Publications by authors named "Murray P Cox"

105 Publications

Chromosome-level genomes provide insights into genome evolution, organization and size in Epichloe fungi.

Genomics 2021 Nov 12;113(6):4267-4275. Epub 2021 Nov 12.

Plant Ecological Genetics Group, Institute of Integrative Biology, ETH Zurich, 8092 Zurich, Switzerland.

Epichloe fungi are endophytes of cool season grasses, both wild species and commercial cultivars, where they may exhibit mutualistic or pathogenic lifestyles. The Epichloe-grass symbiosis is of great interest to agricultural research for the fungal bioprotective properties conferred to host grasses but also serves as an ideal system to study the evolution of fungal plant-pathogens in natural environments. Here, we assembled and annotated gapless chromosome-level genomes of two pathogenic Epichloe sibling species. Both genomes have a bipartite genome organization, with blocks of highly syntenic gene-rich regions separated by blocks of AT-rich DNA. The AT-rich regions show an extensive signature of RIP (repeat-induced point mutation) and the expansion of this compartment accounts for the large difference in genome size between the two species. This study reveals how the rapid evolution of repeat structure can drive divergence between closely related taxa and highlights the evolutionary role of dynamic compartments in fungal genomes.
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http://dx.doi.org/10.1016/j.ygeno.2021.11.009DOI Listing
November 2021

An informatics consult approach for generating clinical evidence for treatment decisions.

BMC Med Inform Decis Mak 2021 10 12;21(1):281. Epub 2021 Oct 12.

Institute of Health Informatics, University College London, London, UK.

Background: An Informatics Consult has been proposed in which clinicians request novel evidence from large scale health data resources, tailored to the treatment of a specific patient. However, the availability of such consultations is lacking. We seek to provide an Informatics Consult for a situation where a treatment indication and contraindication coexist in the same patient, i.e., anti-coagulation use for stroke prevention in a patient with both atrial fibrillation (AF) and liver cirrhosis.

Methods: We examined four sources of evidence for the effect of warfarin on stroke risk or all-cause mortality from: (1) randomised controlled trials (RCTs), (2) meta-analysis of prior observational studies, (3) trial emulation (using population electronic health records (N = 3,854,710) and (4) genetic evidence (Mendelian randomisation). We developed prototype forms to request an Informatics Consult and return of results in electronic health record systems.

Results: We found 0 RCT reports and 0 trials recruiting for patients with AF and cirrhosis. We found broad concordance across the three new sources of evidence we generated. Meta-analysis of prior observational studies showed that warfarin use was associated with lower stroke risk (hazard ratio [HR] = 0.71, CI 0.39-1.29). In a target trial emulation, warfarin was associated with lower all-cause mortality (HR = 0.61, CI 0.49-0.76) and ischaemic stroke (HR = 0.27, CI 0.08-0.91). Mendelian randomisation served as a drug target validation where we found that lower levels of vitamin K1 (warfarin is a vitamin K1 antagonist) are associated with lower stroke risk. A pilot survey with an independent sample of 34 clinicians revealed that 85% of clinicians found information on prognosis useful and that 79% thought that they should have access to the Informatics Consult as a service within their healthcare systems. We identified candidate steps for automation to scale evidence generation and to accelerate the return of results.

Conclusion: We performed a proof-of-concept Informatics Consult for evidence generation, which may inform treatment decisions in situations where there is dearth of randomised trials. Patients are surprised to know that their clinicians are currently not able to learn in clinic from data on 'patients like me'. We identify the key challenges in offering such an Informatics Consult as a service.
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http://dx.doi.org/10.1186/s12911-021-01638-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8506488PMC
October 2021

Correlated Transcriptional Responses Provide Insights into the Synergy Mechanisms of the Furazolidone, Vancomycin, and Sodium Deoxycholate Triple Combination in Escherichia coli.

mSphere 2021 Oct 8;6(5):e0062721. Epub 2021 Sep 8.

School of Fundamental Sciences, Massey Universitygrid.148374.d, Palmerston North, New Zealand.

Effective therapeutic options are urgently needed to tackle antibiotic resistance. Furazolidone (FZ), vancomycin (VAN), and sodium deoxycholate (DOC) show promise as their combination can synergistically inhibit the growth of, and kill, multidrug-resistant Gram-negative bacteria that are classified as critical priority by the World Health Organization. Here, we investigated the mechanisms of action and synergy of this drug combination using a transcriptomics approach in the model bacterium Escherichia coli. We show that FZ and DOC elicit highly similar gene perturbations indicative of iron starvation, decreased respiration and metabolism, and translational stress. In contrast, VAN induced envelope stress responses, in agreement with its known role in peptidoglycan synthesis inhibition. FZ induces the SOS response consistent with its DNA-damaging effects, but we demonstrate that using FZ in combination with the other two compounds enables lower dosages and largely mitigates its mutagenic effects. Based on the gene expression changes identified, we propose a synergy mechanism where the combined effects of FZ, VAN, and DOC amplify damage to Gram-negative bacteria while simultaneously suppressing antibiotic resistance mechanisms. Synergistic antibiotic combinations are a promising alternative strategy for developing effective therapies for multidrug-resistant bacterial infections. The synergistic combination of the existing antibiotics nitrofurans and vancomycin with sodium deoxycholate shows promise in inhibiting and killing multidrug-resistant Gram-negative bacteria. We examined the mechanism of action and synergy of these three antibacterials and proposed a mechanistic basis for their synergy. Our results highlight much-needed mechanistic information necessary to advance this combination as a potential therapy.
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http://dx.doi.org/10.1128/mSphere.00627-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550143PMC
October 2021

Papua New Guinean Genomes Reveal the Complex Settlement of North Sahul.

Mol Biol Evol 2021 Oct;38(11):5107-5121

Laboratoire Évolution and Diversité Biologique (EDB UMR 5174), Université de Toulouse Midi-Pyrénées, CNRS, IRD, UPS, Toulouse, France.

The settlement of Sahul, the lost continent of Oceania, remains one of the most ancient and debated human migrations. Modern New Guineans inherited a unique genetic diversity tracing back 50,000 years, and yet there is currently no model reconstructing their past population dynamics. We generated 58 new whole-genome sequences from Papua New Guinea, filling geographical gaps in previous sampling, specifically to address alternative scenarios of the initial migration to Sahul and the settlement of New Guinea. Here, we present the first genomic models for the settlement of northeast Sahul considering one or two migrations from Wallacea. Both models fit our data set, reinforcing the idea that ancestral groups to New Guinean and Indigenous Australians split early, potentially during their migration in Wallacea where the northern route could have been favored. The earliest period of human presence in Sahul was an era of interactions and gene flow between related but already differentiated groups, from whom all modern New Guineans, Bismarck islanders, and Indigenous Australians descend. The settlement of New Guinea was probably initiated from its southeast region, where the oldest archaeological sites have been found. This was followed by two migrations into the south and north lowlands that ultimately reached the west and east highlands. We also identify ancient gene flows between populations in New Guinea, Australia, East Indonesia, and the Bismarck Archipelago, emphasizing the fact that the anthropological landscape during the early period of Sahul settlement was highly dynamic rather than the traditional view of extensive isolation.
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http://dx.doi.org/10.1093/molbev/msab238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557464PMC
October 2021

Evolution of virulence in a novel family of transmissible mega-plasmids.

Environ Microbiol 2021 Sep 24;23(9):5289-5304. Epub 2021 May 24.

Forage Science, AgResearch, Lincoln Research Centre, Christchurch, New Zealand.

Some Serratia entomophila isolates have been successfully exploited in biopesticides due to their ability to cause amber disease in larvae of the Aotearoa (New Zealand) endemic pasture pest, Costelytra giveni. Anti-feeding prophage and ABC toxin complex virulence determinants are encoded by a 153-kb single-copy conjugative plasmid (pADAP; amber disease-associated plasmid). Despite growing understanding of the S. entomophila pADAP model plasmid, little is known about the wider plasmid family. Here, we sequence and analyse mega-plasmids from 50 Serratia isolates that induce variable disease phenotypes in the C. giveni insect host. Mega-plasmids are highly conserved within S. entomophila, but show considerable divergence in Serratia proteamaculans with other variants in S. liquefaciens and S. marcescens, likely reflecting niche adaption. In this study to reconstruct ancestral relationships for a complex mega-plasmid system, strong co-evolution between Serratia species and their plasmids were found. We identify 12 distinct mega-plasmid genotypes, all sharing a conserved gene backbone, but encoding highly variable accessory regions including virulence factors, secondary metabolite biosynthesis, Nitrogen fixation genes and toxin-antitoxin systems. We show that the variable pathogenicity of Serratia isolates is largely caused by presence/absence of virulence clusters on the mega-plasmids, but notably, is augmented by external chromosomally encoded factors.
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http://dx.doi.org/10.1111/1462-2920.15595DOI Listing
September 2021

Comparative genomics reveals a core gene toolbox for lifestyle transitions in Hypocreales fungi.

Environ Microbiol 2021 06 11;23(6):3251-3264. Epub 2021 May 11.

Statistics and Bioinformatics Group, School of Fundamental Sciences, Massey University, Palmerston North, 4410, New Zealand.

Fungi have evolved diverse lifestyles and adopted pivotal new roles in both natural ecosystems and human environments. However, the molecular mechanisms underlying their adaptation to new lifestyles are obscure. Here, we hypothesize that genes shared across all species with the same lifestyle, but absent in genera with alternative lifestyles, are crucial to that lifestyle. By analysing dozens of species within four genera in a fungal order, with each genus following a different lifestyle, we find that genus-specific genes are typically few in number. Notably, not all genus-specific genes appear to derive from de novo birth, with most instead reflecting recurrent loss across the fungi. Importantly, however, a subset of these genus-specific genes are shared by fungi with the same lifestyle in quite different evolutionary orders, thus supporting the view that some genus-specific genes are necessary for specific lifestyles. These lifestyle-specific genes are enriched for key functional classes and often exhibit specialized expression patterns. Genus-specific selection also contributes to lifestyle transitions, and is especially associated with intensity of pathogenesis. Our study, therefore, suggests that fungal adaptation to new lifestyles often requires just a small number of core genes, with gene turnover and positive selection playing complementary roles.
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http://dx.doi.org/10.1111/1462-2920.15554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360070PMC
June 2021

Widespread Denisovan ancestry in Island Southeast Asia but no evidence of substantial super-archaic hominin admixture.

Nat Ecol Evol 2021 05 22;5(5):616-624. Epub 2021 Mar 22.

ARC Centre of Excellence for Australian Biodiversity and Heritage (CABAH), University of New South Wales, Sydney, New South Wales, Australia.

The hominin fossil record of Island Southeast Asia (ISEA) indicates that at least two endemic 'super-archaic' species-Homo luzonensis and H. floresiensis-were present around the time anatomically modern humans arrived in the region >50,000 years ago. Intriguingly, contemporary human populations across ISEA carry distinct genomic traces of ancient interbreeding events with Denisovans-a separate hominin lineage that currently lacks a fossil record in ISEA. To query this apparent disparity between fossil and genetic evidence, we performed a comprehensive search for super-archaic introgression in >400 modern human genomes, including >200 from ISEA. Our results corroborate widespread Denisovan ancestry in ISEA populations, but fail to detect any substantial super-archaic admixture signals compatible with the endemic fossil record of ISEA. We discuss the implications of our findings for the understanding of hominin history in ISEA, including future research directions that might help to unlock more details about the prehistory of the enigmatic Denisovans.
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http://dx.doi.org/10.1038/s41559-021-01408-0DOI Listing
May 2021

Characterization of Bicistronic Transcription in Budding Yeast.

mSystems 2021 Feb 23;6(1). Epub 2021 Feb 23.

Statistics and Bioinformatics Group, School of Fundamental Sciences, Massey University, Palmerston North, New Zealand

Bicistronic transcripts (operon-like transcripts) have occasionally been reported in eukaryotes, including unicellular yeasts, plants, and humans, despite the fact that they lack -splice mechanisms. However, the characteristics of eukaryotic bicistronic transcripts are poorly understood, except for those in nematodes. Here, we describe the genomic, transcriptomic, and ribosome profiling features of bicistronic transcripts in unicellular yeasts. By comparing the expression level of bicistronic transcripts with their monocistronic equivalents, we identify two main categories of bicistronic transcripts: highly and lowly expressed. These two categories exhibit quite different features. First, highly expressed bicistronic transcripts have higher conservation within and between strains and shorter intergenic spacers with higher GC content and less stable secondary structure. Second, genes in highly expressed bicistronic transcripts have lower translation efficiency, with the second gene showing statistically significant lower translation efficiency than the first. Finally, the genes found in these highly expressed bicistronic transcripts tend to be younger, with more recent origins. Together, these results suggest that bicistronic transcripts in yeast are heterogeneous. We further propose that at least some highly expressed bicistronic transcripts appear to play a role in modulating monocistronic translation. Operons, where a single mRNA transcript encodes multiple adjacent proteins, are a widespread feature of bacteria and archaea. In contrast, the genes of eukaryotes are generally considered monocistronic. However, a number of studies have revealed the presence of bicistronic transcripts in eukaryotes, including humans. The basic features of these transcripts are largely unknown in eukaryotes, especially in organisms lacking -splice mechanisms. Our analyses characterize bicistronic transcripts in one such eukaryotic group, yeasts. We show that highly expressed bicistronic transcripts have unusual features compared to lowly expressed bicistronic transcripts, with several features influencing translational modulation.
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http://dx.doi.org/10.1128/mSystems.01002-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8573964PMC
February 2021

Regulation of host-infection ability in the grass-symbiotic fungus Epichloë festucae by histone H3K9 and H3K36 methyltransferases.

Environ Microbiol 2021 04 31;23(4):2116-2131. Epub 2020 Dec 31.

School of Fundamental Sciences, Massey University, Palmerston North, New Zealand.

Recent studies have identified key genes that control the symbiotic interaction between Epichloë festucae and Lolium perenne. Here we report on the identification of specific E. festucae genes that control host infection. Deletion of setB, which encodes a homologue of the H3K36 histone methyltransferase Set2/KMT3, reduced histone H3K36 trimethylation and led to severe defects in colony growth and hyphal development. The E. festucae ΔclrD mutant, which lacks the gene encoding the homologue of the H3K9 methyltransferase KMT1, displays similar developmental defects. Both mutants are completely defective in their ability to infect L. perenne. Alleles that complement the culture and plant phenotypes of both mutants also complement the histone methylation defects. Co-inoculation of either ΔsetB or ΔclrD with the wild-type strain enables these mutants to colonize the host. However, successful colonization by the mutants resulted in death or stunting of the host plant. Transcriptome analysis at the early infection stage identified four fungal candidate genes, three of which encode small-secreted proteins, that are differentially regulated in these mutants compared to wild type. Deletion of crbA, which encodes a putative carbohydrate binding protein, resulted in significantly reduced host infection rates by E. festucae.
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http://dx.doi.org/10.1111/1462-2920.15370DOI Listing
April 2021

Dense sampling of bird diversity increases power of comparative genomics.

Nature 2020 11 11;587(7833):252-257. Epub 2020 Nov 11.

Centre for Zoo and Wild Animal Health, Copenhagen Zoo, Frederiksberg, Denmark.

Whole-genome sequencing projects are increasingly populating the tree of life and characterizing biodiversity. Sparse taxon sampling has previously been proposed to confound phylogenetic inference, and captures only a fraction of the genomic diversity. Here we report a substantial step towards the dense representation of avian phylogenetic and molecular diversity, by analysing 363 genomes from 92.4% of bird families-including 267 newly sequenced genomes produced for phase II of the Bird 10,000 Genomes (B10K) Project. We use this comparative genome dataset in combination with a pipeline that leverages a reference-free whole-genome alignment to identify orthologous regions in greater numbers than has previously been possible and to recognize genomic novelties in particular bird lineages. The densely sampled alignment provides a single-base-pair map of selection, has more than doubled the fraction of bases that are confidently predicted to be under conservation and reveals extensive patterns of weak selection in predominantly non-coding DNA. Our results demonstrate that increasing the diversity of genomes used in comparative studies can reveal more shared and lineage-specific variation, and improve the investigation of genomic characteristics. We anticipate that this genomic resource will offer new perspectives on evolutionary processes in cross-species comparative analyses and assist in efforts to conserve species.
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http://dx.doi.org/10.1038/s41586-020-2873-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759463PMC
November 2020

Comparative genetic diversity of species causing human infections.

Parasitology 2020 11 10;147(13):1532-1537. Epub 2020 Aug 10.

Molecular Epidemiology and Public Health Laboratory, Hopkirk Research Institute, School of Veterinary Science, Massey University, Private Bag 11 222, Palmerston North, 4442, New Zealand.

Parasites sometimes expand their host range and cause new disease aetiologies. Genetic changes can then occur due to host-specific adaptive alterations, particularly when parasites cross between evolutionarily distant hosts. Characterizing genetic variation in Cryptosporidium from humans and other animals may have important implications for understanding disease dynamics and transmission. We analyse sequences from four loci (gp60, HSP-70, COWP and actin) representing multiple Cryptosporidium species reported in humans. We predicted low genetic diversity in species that present unusual human infections due to founder events and bottlenecks. High genetic diversity was observed in isolates from humans of Cryptosporidium meleagridis, Cryptosporidium cuniculus, Cryptosporidium hominis and Cryptosporidium parvum. A deviation of expected values of neutrality using Tajima's D was observed in C. cuniculus and C. meleagridis. The high genetic diversity in C. meleagridis and C. cuniculus did not match our expectations but deviations from neutrality indicate a recent decrease in genetic variability through a population bottleneck after an expansion event. Cryptosporidium hominis was also found with a significant Tajima's D positive value likely caused by recent population expansion of unusual genotypes in humans. These insights indicate that changes in genetic diversity can help us to understand host-parasite adaptation and evolution.
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http://dx.doi.org/10.1017/S0031182020001493DOI Listing
November 2020

Papuan mitochondrial genomes and the settlement of Sahul.

J Hum Genet 2020 Oct 1;65(10):875-887. Epub 2020 Jun 1.

Laboratoire Évolution and Diversité Biologique (EDB UMR 5174), Université de Toulouse Midi-Pyrénées, CNRS, IRD, UPS, 118 route de Narbonne, Bat 4R1, 31062, Toulouse, France.

New Guineans represent one of the oldest locally continuous populations outside Africa, harboring among the greatest linguistic and genetic diversity on the planet. Archeological and genetic evidence suggest that their ancestors reached Sahul (present day New Guinea and Australia) by at least 55,000 years ago (kya). However, little is known about this early settlement phase or subsequent dispersal and population structuring over the subsequent period of time. Here we report 379 complete Papuan mitochondrial genomes from across Papua New Guinea, which allow us to reconstruct the phylogenetic and phylogeographic history of northern Sahul. Our results support the arrival of two groups of settlers in Sahul within the same broad time window (50-65 kya), each carrying a different set of maternal lineages and settling Northern and Southern Sahul separately. Strong geographic structure in northern Sahul remains visible today, indicating limited dispersal over time despite major climatic, cultural, and historical changes. However, following a period of isolation lasting nearly 20 ky after initial settlement, environmental changes postdating the Last Glacial Maximum stimulated diversification of mtDNA lineages and greater interactions within and beyond Northern Sahul, to Southern Sahul, Wallacea and beyond. Later, in the Holocene, populations from New Guinea, in contrast to those of Australia, participated in early interactions with incoming Asian populations from Island Southeast Asia and continuing into Oceania.
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http://dx.doi.org/10.1038/s10038-020-0781-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449881PMC
October 2020

Genome-wide DNA methylation and gene expression patterns reflect genetic ancestry and environmental differences across the Indonesian archipelago.

PLoS Genet 2020 05 26;16(5):e1008749. Epub 2020 May 26.

Melbourne Integrative Genomics, University of Melbourne, Parkville, Australia.

Indonesia is the world's fourth most populous country, host to striking levels of human diversity, regional patterns of admixture, and varying degrees of introgression from both Neanderthals and Denisovans. However, it has been largely excluded from the human genomics sequencing boom of the last decade. To serve as a benchmark dataset of molecular phenotypes across the region, we generated genome-wide CpG methylation and gene expression measurements in over 100 individuals from three locations that capture the major genomic and geographical axes of diversity across the Indonesian archipelago. Investigating between- and within-island differences, we find up to 10.55% of tested genes are differentially expressed between the islands of Sumba and New Guinea. Variation in gene expression is closely associated with DNA methylation, with expression levels of 9.80% of genes correlating with nearby promoter CpG methylation, and many of these genes being differentially expressed between islands. Genes identified in our differential expression and methylation analyses are enriched in pathways involved in immunity, highlighting Indonesia's tropical role as a source of infectious disease diversity and the strong selective pressures these diseases have exerted on humans. Finally, we identify robust within-island variation in DNA methylation and gene expression, likely driven by fine-scale environmental differences across sampling sites. Together, these results strongly suggest complex relationships between DNA methylation, transcription, archaic hominin introgression and immunity, all jointly shaped by the environment. This has implications for the application of genomic medicine, both in critically understudied Indonesia and globally, and will allow a better understanding of the interacting roles of genomic and environmental factors shaping molecular and complex phenotypes.
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http://dx.doi.org/10.1371/journal.pgen.1008749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274483PMC
May 2020

Plant Resistance and Susceptibility to Petal Blight Disease Are Defined by the Timing of Defense Responses.

Mol Plant Microbe Interact 2020 Jul 20;33(7):982-995. Epub 2020 May 20.

School of Fundamental Sciences, Massey University, Palmerston North, New Zealand.

The family Sclerotiniaceae includes important phytopathogens, such as and , that activate plant immune responses to facilitate infection propagation. The mechanisms of plant resistance to these necrotrophic pathogens are still poorly understood. To discover mechanisms of resistance, we used the (Sclerotiniaceae)- spp. pathosystem. This fungus induces rapid infection of the blooms of susceptible cultivar Nicky Crisp ( × var. ), while is highly resistant. Genome-wide analysis of gene expression in resistant plants revealed fast modulation of host transcriptional activity 6 h after ascospore inoculation. Ascospores induced the same defense pathways in the susceptible cultivar but much delayed and coinciding with disease development. We next tested the hypothesis that differences in defense timing influences disease outcome. We induced early defense in the susceptible cultivar using methyl jasmonate and this strongly reduced disease development. Conversely, delaying the response in the resistant species, by infecting it with actively growing fungal mycelium, increased susceptibility. The same plant defense pathways, therefore, contribute to both resistance and susceptibility, suggesting that defense timing is a critical factor in plant health, and resistance against necrotrophic pathogens may occur during the initial biotrophy-like stages.
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http://dx.doi.org/10.1094/MPMI-10-19-0304-RDOI Listing
July 2020

Conservation and expansion of a necrosis-inducing small secreted protein family from host-variable phytopathogens of the Sclerotiniaceae.

Mol Plant Pathol 2020 04 15;21(4):512-526. Epub 2020 Feb 15.

School of Fundamental Sciences, Massey University, Palmerston North, New Zealand.

Fungal effector proteins facilitate host-plant colonization and have generally been characterized as small secreted proteins (SSPs). We classified and functionally tested SSPs from the secretomes of three closely related necrotrophic phytopathogens: Ciborinia camelliae, Botrytis cinerea, and Sclerotinia sclerotiorum. Alignment of predicted SSPs identified a large protein family that share greater than 41% amino acid identity and that have key characteristics of previously described microbe-associated molecular patterns (MAMPs). Strikingly, 73 of the 75 SSP family members were predicted within the secretome of the host-specialist C. camelliae with single-copy homologs identified in the secretomes of the host generalists S. sclerotiorum and B. cinerea. To explore the potential function of this family of SSPs, 10 of the 73 C. camelliae proteins, together with the single-copy homologs from S. sclerotiorum (SsSSP3) and B. cinerea (BcSSP2), were cloned and expressed as recombinant proteins. Infiltration of SsSSP3 and BcSSP2 into host tissue induced rapid necrosis. In contrast, only one of the 10 tested C. camelliae SSPs was able to induce a limited amount of necrosis. Analysis of chimeric proteins consisting of domains from both a necrosis-inducing and a non-necrosis-inducing SSP demonstrated that the C-terminus of the S. sclerotiorum SSP is essential for necrosis-inducing function. Deletion of the BcSSP2 homolog from B. cinerea did not affect growth or pathogenesis. Thus, this research uncovered a family of highly conserved SSPs present in diverse ascomycetes that exhibit contrasting necrosis-inducing functions.
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http://dx.doi.org/10.1111/mpp.12913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060139PMC
April 2020

Correction to: Archaic mitochondrial DNA inserts in modern day nuclear genomes.

BMC Genomics 2020 01 17;21(1):55. Epub 2020 Jan 17.

Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, D04103, Leipzig, Germany.

Following the publication of this article [1], the authors reported that the captions of Figs. 3 and 4 were published in the incorrect order, whereby they mismatch with their corresponding images.
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http://dx.doi.org/10.1186/s12864-020-6449-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966873PMC
January 2020

Archaic mitochondrial DNA inserts in modern day nuclear genomes.

BMC Genomics 2019 Dec 26;20(1):1017. Epub 2019 Dec 26.

Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Deutscher Platz 6, Leipzig, D04103, Germany.

Background: Traces of interbreeding of Neanderthals and Denisovans with modern humans in the form of archaic DNA have been detected in the genomes of present-day human populations outside sub-Saharan Africa. Up to now, only nuclear archaic DNA has been detected in modern humans; we therefore attempted to identify archaic mitochondrial DNA (mtDNA) residing in modern human nuclear genomes as nuclear inserts of mitochondrial DNA (NUMTs).

Results: We analysed 221 high-coverage genomes from Oceania and Indonesia using an approach which identifies reads that map both to the nuclear and mitochondrial DNA. We then classified reads according to the source of the mtDNA, and found one NUMT of Denisovan mtDNA origin, present in 15 analysed genomes; analysis of the flanking region suggests that this insertion is more likely to have happened in a Denisovan individual and introgressed into modern humans with the Denisovan nuclear DNA, rather than in a descendant of a Denisovan female and a modern human male.

Conclusions: Here we present our pipeline for detecting introgressed NUMTs in next generation sequencing data that can be used on genomes sequenced in the future. Further discovery of such archaic NUMTs in modern humans can be used to detect interbreeding between archaic and modern humans and can reveal new insights into the nature of such interbreeding events.
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http://dx.doi.org/10.1186/s12864-019-6392-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933719PMC
December 2019

Chromosome-Level Reference Genome of , Causative Agent of Pecan Scab.

Mol Plant Microbe Interact 2020 Feb 2;33(2):149-152. Epub 2019 Dec 2.

Noble Research Institute, LLC, Ardmore, OK 73401, U.S.A.

Pecan scab, caused by , is a devastating disease of pecan (), which results in economic losses on susceptible cultivars throughout the southeastern United States. To enhance our understanding of pathogenicity in , we have generated a complete telomere-to-telomere reference genome of isolate FRT5LL7-Albino. By combining Illumina MiSeq and Oxford Nanopore MinION data, we assembled a 45.2-Mb genome represented by 20 chromosomes and containing 10,820 putative genes, of which 7,619 have at least one functional annotation. The likely causative mutation of the albino phenotype was identified as a single base insertion and a resulting frameshift in the gene encoding the polyketide synthase . This genome represents the first full chromosome-level assembly of any sp.
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http://dx.doi.org/10.1094/MPMI-08-19-0236-ADOI Listing
February 2020

Greater genetic and regulatory plasticity of retained duplicates in Epichloë endophytic fungi.

Mol Ecol 2019 12 6;28(23):5103-5114. Epub 2019 Nov 6.

Statistics and Bioinformatics Group, School of Fundamental Sciences, Massey University, Palmerston North, New Zealand.

Gene duplicates can act as a source of genetic material from which new functions arise. Most duplicated genes revert to single copy genes and only a small proportion are retained. However, it remains unclear why some duplicate genes persist in the genome for an extended time. We investigate this question by analysing retained gene duplicates in the fungal genus Epichloë, ascomycete fungi that form close endophytic symbioses with their host grasses. Retained duplicates within this genus have two independent origins, but both long pre-date the origin and diversification of the genus Epichloë. We find that loss of retained duplicates within the genus is frequent and often associated with speciation. Retained duplicates have faster evolutionary rates (Ka) and show relaxed selection (Ka/Ks) compared to single copy genes. Both features are time-dependent. Through comparison of conspecific strains, we find greater evolutionary rates in coding regions and sequence divergence in regulatory regions of retained duplicates than single copy genes, with this pattern more pronounced for strains adapted to different grass host species. Consistent with this sequence divergence in regulatory regions, transcriptome analyses show greater expression variation of retained duplicates than single copy genes. This suggest that cis-regulatory changes make important contributions to the expression patterns of retained duplicates. Coupled with supporting observations from the model yeast Saccharomyces cerevisiae, these data suggest that genetic robustness and regulatory plasticity are common drivers behind the retention of duplicated genes in fungi.
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http://dx.doi.org/10.1111/mec.15275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004115PMC
December 2019

Sex-linked genetic diversity originates from persistent sociocultural processes at microgeographic scales.

R Soc Open Sci 2019 Aug 28;6(8):190733. Epub 2019 Aug 28.

Statistics and Bioinformatics Group, School of Fundamental Sciences, Massey University, Palmerston North 4410, New Zealand.

Population genetics has been successful at identifying the relationships between human groups and their interconnected histories. However, the link between genetic demography inferred at large scales and the individual human behaviours that ultimately generate that demography is not always clear. While anthropological and historical context are routinely presented as adjuncts in population genetic studies to help describe the past, determining how underlying patterns of human sociocultural behaviour impact genetics still remains challenging. Here, we analyse patterns of genetic variation in village-scale samples from two islands in eastern Indonesia, patrilocal Sumba and a matrilocal region of Timor. Adopting a 'process modelling' approach, we iteratively explore combinations of structurally different models as a thinking tool. We find interconnected socio-genetic interactions involving sex-biased migration, lineage-focused founder effects, and on Sumba, heritable social dominance. Strikingly, founder ideology, a cultural model derived from anthropological and archaeological studies at larger regional scales, has both its origins and impact at the scale of villages. Process modelling lets us explore these complex interactions, first by circumventing the complexity of formal inference when studying large datasets with many interacting parts, and then by explicitly testing complex anthropological hypotheses about sociocultural behaviour from a more familiar population genetic standpoint.
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http://dx.doi.org/10.1098/rsos.190733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731738PMC
August 2019

Reduced Virulence of an Introduced Forest Pathogen over 50 Years.

Microorganisms 2019 Oct 5;7(10). Epub 2019 Oct 5.

School of Fundamental Sciences and Bio-Protection Research Centre, Massey University, Palmerston North 4410, New Zealand.

Pathogen incursions are a major impediment for global forest health. How pathogens and forest trees coexist over time, without pathogens simply killing their long-lived hosts, is a critical but unanswered question. The Dothistroma Needle Blight pathogen Dothistroma septosporum was introduced into New Zealand in the 1960s and remains a low-diversity, asexual population, providing a unique opportunity to analyze the evolution of a forest pathogen. Isolates of D. septosporum collected from commercial pine forests over 50 years were compared at whole-genome and phenotype levels. Limited genome diversity and increased diversification among recent isolates support the premise of a single introduction event. Isolates from the 1960s show significantly elevated virulence against Pinus radiata seedlings and produce higher levels of the virulence factor dothistromin compared to isolates collected in the 1990s and 2000s. However, later isolates have no increased tolerance to copper, used in fungicide treatments of infested forests and traditionally assumed to be a strong selection pressure. The isolated New Zealand population of this forest pathogen therefore appears to have become less virulent over time, likely in part to maintain the viability of its long-lived host. This finding has broad implications for forest health and highlights the benefits of long-term pathogen surveys.
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http://dx.doi.org/10.3390/microorganisms7100420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843257PMC
October 2019

Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity.

Nat Immunol 2019 10 18;20(10):1299-1310. Epub 2019 Sep 18.

Research School of Chemistry, The Australian National University, Canberra, Australian Capital Territory, Australia.

Resisting and tolerating microbes are alternative strategies to survive infection, but little is known about the evolutionary mechanisms controlling this balance. Here genomic analyses of anatomically modern humans, extinct Denisovan hominins and mice revealed a TNFAIP3 allelic series with alterations in the encoded immune response inhibitor A20. Each TNFAIP3 allele encoded substitutions at non-catalytic residues of the ubiquitin protease OTU domain that diminished IκB kinase-dependent phosphorylation and activation of A20. Two TNFAIP3 alleles encoding A20 proteins with partial phosphorylation deficits seemed to be beneficial by increasing immunity without causing spontaneous inflammatory disease: A20 T108A;I207L, originating in Denisovans and introgressed in modern humans throughout Oceania, and A20 I325N, from an N-ethyl-N-nitrosourea (ENU)-mutagenized mouse strain. By contrast, a rare human TNFAIP3 allele encoding an A20 protein with 95% loss of phosphorylation, C243Y, caused spontaneous inflammatory disease in humans and mice. Analysis of the partial-phosphorylation A20 I325N allele in mice revealed diminished tolerance of bacterial lipopolysaccharide and poxvirus inoculation as tradeoffs for enhanced immunity.
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http://dx.doi.org/10.1038/s41590-019-0492-0DOI Listing
October 2019

Genetics, adaptation to environmental changes and archaic admixture in the pathogenesis of diabetes mellitus in Indigenous Australians.

Rev Endocr Metab Disord 2019 09;20(3):321-332

Statistics and Bioinformatics Group, School of Fundamental Sciences, Massey University, Palmerston North, 4410, New Zealand.

Indigenous Australians are particularly affected by type 2 diabetes mellitus (T2D) due to both their genetic susceptibility and a range of environmental and lifestyle risk factors. Recent genetic studies link predisposition to some diseases, including T2D, to alleles acquired from archaic hominins, such as Neanderthals and Denisovans, which persist in the genomes of modern humans today. Indo-Pacific human populations, including Indigenous Australians, remain extremely underrepresented in genomic research with a paucity of data examining the impact of Denisovan or Neanderthal lineages on human phenotypes in Oceania. The few genetic studies undertaken emphasize the uniqueness and antiquity of Indigenous Australian genomes, with possibly the largest proportion of Denisovan ancestry of any population in the world. In this review, we focus on the potential contributions of ancient genes/pathways to modern human phenotypes, while also highlighting the evolutionary roles of genetic adaptation to dietary and environmental changes associated with an adopted Western lifestyle. We discuss the role of genetic and epigenetic factors in the pathogenesis of T2D in understudied Indigenous Australians, including the potential impact of archaic gene lineages on this disease. Finally, we propose that greater understanding of the underlying genetic predisposition may contribute to the clinical efficacy of diabetes management in Indigenous Australians. We suggest that improved identification of T2D risk variants in Oceania is needed. Such studies promise to clarify how genetic and phenotypic differences vary between populations and, crucially, provide novel targets for personalised medical therapies in currently marginalized groups.
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http://dx.doi.org/10.1007/s11154-019-09505-zDOI Listing
September 2019

Phylogenetic determinants of toxin gene distribution in genomes of Brevibacillus laterosporus.

Genomics 2020 01 19;112(1):1042-1053. Epub 2019 Jun 19.

Statistics and Bioinformatics Group, Institute of Fundamental Sciences, Massey University, Palmerston North 4410, New Zealand.

Brevibacillus laterosporus is a globally ubiquitous, spore forming bacterium, strains of which have shown toxic activity against invertebrates and microbes and several have been patented due to their commercial potential. Relatively little is known about this bacterium. Here, we examined the genomes of six published and five newly determined genomes of B. laterosporus, with an emphasis on the relationships between known and putative toxin encoding genes, as well as the phylogenetic relationships between strains. Phylogenetically, strain relationships are similar using average nucleotide identity (ANI) values and multi-gene approaches, although PacBio sequencing revealed multiple copies of the 16S rDNA gene which lessened utility at the strain level. Based on ANI values, the New Zealand isolates were distant from other isolates and may represent a new species. While all of the genomes examined shared some putative toxicity or virulence related proteins, many specific genes were only present in a subset of strains.
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http://dx.doi.org/10.1016/j.ygeno.2019.06.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978878PMC
January 2020

Warfare induces post-marital residence change.

J Theor Biol 2019 08 3;474:52-62. Epub 2019 May 3.

Statistics and Bioinformatics Group, School of Fundamental Sciences, Massey University, Palmerston North, New Zealand; Te Pūnaha Matatini, New Zealand Complex Systems Research Centre, Centre of Research Excellence, New Zealand. Electronic address:

Post-marital residence is a sex-biased dispersal defined by the place where a newly-wed couple lives after marriage. Common choices for this practice include patrilocal residence, where the couple lives with the man's family, and matrilocal residence, where they live with the woman's family. Deviations from accepted practice typically invoke strong sanctions, but despite this pressure to conform to post-marital residence norms, residence states are unexpectedly dynamic over time. Theories have been proposed to explain the pressures, both internal and external, that drive these changes in post-marital residence state. Two of the most popular emphasize the importance of warfare, but are largely restricted to qualitative statements. Here, we develop an agent-based model that captures key features of these theories, with a particular focus on warfare. We show that warfare can change post-marital residence practices, but such change only propagates through a wider network of communities under a narrow set of conditions. Additional factors, potentially including a strong sex-bias in the division of labor, are required to induce change more widely. While warfare thus serves as an important trigger for residence change, multiple interacting forces appear to be necessary to shift communities between different post-marital residence states under most conditions.
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http://dx.doi.org/10.1016/j.jtbi.2019.05.002DOI Listing
August 2019

Breaking Free: The Genomics of Allopolyploidy-Facilitated Niche Expansion in White Clover.

Plant Cell 2019 07 25;31(7):1466-1487. Epub 2019 Apr 25.

Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus C, Denmark

The merging of distinct genomes, allopolyploidization, is a widespread phenomenon in plants. It generates adaptive potential through increased genetic diversity, but examples demonstrating its exploitation remain scarce. White clover () is a ubiquitous temperate allotetraploid forage crop derived from two European diploid progenitors confined to extreme coastal or alpine habitats. We sequenced and assembled the genomes and transcriptomes of this species complex to gain insight into the genesis of white clover and the consequences of allopolyploidization. Based on these data, we estimate that white clover originated ∼15,000 to 28,000 years ago during the last glaciation when alpine and coastal progenitors were likely colocated in glacial refugia. We found evidence of progenitor diversity carryover through multiple hybridization events and show that the progenitor subgenomes have retained integrity and gene expression activity as they traveled within white clover from their original confined habitats to a global presence. At the transcriptional level, we observed remarkably stable subgenome expression ratios across tissues. Among the few genes that show tissue-specific switching between homeologous gene copies, we found flavonoid biosynthesis genes strongly overrepresented, suggesting an adaptive role of some allopolyploidy-associated transcriptional changes. Our results highlight white clover as an example of allopolyploidy-facilitated niche expansion, where two progenitor genomes, adapted and confined to disparate and highly specialized habitats, expanded to a ubiquitous global presence after glaciation-associated allopolyploidization.
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http://dx.doi.org/10.1105/tpc.18.00606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635854PMC
July 2019

Multiple Deeply Divergent Denisovan Ancestries in Papuans.

Cell 2019 05 11;177(4):1010-1021.e32. Epub 2019 Apr 11.

Statistics and Bioinformatics Group, School of Fundamental Sciences, Massey University, Palmerston North 4410, New Zealand. Electronic address:

Genome sequences are known for two archaic hominins-Neanderthals and Denisovans-which interbred with anatomically modern humans as they dispersed out of Africa. We identified high-confidence archaic haplotypes in 161 new genomes spanning 14 island groups in Island Southeast Asia and New Guinea and found large stretches of DNA that are inconsistent with a single introgressing Denisovan origin. Instead, modern Papuans carry hundreds of gene variants from two deeply divergent Denisovan lineages that separated over 350 thousand years ago. Spatial and temporal structure among these lineages suggest that introgression from one of these Denisovan groups predominantly took place east of the Wallace line and continued until near the end of the Pleistocene. A third Denisovan lineage occurs in modern East Asians. This regional mosaic suggests considerable complexity in archaic contact, with modern humans interbreeding with multiple Denisovan groups that were geographically isolated from each other over deep evolutionary time.
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http://dx.doi.org/10.1016/j.cell.2019.02.035DOI Listing
May 2019

Global population genomics of the forest pathogen Dothistroma septosporum reveal chromosome duplications in high dothistromin-producing strains.

Mol Plant Pathol 2019 06 1;20(6):784-799. Epub 2019 Apr 1.

Department of Biochemistry, Genetics and Microbiology, Forestry and Agricultural Biotechnology Institute (FABI), University of Pretoria, Pretoria, South Africa.

Dothistroma needle blight is one of the most devastating pine tree diseases worldwide. New and emerging epidemics have been frequent over the last 25 years, particularly in the Northern Hemisphere, where they are in part associated with changing weather patterns. One of the main Dothistroma needle blight pathogens, Dothistroma septosporum, has a global distribution but most molecular plant pathology research has been confined to Southern Hemisphere populations that have limited genetic diversity. Extensive genomic and transcriptomic data are available for a D. septosporum reference strain from New Zealand, where an introduced clonal population of the pathogen predominates. Due to the global importance of this pathogen, we determined whether the genome of this reference strain is representative of the species worldwide by sequencing the genomes of 18 strains sampled globally from different pine hosts. Genomic polymorphism shows substantial variation within the species, clustered into two distinct groups of strains with centres of diversity in Central and South America. A reciprocal chromosome translocation uniquely identifies the New Zealand strains. Globally, strains differ in their production of the virulence factor dothistromin, with extremely high production levels in strain ALP3 from Germany. Comparisons with the New Zealand reference revealed that several strains are aneuploids; for example, ALP3 has duplications of three chromosomes. Increased gene copy numbers therefore appear to contribute to increased production of dothistromin, emphasizing that studies of population structure are a necessary adjunct to functional analyses of genetic polymorphisms to identify the molecular basis of virulence in this important forest pathogen.
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http://dx.doi.org/10.1111/mpp.12791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637865PMC
June 2019

Complex epigenetic regulation of alkaloid biosynthesis and host interaction by heterochromatin protein I in a fungal endophyte-plant symbiosis.

Fungal Genet Biol 2019 04 4;125:71-83. Epub 2019 Feb 4.

School of Fundamental Sciences and the BioProtection Research Centre, Massey University, Private Bag 11 222, Palmerston North 4442, New Zealand. Electronic address:

Epichloë festucae forms mutualistic symbiotic interactions with grasses of the Lolium and Festuca genera. Protection from insect and mammalian herbivory are the best-documented host benefits of these associations. The two main classes of anti-mammalian alkaloids synthesized by E. festucae are the ergot alkaloids and indole diterpenes, of which ergovaline and lolitrems are the principal terminal products. Synthesis of both metabolites require multiple gene products encoded by clusters of 11 genes located at the subtelomeric regions of chromosomes I and III respectively. These loci are essentially unexpressed in axenic culture but among the most highly expressed genes in planta. We show here that heterochromatin 1 protein (HepA) is an important component of the regulatory machinery that maintains these loci in a silent state in culture. Deletion of this gene led to derepression of eas and ltm gene expression under non-symbiotic culture conditions. Although there was no obvious culture phenotype, RNAseq analysis revealed that around 1000 genes were differentially expressed in the ΔhepA mutant compared to wild type with just one-third upregulated. Inoculation of the ΔhepA mutants into seedlings of Lolium perenne led to a severe host interaction phenotype characterized by a reduction in tiller length but an increase in tiller number. Hyphae within the leaves of these associations were much more abundant in the intercellular spaces of the leaves and aberrantly colonized the vascular bundles. This physiological change was accompanied by a dramatic change in the transcriptome with around 900 genes differentially expressed, with two thirds of these upregulated. This major physiological change was accompanied by a decrease in ltm gene expression and loss of the ability to synthesize lolitrems. These results show that HepA has an important role in controlling the chromatin state of these sub-telomeric secondary metabolite genes, including their symbiosis-specific regulation.
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http://dx.doi.org/10.1016/j.fgb.2019.02.001DOI Listing
April 2019
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