Admas Alemu, et al.
(författare)
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Genome-Wide Association Analysis and Genomic Prediction for Adult-Plant Resistance to Septoria Tritici Blotch and Powdery Mildew in Winter Wheat
- 2021
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Ingår i: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Septoria tritici blotch (STB) caused by the fungal pathogen Zymoseptoria tritici and powdery mildew (PM) caused by Blumeria graminis f.sp tritici (Bgt) are among the forefront foliar diseases of wheat that lead to a significant loss of grain yield and quality. Resistance breeding aimed at developing varieties with inherent resistance to STB and PM diseases has been the most sustainable and environment-friendly approach. In this study, 175 winter wheat landraces and historical cultivars originated from the Nordic region were evaluated for adult-plant resistance (APR) to STB and PM in Denmark, Estonia, Lithuania, and Sweden. Genome-wide association study (GWAS) and genomic prediction (GP) were performed based on the adult-plant response to STB and PM in field conditions using 7,401 single-nucleotide polymorphism (SNP) markers generated by 20K SNP chip. Genotype-by-environment interaction was significant for both disease scores. GWAS detected stable and environment-specific quantitative trait locis (QTLs) on chromosomes 1A, 1B, 1D, 2B, 3B, 4A, 5A, 6A, and 6B for STB and 2A, 2D, 3A, 4B, 5A, 6B, 7A, and 7B for PM adult-plant disease resistance. GP accuracy was improved when assisted with QTL from GWAS as a fixed effect. The GWAS-assisted GP accuracy ranged within 0.53-0.75 and 0.36-0.83 for STB and PM, respectively, across the tested environments. This study highlights that landraces and historical cultivars are a valuable source of APR to STB and PM. Such germplasm could be used to identify and introgress novel resistance genes to modern breeding lines.
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| 3. |
- Ahsan, Muhammad, et al.
(författare)
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Identification of candidate genes and mutations in QTL regions for chicken growth using bioinformatic analysis of NGS and SNP-chip data.
- 2013
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Ingår i: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Mapping of chromosomal regions harboring genetic polymorphisms that regulate complex traits is usually followed by a search for the causative mutations underlying the observed effects. This is often a challenging task even after fine mapping, as millions of base pairs including many genes will typically need to be investigated. Thus to trace the causative mutation(s) there is a great need for efficient bioinformatic strategies. Here, we searched for genes and mutations regulating growth in the Virginia chicken lines - an experimental population comprising two lines that have been divergently selected for body weight at 56 days for more than 50 generations. Several quantitative trait loci (QTL) have been mapped in an F2 intercross between the lines, and the regions have subsequently been replicated and fine mapped using an Advanced Intercross Line. We have further analyzed the QTL regions where the largest genetic divergence between the High-Weight selected (HWS) and Low-Weight selected (LWS) lines was observed. Such regions, covering about 37% of the actual QTL regions, were identified by comparing the allele frequencies of the HWS and LWS lines using both individual 60K SNP chip genotyping of birds and analysis of read proportions from genome resequencing of DNA pools. Based on a combination of criteria including significance of the QTL, allele frequency difference of identified mutations between the selected lines, gene information on relevance for growth, and the predicted functional effects of identified mutations we propose here a subset of candidate mutations of highest priority for further evaluation in functional studies. The candidate mutations were identified within the GCG, IGFBP2, GRB14, CRIM1, FGF16, VEGFR-2, ALG11, EDN1, SNX6, and BIRC7 genes. We believe that the proposed method of combining different types of genomic information increases the probability that the genes underlying the observed QTL effects are represented among the candidate mutations identified.
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| 4. |
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| 5. |
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| 6. |
- Aleshin, VA, et al.
(författare)
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Interplay Between Thiamine and p53/p21 Axes Affects Antiproliferative Action of Cisplatin in Lung Adenocarcinoma Cells by Changing Metabolism of 2-Oxoglutarate/Glutamate
- 2021
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Ingår i: Frontiers in genetics. - : Frontiers Media SA. - 1664-8021. ; 12, s. 658446-
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Tidskriftsartikel (refereegranskat)abstract
- Thiamine (vitamin B1) is often deficient in oncopatients, particularly those undergoing chemotherapy. However, interaction between the thiamine deficiency and anticancer action of drugs has not been characterized. A major natural thiamine derivative, thiamine diphosphate (ThDP), is a coenzyme of central metabolism, also known to affect transcriptional activity of the master metabolic regulator and genome guardian p53. A direct transcriptional target of p53, p21, regulates cell cycle dynamics and DNA damage response. Our work focuses on dependence of the action of the DNA damaging anticancer drug cisplatin on metabolic regulation through p53/p21 axes and cellular thiamine status in human lung adenocarcinoma cells A549. These cells are used as a model of a hardly curable cancer, known to develop chemoresistance to platinum drugs, such as cisplatin. Compared to wild type (A549WT), a stable line with a 60% knockdown of p21 (A549p21–) is less sensitive to antiproliferative action of cisplatin. In contrast, in the thiamine-deficient medium, cisplatin impairs the viability of A549p21– cells more than that of A549WT cells. Analysis of the associated metabolic changes in the cells indicates that (i) p21 knockdown restricts the production of 2-oxoglutarate via glutamate oxidation, stimulating that within the tricarboxylic acid (TCA) cycle; (ii) cellular cisplatin sensitivity is associated with a 4-fold upregulation of glutamic-oxaloacetic transaminase (GOT2) by cisplatin; (iii) cellular cisplatin resistance is associated with a 2-fold upregulation of p53 by cisplatin. Correlation analysis of the p53 expression and enzymatic activities upon variations in cellular thiamine/ThDP levels indicates that p21 knockdown substitutes positive correlation of the p53 expression with the activity of 2-oxoglutarate dehydrogenase complex (OGDHC) for that with the activity of glutamate dehydrogenase (GDH). The knockdown also changes correlations of the levels of OGDHC, GDH and GOT2 with those of the malate and isocitrate dehydrogenases. Thus, a p53/p21-dependent change in partitioning of the glutamate conversion to 2-oxoglutarate through GOT2 or GDH, linked to NAD(P)-dependent metabolism of 2-oxoglutarate in affiliated pathways, adapts A549 cells to thiamine deficiency or cisplatin treatment. Cellular thiamine deficiency may interfere with antiproliferative action of cisplatin due to their common modulation of the p53/p21-dependent metabolic switch between the glutamate oxidation and transamination.
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| 7. |
- Andermann, Tobias, et al.
(författare)
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A Guide to Carrying Out a Phylogenomic Target Sequence Capture Project
- 2020
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Ingår i: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- High-throughput DNA sequencing techniques enable time- and cost-effective sequencing of large portions of the genome. Instead of sequencing and annotating whole genomes, many phylogenetic studies focus sequencing effort on large sets of pre-selected loci, which further reduces costs and bioinformatic challenges while increasing coverage. One common approach that enriches loci before sequencing is often referred to as target sequence capture. This technique has been shown to be applicable to phylogenetic studies of greatly varying evolutionary depth. Moreover, it has proven to produce powerful, large multi-locus DNA sequence datasets suitable for phylogenetic analyses. However, target capture requires careful considerations, which may greatly affect the success of experiments. Here we provide a simple flowchart for designing phylogenomic target capture experiments. We discuss necessary decisions from the identification of target loci to the final bioinformatic processing of sequence data. We outline challenges and solutions related to the taxonomic scope, sample quality, and available genomic resources of target capture projects. We hope this review will serve as a useful roadmap for designing and carrying out successful phylogenetic target capture studies.
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| 8. |
- Andreeva, S, et al.
(författare)
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Case Report: Two New Cases of Autosomal-Recessive Hypertrophic Cardiomyopathy Associated With TRIM63-Compound Heterozygous Variant
- 2022
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Ingår i: Frontiers in genetics. - : Frontiers Media SA. - 1664-8021. ; 13, s. 743472-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Hypertrophic cardiomyopathy (HCM) is one of the most common hereditary diseases, and it is associated with fatal complications. The clinical heterogeneity of HCM requires risk prediction models to identify patients at a high risk of adverse events. Most HCM cases are caused by mutations in genes encoding sarcomere proteins. However, HCM is associated with rare genetic variants with limited data about its clinical course and prognosis, and existing risk prediction models are not validated for such patients’ cohorts. TRIM63 is one of the rare genes recently described as a cause of HCM with autosomal-recessive inheritance. Herein, we present two cases of HCM associated with TRIM63-compound heterozygous variants in young male sportsmen. They demonstrated progressively marked hypertrophy, advanced diastolic dysfunction, a significant degree of fibrosis detected by magnetic resonance imaging, and clear indications for implantable cardioverter-defibrillator. One of the cases includes the first description of TRIM63-HCM with extreme hypertrophy. The presented cases are discussed in light of molecular consequences that might underlie cardiac and muscle phenotype in patients with mutations of TRIM63, the master regulator of striated muscle mass.
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| 9. |
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| 10. |
- Antonelli, Alexandre, 1978, et al.
(författare)
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An engine for global plant diversity: Highest evolutionary turnover and emigration in the American tropics
- 2015
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Ingår i: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 6:130
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the processes that have generated the latitudinal biodiversity gradient and the continental differences in tropical biodiversity remains a major goal of evolutionary biology. Here we estimate the timing and direction of range shifts of extant flowering plants (angiosperms) between tropical and non-tropical zones, and into and out of the major tropical regions of the world. We then calculate rates of speciation and extinction taking into account incomplete taxonomic sampling. We use a recently published fossil calibrated phylogeny and apply novel bioinformatic tools to code species into user-defined polygons. We reconstruct biogeographic history using stochastic character mapping to compute relative numbers of range shifts in proportion to the number of available lineages through time. Our results, based on the analysis of c. 22,600 species and c. 20 million geo-referenced occurrence records, show no significant differences between the speciation and extinction of tropical and non-tropical angiosperms. This suggests that at least in plants, the latitudinal biodiversity gradient primarily derives from other factors than differential rates of diversification. In contrast, the outstanding species richness found today in the American tropics (the Neotropics), as compared to tropical Africa and tropical Asia, is associated with significantly higher speciation and extinction rates. This suggests an exceedingly rapid evolutionary turnover, i.e., Neotropical species being formed and replaced by one another at unparalleled rates. In addition, tropical America stands out from other continents by having "pumped out" more species than it received through most of the last 66 million years. These results imply that the Neotropics have acted as an engine for global plant diversity. © 2015 Antonelli, Zizka, Silvestro, Scharn, Cascales-Miñana and Bacon.
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| 11. |
- Armstrong, Kate E., et al.
(författare)
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Patterns of diversification amongst tropical regions compared: a case study in Sapotaceae.
- 2014
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Ingår i: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 5:362
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Tidskriftsartikel (refereegranskat)abstract
- Species diversity is unequally distributed across the globe,with the greatest concentration occurring in the tropics. Even within the tropics, there are significant differences in the numbers of taxa found in each continental region. Manilkara is a pantropical genus of trees in the Sapotaceae comprising c.78 species. Its distribution allows for biogeographic investigation and testing of whether rates of diversification differ amongst tropical regions. The age and geographical origin of Manilkara are inferred to determine whether Gondwanan break-up, boreotropical migration or long distance dispersal have shaped its current disjunct distribution. Diversification rates through time are also analyzed to determine whether the timing and tempo of speciation on each continent coincides with geoclimatic events. Bayesian analyses of nuclear (ITS) and plastid (rpl32-trnL,rps16-trnK,and trnS-trnFM) sequences were used to reconstruct a species level phylogeny of Manilkara and related genera in the tribe Mimusopeae. Analyses of the nuclear data using a fossil-calibrated relaxed molecular clock indicate that Manilkara evolved 32–29 million years ago (Mya) in Africa. Lineages within the genus dispersed to the Neotropics 26–18 Mya and to Asia 28–15 Mya. Higher speciation rates are found in the Neotropical Manilkara clade than in either African or Asian clades. Dating of regional diversification correlates with known palaeoclimatic events. In South America, the divergence between Atlantic coastal forest and Amazonian clades coincides with the formation of drier Cerrado and Caatinga habitats between them. In Africa diversification coincides with Tertiary cycles of aridification an duplif tof the east African plateaux. In South east Asia dispersal may have been limited by the relatively recent emergence of land in New Guinea and islands further east c.10 Mya.
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| 12. |
- Attelind, Sofia, et al.
(författare)
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Genetic determinants of apixaban plasma levels and their relationship to bleeding and thromboembolic events
- 2022
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Ingår i: Frontiers in Genetics. - : Frontiers Media S.A.. - 1664-8021. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Apixaban is a direct oral anticoagulant, a factor Xa inhibitor, used for the prevention of ischemic stroke in patients with atrial fibrillation. Despite using recommended dosing a few patients might still experience bleeding or lack of efficacy that might be related to inappropriate drug exposure. We conducted a genome-wide association study using data from 1,325 participants in the pivotal phase three trial of apixaban with the aim to identify genetic factors affecting the pharmacokinetics of apixaban. A candidate gene analysis was also performed for pre-specified variants in ABCB1, ABCG2, CYP3A4, CYP3A5, and SULT1A1, with a subsequent analysis of all available polymorphisms within the candidate genes. Significant findings were further evaluated to assess a potential association with clinical outcome such as bleeding or thromboembolic events. No variant was consistently associated with an altered apixaban exposure on a genome-wide level. The candidate gene analyses showed a statistically significant association with a well-known variant in the drug transporter gene ABCG2 (c.421G > T, rs2231142). Patients carrying this variant had a higher exposure to apixaban [area under the curve (AUC), beta = 151 (95% CI 59-243), p = 0.001]. On average, heterozygotes displayed a 5% increase of AUC and homozygotes a 17% increase of AUC, compared with homozygotes for the wild-type allele. Bleeding or thromboembolic events were not significantly associated with ABCG2 rs2231142. This large genome-wide study demonstrates that genetic variation in the drug transporter gene ABCG2 is associated with the pharmacokinetics of apixaban. However, the influence of this finding on drug exposure was small, and further studies are needed to better understand whether it is of relevance for ischemic and bleeding events.
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| 13. |
- Bai, Wen Feng, et al.
(författare)
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Phylogenetic Analysis of Small Hive Beetles From Native to Introduced Populations
- 2022
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Ingår i: Frontiers in Genetics. - : Frontiers Media S.A.. - 1664-8021. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- The small hive beetle (SHB), a social parasite of beehives, is native to sub-Saharan Africa and has spread to America, Europe, and Australia. Recently, these beetles invaded China, causing widespread colony collapses in the honeybee, Apis cerana. In this study, single nucleotide polymorphisms (SNPs) were identified in the beetle genome from its native range (Africa), a region that was invaded by SHBs nearly 30 years ago (America), and more recent invasions (Asia). The beetles in the United States formed the earliest branch and show signs of two decades of gene flow and local adaptation to differentiate this population from the native ones. The beetles in China were deep branched and showed the highest fixation index when compared to the US populations. The number of SNPs in overexpressed genes was significantly higher than the transcriptome. Gene-expression profiles presented here distinguish the characters between adult and larvae SHBs.
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| 14. |
- Banabazi, Mohammad Hossein
(författare)
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Genome-Wide Selection Signatures and Human-Mediated Introgression Events in Bos taurus indicus-influenced Composite Beef Cattle
- 2022
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Ingår i: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Genetic introgression from interbreeding hybridization of European Bos taurus taurus (EBT) and Indian Bos taurus indicus (IBI) cattle breeds have been widely used to combine the climatic resilience of the IBI cattle and the higher productivity of EBT when forming new composite beef cattle (CB) populations. The subsequent breeding strategies have shifted their initial genomic compositions. To uncover population structure, signatures of selection, and potential introgression events in CB populations, high-density genotypes [containing 492,954 single nucleotide polymorphisms (SNPs) after the quality control] of 486 individuals from 15 cattle breeds, including EBT, IBI, and CB populations, along with two Bos grunniens genotypes as outgroup were used in this study. Then, in-depth population genetics analyses were performed for three CB breeds of Beefmaster, Brangus, and Santa Gertrudis. Neighbor-joining, principal components, and admixture analyses confirmed the historical introgression of EBT and IBI haplotypes into CB breeds. The f(dM) statistics revealed that only 12.9% of CB populations' genetic components are of IBI origin. The results of signatures of selection analysis indicated different patterns of selection signals in the three CB breeds with primary pressure on pathways involved in protein processing and stress response in Beefmaster, cell proliferation regulation and immune response in Brangus, and amino acids and glucose metabolisms in Santa Gertrudis. An average of >90% of genomic regions underlying selection signatures were of EBT origin in the studied CB populations. Investigating the CB breeds' genome allows the estimation of EBT and IBI ancestral proportions and the locations within the genome where either taurine or indicine origin alleles are under selective pressure. Such findings highlight various opportunities to control the selection process more efficiently and explore complementarity at the genomic level in CB populations.
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| 15. |
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| 16. |
- Bergland, AK, et al.
(författare)
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Effects of Anthocyanin Supplementation on Serum Lipids, Glucose, Markers of Inflammation and Cognition in Adults With Increased Risk of Dementia - A Pilot Study
- 2019
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Ingår i: Frontiers in genetics. - : Frontiers Media SA. - 1664-8021. ; 10, s. 536-
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Tidskriftsartikel (refereegranskat)abstract
- Anthocyanins may protect against cardiovascular related cognitive decline and dementia.ObjectiveOpen-label study to measure changes in serum lipids, glucose, glycosylated hemoglobin (HbA1c), and markers of inflammation after anthocyanin supplementation in people with increased risk of dementia. As a secondary endpoint we examined potential changes in a battery of cognitive test in the anthocyanin group (AG). A total of 27 individuals with mild cognitive impairment (MCI) (n = 8) or stable non-obstructive coronary artery disease (CAD) (n = 19) consumed two Medox® capsules, each containing 80 mg of natural purified anthocyanins, twice daily for 16 weeks. They provided blood samples and performed a short battery of cognitive tests. Twenty healthy normal controls (NC) (n = 20) provided blood samples, but did not receive any intervention and did not perform cognitive tests.ResultsThere was a significant difference between groups for monocyte chemoattractant protein (MCP-1) and fasting glucose. In addition, total cholesterol and triglycerides were significantly increased in the AG. Improvements in memory and executive test scores were observed. No adverse effects were reported.ConclusionThe results of this pilot study were largely inconclusive with regard to the potential protective effects of anthocyanin supplementation. However, anthocyanins were well tolerated, and compliance was high. Larger, placebo-controlled studies to explore the potential effects of anthocyanins on dementia risk are encouraged.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier NCT02409446
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| 19. |
- Brhanie Mesfin, Haftom, et al.
(författare)
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Novel GBS-Based SNP Markers for Finger Millet and Their Use in Genetic Diversity Analyses
- 2022
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Ingår i: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Eleusine coracana (L.) Gaertn., commonly known as finger millet, is a multipurpose crop used for food and feed. Genomic tools are required for the characterization of crop gene pools and their genomics-led breeding. High-throughput sequencing-based characterization of finger millet germplasm representing diverse agro-ecologies was considered an effective method for determining its genetic diversity, thereby suggesting potential candidates for breeding. In this study, the genotyping-by-sequencing (GBS) method was used to simultaneously identify novel single nucleotide polymorphism (SNP) markers and genotype 288 finger millet accessions collected from Ethiopia and Zimbabwe. The accessions were characterized at individual and group levels using 5,226 bi-allelic SNPs, with a minimum allele frequency (MAF) of above 0.05, distributed across 2,500 scaffolds of the finger millet reference genome. The polymorphism information content (PIC) of the SNPs was 0.23 on average, and a quarter of them have PIC values over 0.32, making them highly informative. The grouping of the 288 accessions into seven populations based on geographic proximity and the potential for germplasm exchange revealed a narrow range of observed heterozygosity (Ho; 0.09-0.11) and expected heterozygosity (He) that ranged over twofold, from 0.11 to 0.26. Alleles unique to the different groups were also identified, which merit further investigation for their potential association with desirable traits. The analysis of molecular variance (AMOVA) revealed a highly significant genetic differentiation among groups of accessions classified based on the geographic region, country of origin, days to flowering, panicle type, and Al tolerance (p < 0.01). The high genetic differentiation between Ethiopian and Zimbabwean accessions was evident in the AMOVA, cluster, principal coordinate, and population structure analyses. The level of genetic diversity of finger millet accessions varies moderately among locations within Ethiopia, with accessions from the northern region having the lowest level. In the neighbor-joining cluster analysis, most of the improved cultivars included in this study were closely clustered, probably because they were developed using genetically less diverse germplasm and/or selected for similar traits, such as grain yield. The recombination of alleles via crossbreeding genetically distinct accessions from different regions of the two countries can potentially lead to the development of superior cultivars.
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| 20. |
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| 21. |
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| 22. |
- Castresana-Aguirre, Miguel, 1991-, et al.
(författare)
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Benefits and Challenges of Pre-clustered Network-Based Pathway Analysis
- 2022
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Ingår i: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Functional analysis of gene sets derived from experiments is typically done by pathway annotation. Although many algorithms exist for analyzing the association between a gene set and a pathway, an issue which is generally ignored is that gene sets often represent multiple pathways. In such cases an association to a pathway is weakened by the presence of genes associated with other pathways. A way to counteract this is to cluster the gene set into more homogenous parts before performing pathway analysis on each module. We explored whether network-based pre-clustering of a query gene set can improve pathway analysis. The methods MCL, Infomap, and MGclus were used to cluster the gene set projected onto the FunCoup network. We characterized how well these methods are able to detect individual pathways in multi-pathway gene sets, and applied each of the clustering methods in combination with four pathway analysis methods: Gene Enrichment Analysis, BinoX, NEAT, and ANUBIX. Using benchmarks constructed from the KEGG pathway database we found that clustering can be beneficial by increasing the sensitivity of pathway analysis methods and by providing deeper insights of biological mechanisms related to the phenotype under study. However, keeping a high specificity is a challenge. For ANUBIX, clustering caused a minor loss of specificity, while for BinoX and NEAT it caused an unacceptable loss of specificity. GEA had very low sensitivity both before and after clustering. The choice of clustering method only had a minor effect on the results. We show examples of this approach and conclude that clustering can improve overall pathway annotation performance, but should only be used if the used enrichment method has a low false positive rate.
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| 23. |
- Castro, LP, et al.
(författare)
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XPC and POLH/XPV Genes Mutated in a Genetic Cluster of Xeroderma Pigmentosum Patients in Northeast Brazil
- 2022
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Ingår i: Frontiers in genetics. - : Frontiers Media SA. - 1664-8021. ; 12, s. 784963-
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Tidskriftsartikel (refereegranskat)abstract
- Xeroderma pigmentosum (XP) is a rare genetic condition in which exposure to sunlight leads to a high tumor incidence due to defective DNA repair machinery. Herein, we investigated seven patients clinically diagnosed with XP living in a small city, Montanhas (Rio Grande do Norte), in the Northeast region of Brazil. We performed high-throughput sequencing and, surprisingly, identified two different mutated genes. Six patients carry a novel homozygote mutation in the POLH/XPV gene, c.672_673insT (p.Leu225Serfs*33), while one patient carries a homozygote mutation in the XPC gene, c.2251-1G>C. This latter mutation was previously described in Southeastern Africa (Comoro Island and Mozambique), Pakistan, and in a high incidence in Brazil. The XP-C patient had the first symptoms before the first year of life with aggressive ophthalmologic tumor progression and a melanoma onset at 7 years of age. The XP-V patients presented a milder phenotype with later onset of the disorder (mean age of 16 years old), and one of the six XP-V patients developed melanoma at 72 years. The photoprotection is minimal among them, mainly for the XP-V patients. The differences in the disease severity between XP-C (more aggressive) and XP-V (milder) patients are obvious and point to the major role of photoprotection in the XPs. We estimate that the incidence of XP patients at Montanhas can be higher, but with no diagnosis, due to poor health assistance. Patients still suffer from the stigmatization of the condition, impairing diagnosis, education for sun protection, and medical care.
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| 24. |
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| 25. |
- Cediel Ulloa, Andrea, et al.
(författare)
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Methylmercury-induced DNA methylation—From epidemiological observations to experimental evidence
- 2022
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Ingår i: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Methylmercury (MeHg) is a developmental neurotoxicant, and one potential mechanism of MeHg toxicity is epigenetic dysregulation. In a recent meta-analysis of epigenome-wide association studies (EWAS), associations between prenatal MeHg exposure and DNA methylation at several genomic sites were identified in blood from newborns and children. While EWASs reveal human-relevant associations, experimental studies are required to validate the relationship between exposure and DNA methylation changes, and to assess if such changes have implications for gene expression. Herein, we studied DNA methylation and gene expression of five of the top genes identified in the EWAS meta-analysis, MED31, MRPL19, GGH, GRK1, and LYSMD3, upon MeHg exposure in human SH-SY5Y cells exposed to 8 or 40 nM of MeHg during differentiation, using bisulfite-pyrosequencing and qPCR, respectively. The concentrations were selected to cover the range of MeHg concentrations in cord blood (2–8.5 μg/L) observed in the cohorts included in the EWAS. Exposure to MeHg increased DNA methylation at MED31, a transcriptional regulator essential for fetal development. The results were in concordance with the epidemiological findings where more MED31 methylation was associated with higher concentrations of MeHg. Additionally, we found a non-significant decrease in DNA methylation at GGH, which corresponds to the direction of change observed in the EWAS, and a significant correlation of GGH methylation with its expression. In conclusion, this study corroborates some of the EWAS findings and puts forward candidate genes involved in MeHg’s effects on the developing brain, thus highlighting the value of experimental validation of epidemiological association studies.
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