@article{Schorn2021,

title = {A community resource for paired genomic and metabolomic data mining},

author = {Michelle A Schorn and Stefan Verhoeven and Lars Ridder and Florian Huber and Deepa D Acharya and Alexander A Aksenov and Gajender Aleti and Jamshid Amiri Moghaddam and Allegra T Aron and Saefuddin Aziz and Anelize Bauermeister and Katherine D Bauman and Martin Baunach and Christine Beemelmanns and Michael J Beman and Mar\'{i}a Victoria Berlanga-Clavero and Alex A Blacutt and Helge B Bode and Anne Boullie and Asker Brejnrod and Tim S Bugni and Alexandra Calteau and Liu Cao and V\'{i}ctor J Carri\'{o}n and Raquel Castelo-Branco and Shaurya Chanana and Alexander B Chase and Marc G Chevrette and Leticia V Costa-Lotufo and Jason M Crawford and Cameron R Currie and Bart Cuypers and Tam Dang and Tristan de Rond and Alyssa M Demko and Elke Dittmann and Chao Du and Christopher Drozd and Jean-Claude Dujardin and Rachel J Dutton and Anna Edlund and David P Fewer and Neha Garg and Julia M Gauglitz and Emily C Gentry and Lena Gerwick and Evgenia Glukhov and Harald Gross and Muriel Gugger and Dulce G Guill\'{e}n Matus and Eric J N Helfrich and Benjamin-Florian Hempel and Jae-Seoun Hur and Marianna Iorio and Paul R Jensen and Kyo Bin Kang and Leonard Kaysser and Neil L Kelleher and Chung Sub Kim and Ki Hyun Kim and Irina Koester and Gabriele M K\"{o}nig and Tiago Leao and Seoung Rak Lee and Yi-Yuan Lee and Xuanji Li and Jessica C Little and Katherine N Maloney and Daniel M\"{a}nnle and Christian Martin H. and Andrew C McAvoy and Willam W Metcalf and Hosein Mohimani and Carlos Molina-Santiago and Bradley S Moore and Michael W Mullowney and Mitchell Muskat and Louis-F\'{e}lix Nothias and Ellis C O'Neill and Elizabeth I Parkinson and Daniel Petras and J\"{o}rn Piel and Emily C Pierce and Karine Pires and Raphael Reher and Diego Romero and Caroline M Roper and Michael Rust and Hamada Saad and Carmen Saenz and Laura M Sanchez and S\oren Johannes S\orensen and Margherita Sosio and Roderich D S\"{u}ssmuth and Douglas Sweeney and Kapil Tahlan and Regan J Thomson and Nicholas J Tobias and Amaro E Trindade-Silva and Gilles P van Wezel and Mingxun Wang and Kelly C Weldon and Fan Zhang and Nadine Ziemert and Katherine R Duncan and Max Cr\"{u}semann and Simon Rogers and Pieter C Dorrestein and Marnix H Medema and Justin J J van der Hooft},

url = {https://doi.org/10.1038/s41589-020-00724-z},

doi = {10.1038/s41589-020-00724-z},

issn = {1552-4469},

year  = {2021},

date = {2021-02-15},

journal = {Nature Chemical Biology},

abstract = {Genomics and metabolomics are widely used to explore specialized metabolite diversity. The Paired Omics Data Platform is a community initiative to systematically document links between metabolome and (meta)genome data, aiding identification of natural product biosynthetic origins and metabolite structures.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{VANHOUTVEN2021166966,

title = {Constrained Standardization of Count Data from Massive Parallel Sequencing},

author = {Joris Van Houtven and Bart Cuypers and Pieter Meysman and Jef Hooyberghs and Kris Laukens and Dirk Valkenborg},

url = {https://www.sciencedirect.com/science/article/pii/S0022283621001674},

doi = {https://doi.org/10.1016/j.jmb.2021.166966},

issn = {0022-2836},

year  = {2021},

date = {2021-01-01},

journal = {Journal of Molecular Biology},

pages = {166966},

abstract = {In high-throughput omics disciplines like transcriptomics, researchers face a need to assess the quality of an experiment prior to an in-depth statistical analysis. To efficiently analyze such voluminous collections of data, researchers need triage methods that are both quick and easy to use. Such a normalization method for relative quantitation, CONSTANd, was recently introduced for isobarically-labeled mass spectra in proteomics. It transforms the data matrix of abundances through an iterative, convergent process enforcing three constraints: (I) identical column sums; (II) each row sum is fixed (across matrices) and (III) identical to all other row sums. In this study, we investigate whether CONSTANd is suitable for count data from massively parallel sequencing, by qualitatively comparing its results to those of DESeq2. Further, we propose an adjustment of the method so that it may be applied to identically balanced but differently sized experiments for joint analysis. We find that CONSTANd can process large data sets at well over 1 million count records per second whilst mitigating unwanted systematic bias and thus quickly uncovering the underlying biological structure when combined with a PCA plot or hierarchical clustering. Moreover, it allows joint analysis of data sets obtained from different batches, with different protocols and from different labs but without exploiting information from the experimental setup other than the delineation of samples into identically processed sets (IPSs). CONSTANd’s simplicity and applicability to proteomics as well as transcriptomics data make it an interesting candidate for integration in multi-omics workflows.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{CUYPERS2018170,

title = {Integrated genomic and metabolomic profiling of ISC1, an emerging Leishmania donovani population in the Indian subcontinent},

author = {Bart Cuypers and Maya Berg and Hideo Imamura and Franck Dumetz and G\'{e}raldine [De Muylder] and Malgorzata A Domagalska and Suman Rijal and Narayan Raj Bhattarai and Ilse Maes and Mandy Sanders and James A Cotton and Pieter Meysman and Kris Laukens and Jean-Claude Dujardin},

url = {http://www.sciencedirect.com/science/article/pii/S1567134818302004},

doi = {https://doi.org/10.1016/j.meegid.2018.04.021},

issn = {1567-1348},

year  = {2018},

date = {2018-01-01},

journal = {Infection, Genetics and Evolution},

volume = {62},

pages = {170 - 178},

abstract = {Leishmania donovani is the responsible agent for visceral leishmaniasis (VL) in the Indian subcontinent (ISC). The disease is lethal without treatment and causes 0.2 to 0.4 million cases each year. Recently, reports of VL in Nepalese hilly districts have increased as well as VL cases caused by L. donovani from the ISC1 genetic group, a new and emerging genotype. In this study, we perform for the first time an integrated, untargeted genomics and metabolomics approach to characterize ISC1, in comparison with the Core Group (CG), main population that drove the most recent outbreak of VL in the ISC. We show that the ISC1 population is very different from the CG, both at genome and metabolome levels. The genomic differences include SNPs, CNV and small indels in genes coding for known virulence factors, immunogens and surface proteins. Both genomic and metabolic approaches highlighted dissimilarities related to membrane lipids, the nucleotide salvage pathway and the urea cycle in ISC1 versus CG. Many of these pathways and molecules are important for the interaction with the host/extracellular environment. Altogether, our data predict major functional differences in ISC1 versus CG parasites, including virulence. Therefore, particular attention is required to monitor the fate of this emerging ISC1 population in the ISC, especially in a post-VL elimination context.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Dumetze00548-17,

title = {Molecular Preadaptation to Antimony Resistance in Leishmania donovani on the Indian Subcontinent},

author = {F Dumetz and B Cuypers and H Imamura and D Zander and E D{textquoteright}Haenens and I Maes and M A Domagalska and J Clos and J -C Dujardin and G De Muylder},

editor = {Margaret Phillips},

url = {https://msphere.asm.org/content/3/2/e00548-17},

doi = {10.1128/mSphere.00548-17},

year  = {2018},

date = {2018-01-01},

journal = {mSphere},

volume = {3},

number = {2},

publisher = {American Society for Microbiology Journals},

abstract = {Antimonials (Sb) were used for decades for chemotherapy of visceral leishmaniasis (VL). Now abandoned in the Indian subcontinent (ISC) because of Leishmania donovani resistance, this drug offers a unique model for understanding drug resistance dynamics. In a previous phylogenomic study, we found two distinct populations of L. donovani: the core group (CG) in the Gangetic plains and ISC1 in the Nepalese highlands. Sb resistance was only encountered within the CG, and a series of potential markers were identified. Here, we analyzed the development of resistance to trivalent antimonials (SbIII) upon experimental selection in ISC1 and CG strains. We observed that (i) baseline SbIII susceptibility of parasites was higher in ISC1 than in the CG, (ii) time to SbIII resistance was higher for ISC1 parasites than for CG strains, and (iii) untargeted genomic and metabolomic analyses revealed molecular changes along the selection process: these were more numerous in ISC1 than in the CG. Altogether these observations led to the hypothesis that CG parasites are preadapted to SbIII resistance. This hypothesis was experimentally confirmed by showing that only wild-type CG strains could survive a direct exposure to the maximal concentration of SbIII. The main driver of this preadaptation was shown to be MRPA, a gene involved in SbIII sequestration and amplified in an intrachromosomal amplicon in all CG strains characterized so far. This amplicon emerged around 1850 in the CG, well before the implementation of antimonials for VL chemotherapy, and we discuss here several hypotheses of selective pressure that could have accompanied its emergence.IMPORTANCE The textquotedblleftantibiotic resistance crisistextquotedblright is a major challenge for scientists and medical professionals. This steady rise in drug-resistant pathogens also extends to parasitic diseases, with antimony being the first anti-Leishmania drug that fell in the Indian subcontinent (ISC). Leishmaniasis is a major but neglected infectious disease with limited therapeutic options. Therefore, understanding how parasites became resistant to antimonials is of commanding importance. In this study, we experimentally characterized the dynamics of this resistance acquisition and show for the first time that some Leishmania populations of the ISC were preadapted to antimony resistance, likely driven by environmental factors or by drugs used in the 19th century.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Dumetze00599-17,

title = {Modulation of Aneuploidy in Leishmania donovani during Adaptation to Different In Vitro and In Vivo Environments and Its Impact on Gene Expression},

author = {F Dumetz and H Imamura and M Sanders and V Seblova and J Myskova and P Pescher and M Vanaerschot and C J Meehan and B Cuypers and G De Muylder and G F Sp\"{a}th and G Bussotti and J R Vermeesch and M Berriman and J A Cotton and P Volf and J C Dujardin and M A Domagalska},

editor = {Keith Gull},

url = {https://mbio.asm.org/content/8/3/e00599-17},

doi = {10.1128/mBio.00599-17},

year  = {2017},

date = {2017-01-01},

journal = {mBio},

volume = {8},

number = {3},

publisher = {American Society for Microbiology},

abstract = {Aneuploidy is usually deleterious in multicellular organisms but appears to be tolerated and potentially beneficial in unicellular organisms, including pathogens. Leishmania, a major protozoan parasite, is emerging as a new model for aneuploidy, since in vitro-cultivated strains are highly aneuploid, with interstrain diversity and intrastrain mosaicism. The alternation of two life stages in different environments (extracellular promastigotes and intracellular amastigotes) offers a unique opportunity to study the impact of environment on aneuploidy and gene expression. We sequenced the whole genomes and transcriptomes of Leishmania donovani strains throughout their adaptation to in vivo conditions mimicking natural vertebrate and invertebrate host environments. The nucleotide sequences were almost unchanged within a strain, in contrast to highly variable aneuploidy. Although high in promastigotes in vitro, aneuploidy dropped significantly in hamster amastigotes, in a progressive and strain-specific manner, accompanied by the emergence of new polysomies. After a passage through a sand fly, smaller yet consistent karyotype changes were detected. Changes in chromosome copy numbers were correlated with the corresponding transcript levels, but additional aneuploidy-independent regulation of gene expression was observed. This affected stage-specific gene expression, downregulation of the entire chromosome 31, and upregulation of gene arrays on chromosomes 5 and 8. Aneuploidy changes in Leishmania are probably adaptive and exploited to modulate the dosage and expression of specific genes; they are well tolerated, but additional mechanisms may exist to regulate the transcript levels of other genes located on aneuploid chromosomes. Our model should allow studies of the impact of aneuploidy on molecular adaptations and cellular fitness.IMPORTANCE Aneuploidy is usually detrimental in multicellular organisms, but in several microorganisms, it can be tolerated and even beneficial. Leishmania\textemdasha protozoan parasite that kills more than 30,000 people each year\textemdashis emerging as a new model for aneuploidy studies, as unexpectedly high levels of aneuploidy are found in clinical isolates. Leishmania lacks classical regulation of transcription at initiation through promoters, so aneuploidy could represent a major adaptive strategy of this parasite to modulate gene dosage in response to stressful environments. For the first time, we document the dynamics of aneuploidy throughout the life cycle of the parasite, in vitro and in vivo. We show its adaptive impact on transcription and its interaction with regulation. Besides offering a new model for aneuploidy studies, we show that further genomic studies should be done directly in clinical samples without parasite isolation and that adequate methods should be developed for this.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}