Research Articles (Genetics)

Permanent URI for this collectionhttp://hdl.handle.net/2263/1837

A collection containing some of the full text peer-reviewed/ refereed articles published by researchers from the Department of Genetics

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Intra- and interspecific variation of Amblyomma ticks from southern Africa
(BMC, 2024-08) Smit, Andeliza; Mulandane, Fernando; Labuschagne, Martinet; Wójick, Stephané H.; Malabwa, Choolwe; Sili, Gourgelia; Mandara, Stephen; Dlamkile, Zinathi; Ackermann, Rebecca; Vineer, Hannah Rose; Stoltsz, Wilhelm Heinrich; Huber, Karine; Horak, Ivan Gerard; Morar‑Leather, Darshana; Makepeace, Benjamin L.; Das Neves, Luis Carlos Bernardo G.; u14023190@tuks.co.za
BACKGROUND: Amblyomma spp. ticks, known for their long mouthparts, bright ornate appearance and aggressive hunting behaviour, are vectors of a number of important pathogens. In southern Africa, 17 Amblyomma spp. are currently documented. Of these species, Amblyomma hebraeum and Amblyomma variegatum have been well studied due to their wide geographical range and their status as competent vectors of pathogens that are of veterinary and medical importance. Studies on other Amblyomma spp. in southern Africa have been neglected, fostering ongoing debates on the validity of certain species such as Amblyomma pomposum. This study investigated the inter- and intra-species variation of Amblyomma ticks collected in southern Africa, focusing on resolving the dispute about A. pomposum and A. variegatum being distinct species. METHODS: Four Amblyomma tick species were collected from Angola, Mozambique, South Africa, Zambia and Zimbabwe, and were identified morphologically as Amblyomma eburneum (208), A. hebraeum (4758), A. pomposum (191) and A. variegatum (2577) using identification keys. Gene amplification targeting the 12S and 16S rRNA, cytochrome oxidase I, cytochrome B and internal transcribed spacer-2 genes was conducted for 204 ticks, for which varying success was achieved during amplification for each of the markers. Maximum likelihood analyses were performed in IQ-TREE. RESULTS: The phylogenetic topologies and ABGD analyses of each individual gene clustered A. pomposum within the A. variegatum clade, while clearly separating A. eburneum and A. hebraeum from all other species. None of the genetic markers indicated intraspecific structuring on the basis of geographical origin, despite great distances between sampling sites. CONCLUSION: Our study concludes that there is insufficient molecular evidence to differentiate A. pomposum and A. variegatum from each other. We highlight the need for whole mitochondrial genome sequencing of these two species to resolve the ongoing controversies. Furthermore, we propose mating and hybrid viability studies between the two species to confirm their reproductive isolation.
Benchmarking bacterial taxonomic classification using nanopore metagenomics data of several mock communities
(Nature Research, 2024-08) Van Uffelen, Alexander; Posadas, Andres; Roosens, Nancy H.C.; Marchal, Kathleen; De Keersmaecker, Sigrid C. J.; Vanneste, Kevin
Taxonomic classification is crucial in identifying organisms within diverse microbial communities when using metagenomics shotgun sequencing. While second-generation Illumina sequencing still dominates, third-generation nanopore sequencing promises improved classification through longer reads. However, extensive benchmarking studies on nanopore data are lacking. We systematically evaluated performance of bacterial taxonomic classification for metagenomics nanopore sequencing data for several commonly used classifiers, using standardized reference sequence databases, on the largest collection of publicly available data for defined mock communities thus far (nine samples), representing different research domains and application scopes. Our results categorize classifiers into three categories: low precision/high recall; medium precision/medium recall, and high precision/medium recall. Most fall into the first group, although precision can be improved without excessively penalizing recall with suitable abundance filtering. No definitive ‘best’ classifier emerges, and classifier selection depends on application scope and practical requirements. Although few classifiers designed for long reads exist, they generally exhibit better performance. Our comprehensive benchmarking provides concrete recommendations, supported by publicly available code for reassessment and fine-tuning by other scientists.
Complex patterns of gene flow and convergence in the evolutionary history of the spiral-horned antelopes (Tragelaphini)
(Elsevier, 2024-09) Rakotoarivelo, Andrinajoro R.; Rambuda, Thabelo; Taron, Ulrike H.; Stalder, Gabrielle; O'Donoghue, Paul; Robovsky, Jan; Hartmann, Stefanie; Hofreiter, Michael; Moodley, Yoshan
The Tragelaphini, also known as spiral-horned antelope, is a phenotypically diverse mammalian tribe comprising a single genus, Tragelaphus. The evolutionary history of this tribe has attracted the attention of taxonomists and molecular geneticists for decades because its diversity is characterised by conflicts between morphological and molecular data as well as between mitochondrial, nuclear and chromosomal DNA. These inconsistencies point to a complex history of ecological diversification, coupled by either phenotypic convergence or introgression. Therefore, to unravel the phylogenetic relationships among spiral-horned antelopes, and to further investigate the role of divergence and gene flow in trait evolution, we sequenced genomes for all nine accepted species of the genus Tragelaphus, including a genome each for the highly divergent bushbuck lineages (T. s. scriptus and T. s. sylvaticus). We successfully reconstructed the Tragelaphus species tree, providing genome-level support for the early Pliocene divergence and monophyly of the nyala (T. angasii) and lesser kudu (T. imberbis), the monophyly of the two eland species (T. oryx and T. derbianus) and, importantly, the monophyly of kéwel (T. s. scriptus) and imbabala (T. s. sylvaticus) bushbuck. We found strong evidence for gene flow in at least four of eight nodes on the species tree. Among the six phenotypic traits assessed here, only habitat type mapped onto the species tree without homoplasy, showing that trait evolution was the result of complex patterns of divergence, introgression and convergent evolution.
Poaching forensics : animal victims in the courtroom
(Annual Reviews, 2023) Harper, Cindy Kim; cindy.harper@up.ac.za
Poaching and the international trade in wildlife are escalating problems driven by poverty and greed and coordinated by increasingly sophisticated criminal networks. Biodiversity loss, caused by habitat change, is exacerbated by poaching, and species globally are facing extinction. Forensic evidence underpins human and animal criminal investigations and is critical in criminal prosecution and conviction. The application of forensic tools, particularly forensic genetics, to animal case work continues to advance, providing the systems to confront the challenges of wildlife investigations. This article discusses some of these tools, their development, and implementations, as well as recent advances. Examples of cases are provided in which forensic evidence played a key role in obtaining convictions, thus laying the foundation for the future application of techniques to disrupt the criminal networks and safeguard biodiversity through species protection.
Nanoplankton : the dominant vector for carbon export across the Atlantic Southern Ocean in spring
(American Association for the Advancement of Science, 2023-12) Flynn, Raquel F.; Haraguchi, Lumi; Mcquaid, Jeff; Burger, Jessica M.; Lunga, Percy Mutseka; Stirnimann, Luca; Samanta, Saumik; Roychoudhury, Alakendra N.; Fawcett, Sarah E.
Across the Southern Ocean, large (≥20 μm) diatoms are generally assumed to be the primary vector for carbon export, although this assumption derives mainly from summertime observations. Here, we investigated carbon production and export potential during the Atlantic Southern Ocean’s spring bloom from size-fractionated measurements of net primary production (NPP), nitrogen (nitrate, ammonium, urea) and iron (labile inorganic iron, organically complexed iron) uptake, and a high-resolution characterization of phytoplankton community composition. The nanoplankton-sized (2.7 to 20 μm) diatom, Chaetoceros spp., dominated the biomass, NPP, and nitrate uptake across the basin (40°S to 56°S), which we attribute to their low iron requirement, rapid response to increased light, and ability to escape grazing when aggregated into chains. We estimate that the spring Chaetoceros bloom accounted for >25% of annual export production across the Atlantic Southern Ocean, a finding consistent with recent observations from other regions highlighting the central role of the phytoplankton “middle class” in carbon export.
Standardized multi-omics of Earth’s microbiomes reveals microbial and metabolite diversity
(Nature Research, 2022-12) Shaffer, Justin P.; Nothias, Louis-Felix; Thompson, Luke R.; Sanders, Jon G.; Salido, Rodolfo A.; Couvillion, Sneha P.; Brejnrod, Asker D.; Lejzerowicz, Franck; Haiminen, Niina; Huang, Shi; Lutz, Holly L.; Zhu, Qiyun; Martino, Cameron; Morton, James T.; Karthikeyan, Smruthi; Nothias-Esposito, Melissa; Duhrkop, Kai; Bocker, Sebastian; Kim, Hyun Woo; Aksenov, Alexander A.; Bittremieux, Wout; Minich, Jeremiah J.; Marotz, Clarisse; Bryant, MacKenzie M.; Sanders, Karenina; Schwartz, Tara; Humphrey, Greg; Vasquez-Baeza, Yoshiki; Tripathi, Anupriya; Parida, Laxmi; Carrieri, Anna Paola; Beck, Kristen L.; Das, Promi; Gonzalez, Antonio; McDonald, Daniel; Ladau, Joshua; Karst, Soren M.; Albertsen, Mads; Ackermann, Gail; DeReus, Jeff; Thomas, Torsten; Petras, Daniel; Shade, Ashley; Stegen, James; Song, Se Jin; Metz, Thomas O.; Swafford, Austin D.; Dorrestein, Pieter C.; Jansson, Janet K.; Gilbert, Jack A.; Knight, Rob; The Earth Microbiome Project 500 (EMP500) Consortium; Angenant, Lars T.; Berry, Alison M.; Bittleston, Leonora S.; Bowen, Jennifer L.; Chavarria, Max; Cowan, Don A.; Distel, Dan; Girguis, Peter R.; Huerta-Cepas, Jaime; Jensen, Paul R.; Jiang, Lingjing; King, Gary M.; Lavrinienko, Anton; MacRae-Crerar, Aurora; Makhalanyane, Thulani Peter; Mappes, Tapio; Marzinelli, Ezequiel M.; Mayer, Gregory; McMahon, Katherine D.; Metcalf, Jessica L.; Miyake, Sou; Mousseau, Timothy A.; Murillo-Cruz, Catalina; Myrold, David; Palenik, Brian; Pinto-Tomas, Adrian A.; Porazinska, Dorota L.; Ramond, Jean-Baptiste; owher, Forest R.; RoyChowdhury, Taniya; Sandin, Stuart A.; Schmidt, Steven K.; Seedorf, Henning; Shade, Ashley; Shipway, J. Reuben; Smith, Jennifer E.; Stegen, James; Stewart, Frank J.; Tait, Karen; Thomas, Torsten; Tucker, Yael; U’Ren, Jana M.; Watts, Phillip C.; Webster, Nicole S.; Zaneveld, Jesse R.; Zhang, Shan
Despite advances in sequencing, lack of standardization makes comparisons across studies challenging and hampers insights into the structure and function of microbial communities across multiple habitats on a planetary scale. Here we present a multi-omics analysis of a diverse set of 880 microbial community samples collected for the Earth Microbiome Project. We include amplicon (16S, 18S, ITS) and shotgun metagenomic sequence data, and untargeted metabolomics data (liquid chromatography-tandem mass spectrometry and gas chromatography mass spectrometry). We used standardized protocols and analytical methods to characterize microbial communities, focusing on relationships and co-occurrences of microbially related metabolites and microbial taxa across environments, thus allowing us to explore diversity at extraordinary scale. In addition to a reference database for metagenomic and metabolomic data, we provide a framework for incorporating additional studies, enabling the expansion of existing knowledge in the form of an evolving community resource. We demonstrate the utility of this database by testing the hypothesis that every microbe and metabolite is everywhere but the environment selects. Our results show that metabolite diversity exhibits turnover and nestedness related to both microbial communities and the environment, whereas the relative abundances of microbially related metabolites vary and co-occur with specific microbial consortia in a habitat-specific manner. We additionally show the power of certain chemistry, in particular terpenoids, in distinguishing Earth’s environments (for example, terrestrial plant surfaces and soils, freshwater and marine animal stool), as well as that of certain microbes including Conexibacter woesei (terrestrial soils), Haloquadratum walsbyi (marine deposits) and Pantoea dispersa (terrestrial plant detritus). This Resource provides insight into the taxa and metabolites within microbial communities from diverse habitats across Earth, informing both microbial and chemical ecology, and provides a foundation and methods for multi-omics microbiome studies of hosts and the environment.
Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers
(Springer Nature, 2022-10-06) Hakkaart, Christopher; Pearson, John F.; Marquart, Louise; Dennis, Joe; Wiggins, George A.R.; Barnes, Daniel R.; Robinson, Bridget A.; Mace, Peter D.; Aittomaki, Kristiina; Andrulis, Irene L.; Arun, Banu K.; Azzollini, Jacopo; Balmana, Judith; Barkardottir, Rosa B.; Belhadj, Sami; Berger, Lieke; Blok, Marinus J.; Boonen, Susanne E.; Borde, Julika; Bradbury, Angela R.; Brunet, Joan; Buys, Saundra S.; Caligo, Maria A.; Campbell, Ian; Chung, Wendy K.; Claes, Kathleen B.M.; GEMO Study Collaborators; EMBRACE Collaborators; Collonge-Rame, Marie-Agnes; Cook, Jackie; Cosgrove, Casey; Couch, Fergus J.; Daly, Mary B.; Dandiker, Sita; Davidson, Rosemarie; De la Hoya, Miguel; De Putter, Robin; Delnatte, Capucine; Dhawan, Mallika; Diez, Orland; Ding, Yuan Chun; Domchek, Susan M.; Donaldson, Alan; Eason, Jacqueline; Easton, Douglas F.; Ehrencrona, Hans; Engel, Christoph; Evans, D. Gareth; Faust, Ulrike; Feliubadalo, Lidia; Fostira, Florentia; Friedman, Eitan; Frone, Megan; Frost, Debra; Garber, Judy; Gayther, Simon A.; Gehrig, Andrea; Gesta, Paul; Godwin, Andrew K.; Goldgar, David E.; Greene, Mark H.; Hahnen, Eric; Hake, Christopher R.; Hamann, Ute; Hansen, Thomas V.O.; Hauke, Jan; Hentschel, Julia; Herold, Natalie; Honisch, Ellen; Hulick, Peter J.; Imyanitov, Evgeny N.; SWE-BRCA Investigators; kConFab Investigators; HEBON Investigators; Isaacs, Claudine; Izatt, Louise; Izquierdo, Angel; Jakubowska, Anna; James, Paul A.; Janavicius, Ramunas; John, Esther M.; Joseph, Vijai; Karlan, Beth Y.; Kemp, Zoe; Kirk, Judy; Konstantopoulou, Irene; Koudijs, Marco; Kwong, Ava; Laitman, Yael; Lalloo, Fiona; Lasset, Christine; Lautrup, Charlotte; Lazaro, Conxi; Legrand, Clementine; Leslie, Goska; Lesueur, Fabienne; Mai, Phuong L.; Manoukian, Siranoush; Mari, Veronique; Martens, John W.M.; McGuffog, Lesley; Mebirouk, Noura; Meindl, Alfons; Miller, Austin; Montagna, Marco; Moserle, Lidia; Mouret-Fourme, Emmanuelle; Musgrave, Hannah; Nambot, Sophie; Nathanson, Katherine L.; Neuhausen, Susan L.; Nevanlinna, Heli; Yuen Yie, Joanne Ngeow; Nguyen-Dumont, Tu; Nikitina-Zake, Liene; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I.; Osorio, Ana; Ott, Claus-Eric; Park, Sue K.; Parsons, Michael T.; Pedersen, Inge Sokilde; Peixoto, Ana; Perez-Segura, Pedro; Peterlongo, Paolo; Pocza, Timea; Radice, Paolo; Ramser, Juliane; Rantala, Johanna; Rodriguez, Gustavo C.; Ronlund, Karina; Rosenberg, Efraim H.; Rossing, Maria; Schmutzler, Rita K.; Shah, Payal D.; Sharif, Saba; Sharma, Priyanka; Side, Lucy E.; Simard, Jacques; Singer, Christian F.; Snape, Katie; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sutter, Christian; Tan, Yen Yen; Teixeira, Manuel R.; Teo, Soo Hwang; Thomassen, Mads; Thull, Darcy L.; Tischkowitz, Marc; Toland, Amanda E.; Trainer, Alison H.; Tripathi, Vishakha; Tung, Nadine; Van Engelen, Klaartje; Jansen van Rensburg, Elizabeth; Vega, Ana; Viel, Alessandra; Weitzel, Jeffrey N.; Wevers, Marike R.; Chenevix-Trench, Georgia; Spurdle, Amanda B.; Antoniou, Antonis C.
The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer riskmodifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09–1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.
Wonders of the Namib Desert
(Academy of Science South Africa, 2022) Cowan, Don A.; Maggs‑Kolling, Gillian
You might think that nothing exists in a desert? Think again! The Namib Desert is teeming with life if you look closely.
Cultivated hawthorn (Crataegus pinnatifida var. major) genome sheds light on the evolution of Maleae (apple tribe)
(Wiley, 2022-08) Zhang, Ticao; Qiao, Qin; Du, Xiao; Zhang, Xiao; Hou, Yali; Wei, Xin; Sun, Chao; Zhang, Rengang; Yun, Quanzheng; Crabbe, M. James C.; Van de Peer, Yves; Dong, Wenxuan
Cultivated hawthorn (Crataegus pinnatifida var. major) is an important medicinal and edible plant with a long history of use for health protection in China. Herein, we provide a de novo chromosomelevel genome sequence of the hawthorn cultivar “Qiu Jinxing.” We assembled an 823.41Mb genome encoding 40 571 genes and further anchored the 779.24Mb sequence into 17 pseudo‐chromosomes, which account for 94.64% of the assembled genome. Phylogenomic analyses revealed that cultivated hawthorn diverged from other species within the Maleae (apple tribe) at approximately 35.4 Mya. Notably, genes involved in the flavonoid and triterpenoid biosynthetic pathways have been significantly amplified in the hawthorn genome. In addition, our results indicated that the Maleae share a unique ancient tetraploidization event; however, no recent independent whole‐genome duplication event was specifically detected in hawthorn. The amplification of non‐specific long terminal repeat retrotransposons contributed the most to the expansion of the hawthorn genome. Furthermore, we identified two paleo‐sub‐genomes in extant species of Maleae and found that these two sub‐genomes showed different rearrangement mechanisms. We also reconstructed the ancestral chromosomes of Rosaceae and discussed two possible paleopolyploid origin patterns (autopolyploidization or allopolyploidization) of Maleae. Overall, our study provides an improved context for understanding the evolution of Maleae species, and this new highquality reference genome provides a useful resource for the horticultural improvement of hawthorn.
The neighborhood of the spike gene Is a hotspot for modular intertypic homologous and nonhomologous recombination in coronavirus genomes
(Oxford University Press, 2022-01) Nikolaidis, Marios; Markoulatos, Panayotis; Van de Peer, Yves; Oliver, Stephen G.; Amoutzias, Grigorios D.
Coronaviruses (CoVs) have very large RNA viral genomes with a distinct genomic architecture of core and accessory open reading frames (ORFs). It is of utmost importance to understand their patterns and limits of homologous and nonhomologous recombination, because such events may affect the emergence of novel CoV strains, alter their host range, infection rate, tissue tropism pathogenicity, and their ability to escape vaccination programs. Intratypic recombination among closely related CoVs of the same subgenus has often been reported; however, the patterns and limits of genomic exchange between more distantly related CoV lineages (intertypic recombination) need further investigation. Here, we report computational/evolutionary analyses that clearly demonstrate a substantial ability for CoVs of different subgenera to recombine. Furthermore, we show that CoVs can obtain—through nonhomologous recombination—accessory ORFs from core ORFs, exchange accessory ORFs with different CoV genera, with other viruses (i.e., toroviruses, influenza C/D, reoviruses, rotaviruses, astroviruses) and even with hosts. Intriguingly, most of these radical events result from double crossovers surrounding the Spike ORF, thus highlighting both the instability and mobile nature of this genomic region. Although many such events have often occurred during the evolution of various CoVs, the genomic architecture of the relatively young SARS-CoV/SARS-CoV-2 lineage so far appears to be stable.
Evolution of isoform-level gene expression patterns across tissues during lotus species divergence
(Wiley, 2022-11) Zhang, Yue; Yang, Xingyu; Van de Peer, Yves; Chen, Jinming; Marchal, Kathleen; Shi, Tao
Both gene duplication and alternative splicing (AS) drive the functional diversity of gene products in plants, yet the relative contributions of the two key mechanisms to the evolution of gene function are largely unclear. Here, we studied AS in two closely related lotus plants, Nelumbo lutea and Nelumbo nucifera, and the outgroup Arabidopsis thaliana, for both single-copy and duplicated genes. We show that most splicing events evolved rapidly between orthologs and that the origin of lineage-specific splice variants or isoforms contributed to gene functional changes during species divergence within Nelumbo. Single-copy genes contain more isoforms, have more AS events conserved across species, and show more complex tissue-dependent expression patterns than their duplicated counterparts. This suggests that expression divergence through isoforms is a mechanism to extend the expression breadth of genes with low copy numbers. As compared to isoforms of local, small-scale duplicates, isoforms of whole-genome duplicates are less conserved and display a less conserved tissue bias, pointing towards their contribution to subfunctionalization. Through comparative analysis of isoform expression networks, we identified orthologous genes of which the expression of at least some of their isoforms displays a conserved tissue bias across species, indicating a strong selection pressure for maintaining a stable expression pattern of these isoforms. Overall, our study shows that both AS and gene duplication contributed to the diversity of gene function during the evolution of lotus.
Divergence of active site motifs among different classes of Populus glutaredoxins results in substrate switches
(Wiley, 2022-04) Xu, Hui; Li, Zhen; Jiang, Peng-Fei; Zhao, Li; Qu, Chang; Van de Peer, Yves; Liu, Yan-Jing; Zeng, Qing-Yin
Enzymes are essential components of all biological systems. The key characteristics of proteins functioning as enzymes are their substrate specificities and catalytic efficiencies. In plants, most genes encoding enzymes are members of large gene families. Within such families, the contributions of active site motifs to the functional divergence of duplicate genes have not been well elucidated. In this study, we identified 41 glutaredoxin (GRX) genes in the Populus trichocarpa genome. GRXs are ubiquitous enzymes in plants that play important roles in developmental and stress tolerance processes. In poplar, GRX genes were divided into four classes based on clear differences in gene structure and expression pattern, subcellular localization, enzymatic activity, and substrate specificity of the encoded proteins. Using site-directed mutagenesis, this study revealed that the divergence of the active site motif among different classes of GRX proteins resulted in substrate switches and thus provided new insights into the molecular evolution of these important plant enzymes.
In vitro dual activity of Aloe marlothii roots and its chemical constituents against Plasmodium falciparum asexual and sexual stage parasites
(Elsevier, 2022-10) Mianda, S.M.; Invernizzi, Luke; Van der Watt, Mariette Elizabeth; Reader, Janette; Moyo, Phanankosi; Birkholtz, Lyn-Marie; Maharaj, Vinesh J.; lbirkholtz@up.ac.za
Please abstract in the article.
New transmission-selective antimalarial agents through hit-to-lead optimization of 2-([1,1 '-Biphenyl]-4-carboxamido)benzoic acid derivatives
(Wiley, 2022-11) Reader, Janette; Opperman, Daniel; Van der Watt, Mariette Elizabeth; Theron, Anjo; Leshabane, Meta Kgaogelo; Da Rocha, Michelle; Turner, Jonathan; Garrabrant, Kathleen; Pina, Ivett; Mills, Catherine; Woster, Patrick M.; Birkholtz, Lyn-Marie; lbirkholtz@up.ac.za
Malaria elimination requires multipronged approaches, including the application of antimalarial drugs able to block humanto- mosquito transmission of malaria parasites. The transmissible gametocytes of Plasmodium falciparum seem to be highly sensitive towards epidrugs, particularly those targeting demethylation of histone post-translational marks. Here, we report exploration of compounds from a chemical library generated during hit-to-lead optimization of inhibitors of the human histone lysine demethylase, KDM4B. Derivatives of 2-([1,1’- biphenyl]-4-carboxamido) benzoic acid, around either the amide or a sulfonamide linker backbone (2-(arylcarboxamido) benzoic acid, 2-carboxamide (arylsulfonamido)benzoic acid and N-(2-(1H-tetrazol-5-yl)phenyl)-arylcarboxamide), showed potent activity towards late-stage gametocytes (stage IV/V) of P. falciparum, with the most potent compound reaching single digit nanomolar activity. Structure-activity relationship trends were evident and frontrunner compounds also displayed microsomal stability and favourable solubility profiles. Simplified synthetic routes support further derivatization of these compounds for further development of these series as malaria transmission-blocking agents.
syntenet : an R/Bioconductor package for the inference and analysis of synteny networks
(Oxford University Press, 2023-01) Almeida-Silva, Fabricio; Zhao, Tao; Ullrich, Kristian K.; Schranz, M. Eric; Van de Peer, Yves
Interpreting and visualizing synteny relationships across several genomes is a challenging task. We previously proposed a network-based approach for better visualization and interpretation of large-scale microsynteny analyses. Here, we present syntenet, an R package to infer and analyze synteny networks from whole-genome protein sequence data. The package offers a simple and complete framework, including data preprocessing, synteny detection and network inference, network clustering and phylogenomic profiling, and microsynteny-based phylogeny inference. Graphical functions are also available to create publication-ready plots. Synteny networks inferred with syntenet can highlight taxon-specific gene clusters that likely contributed to the evolution of important traits, and microsynteny-based phylogenies can help resolve phylogenetic relationships under debate.
By blood or by choice? On relational autonomy and the familial ties that bind us
(Stellenbosch University, Faculty of Theology, 2022) Van Wyk, Tanya; tanya.vanwyk@up.ac.za
This article explores the range of the construct “family” in light of the author’s experience of how the death of a congregation-member exposed the strength, persistence and immovability of the construct, “family”. Despite different attempts and approaches to deconstruct and broaden the notion of what family refers to that originated in the 1970s, a traditional notion of what kinship (family) entails remains focused on ties that bind people by blood or by marriage. The article provides a brief overview and evaluation of different attempts at a postmodern understanding of family, but ultimately it is illustrated that there has been little change to the construct of family. The notion of “relational autonomy” from a Trinitarian theological perspective is presented as a more thorough foundation for familial ties that are characterised by a creative tension of both distance and belonging. This theological foundation provides a point of departure for a dynamic understanding of the range of choices related to what constitutes, “family”, which does not cast someone in the stone of the construct of a “family”, even beyond their own death.
Novel 3-trifluoromethyl-1,2,4-oxadiazole analogues of astemizole with multi-stage antiplasmodium activity and in vivo efficacy in a Plasmodium berghei mouse malaria infection model
(American Chemical Society, 2022-12) Mambwe, Dickson; Korkor, Constance M.; Mabhula, Amanda; Ngqumba, Zama; Cloete, Cleavon; Kumar, Malkeet; Barros, Paula Ladeia; Leshabane, Meta Kgaogelo; Coertzen, Dina; Taylor, Dale; Gibhard, Liezl; Njoroge, Mathew; Lawrence, Nina; Reader, Janette; Moreira, Diogo Rodrigo; Birkholtz, Lyn-Marie; Wittlin, Sergio; Egan, Timothy J.; Chibale, Kelly
Please read abstract in the article.
Population genetics of a lethally managed medium-sized predator
(Wiley, 2022-09) Slater, K.; De Jager, Deon; Van Wyk, A.M.; Dalton, Desire Lee; Kropff, Anna S.; Du Preez, Ilse
Globally, levels of human–wildlife conflict are increasing as a direct consequence of the expansion of people into natural areas resulting in competition with wildlife for food and other resources. By being forced into increasingly smaller pockets of suitable habitat, many animal species are at risk of becoming susceptible to loss of genetic diversity, inbreeding depression and the associated inability to adapt to environmental changes. Predators are often lethally controlled due to their threat to livestock. Predators such as jackals (black backed, golden and side striped; Canis mesomelas, C. aureus and C. adustus, respectively), red foxes (Vulpes vulpes) and coyotes (C. latrans) are highly adaptable and may respond to ongoing persecution through compensatory reproduction such as reproducing at a younger age, producing larger litters and/or compensatory immigration including dispersal into vacant territories. Despite decades of lethal management, jackals are problematic predators of livestock in South Africa and, although considered a temporary measure, culling of jackals is still common. Culling may affect social groups, kinship structure, reproductive strategies and sex-biased dispersal in this species. Here, we investigated genetic structure, variation and relatedness of 178 culled jackals on private small-livestock farms in the central Karoo of South Africa using 13 microsatellites. Genetic variation was moderate to high and was similar per year and per farm. An absence of genetic differentiation was observed based on STRUCTURE, principal component analysis and AMOVA. Relatedness was significantly higher within farms (r = 0.189) than between farms (r = 0.077), a result corroborated by spatial autocorrelation analysis. We documented 18 occurrences of dispersal events where full siblings were detected on different farms (range: 0.78–42.93 km). Distance between identified parent–offspring varied from 0 to 36.49 km. No evidence for sex-biased dispersal was found. Our results suggest that in response to ongoing lethal management, this population is most likely able to maintain genetic diversity through physiological and behavioural compensation mechanisms.
Sapwood mycobiome varies across host, plant compartment and environments in Nothofagus forests from Northern Patagonia
(Wiley, 2023-12) Molina, Lucia; Rajchenberg, Mario; De Errasti, Andres; Vogel, Braian; Coetzee, Martin Petrus Albertus; Aime, Mary Catherine; Pildain, Maria Belen
Global forests are increasingly being threatened by altered climatic conditions and increased attacks by pests and pathogens. The complex ecological interactions among pathogens, microbial communities, tree hosts and the environment are important drivers of forest dynamics. Little is known about the ecology of forest pathology and related microbial communities in temperate forests of the southern hemisphere. In this study, we used next-generation sequencing to characterize sapwood-inhabiting fungal communities in North Patagonian Nothofagus forests and assessed patterns of diversity of taxa and ecological guilds across climatic, site and host variables (health condition and compartment) as a contribution to Nothofagus autecology. The diversity patterns inferred through the metabarcoding analysis were similar to those obtained through culture-dependent approaches. However, we detected additional heterogeneity and greater richness with culture-free methods. Host species was the strongest driver of fungal community structure and composition, while host health status was the weakest. The relative impacts of site, season, plant compartment and health status were different for each tree species; these differences can be interpreted as a matter of water availability. For Nothofagus dombeyi, which is distributed across a wide range of climatic conditions, site was the strongest driver of community composition. The microbiome of N. pumilio varied more with season and temperature, a relevant factor for forest conservation in the present climate change scenario. Both species carry a number of potential fungal pathogens in their sapwood, whether they exhibit symptoms or not. Our results provide insight into the diversity of fungi associated with the complex pathobiome of the dominant Nothofagus species in southern South America.
The predictive ability of the 313 variant–based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant
(Elsevier, 2021-06-10) Lakeman, Inge M.M.; Van den Broek, Alexandra J.; Vos, Julien A.M.; Barnes, Daniel R.; Adlard, Julian; Andrulis, Irene L.; Arason, Adalgeir; Arnold, Norbert; Arun, Banu K.; Balmana, Judith; Barrowdale, Daniel; Benitez, Javier; Borg, Ake; Caldes, Trinidad; Caligo, Maria A.; Chung, Wendy K.; Claes, Kathleen B.M.; GEMO Study Collaborators; EMBRACE Collaborators; Collee, J. Margriet; Couch, Fergus J.; Daly, Mary B.; Dennis, Joe; Dhawan, Mallika; Domchek, Susan M.; Eeles, Ros; Engel, Christoph; Evans, D. Gareth; Feliubadalo, Lidia; Foretova, Lenka; Friedman, Eitan; Frost, Debra; Ganz, Patricia A.; Garber, Judy; Gayther, Simon A.; Gerdes, Anne-Marie; Godwin, Andrew K.; Goldgar, David E.; Hahnen, Eric; Hake, Christopher R.; Hamann, Ute; Hogervorst, Frans B.L.; Hooning, Maartje J.; Hopper, John L.; Hulick, Peter J.; Imyanitov, Evgeny N.; OCGN Investigators; HEBON Investigators; KconFab Investigators; Isaacs, Claudine; Izatt, Louise; Jakubowska, Anna; James, Paul A.; Janavicius, Ramunas; Jensen, Uffe Birk; Jiao, Yue; John, Esther M.; Joseph, Vijai; Karlan, Beth Y.; Kets, Carolien M.; Konstantopoulou, Irene; Kwong, Ava; Legrand, Clementine; Leslie, Goska; Lesueur, Fabienne; Loud, Jennifer T.; Lubinski, Jan; Manoukian, Siranoush; McGuffog, Lesley; Miller, Austin; Gomes, Denise Molina; Montagna, Marco; Mouret-Fourme, Emmanuelle; Nathanson, Katherine L.; Neuhausen, Susan L.; Nevanlinna, Heli; Yuen Yie, Joanne Ngeow; Olah, Edith; Olopade, Olufunmilayo I.; Park, Sue K.; Parsons, Michael T.; Peterlongo, Paolo; Piedmonte, Marion; Radice, Paolo; Rantala, Johanna; Rennert, Gad; Risch, Harvey A.; Schmutzler, Rita K.; Sharma, Priyanka; Simard, Jacques; Singer, Christian F.; Stadler, Zsofia; Stoppa-Lyonnet, Dominique; Sutter, Christian; Tan, Yen Yen; Teixeira, Manuel R.; Teo, Soo Hwang; Teule, Alex; Thomassen, Mads; Thull, Darcy L.; Tischkowitz, Marc; Toland, Amanda E.; Tung, Nadine; Janse van Rensburg, Elizabeth
PURPOSE : To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. METHODS : We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. RESULTS : For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06–1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR= 1.15, 95% CI (1.07–1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. CONCLUSION : The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decisionmaking.

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