Wednesday, 9 November 2016
Genetics’ significant contribution to fundamental research across the sciences, and Otago’s fantastic breadth of expertise in the field, have shone through in the 2016 annual Marsden Funding round.
Genetics features in 10 of the 23 University of Otago projects awarded under the highly competitive fund. Together the projects will explore a wonderful array of the story and challenges of life: the beginnings of individual life, the arc of evolution and biodiversity through time, control of fertility, the restoration of native bird populations, the skeleton’s response to gravity, new battle fronts against cancer and bacteria, and more.
Read more about the fantastic ten genetics-related research projects below.
Becoming master of your destiny: insights into genome activation from nuclear structure
Associate Professor JA Horsfield
When a zygote forms, its newly-minted genome remains mostly inactive until a defined time point when the zygotic genome activates and is transcribed. What triggers this exact moment when the embryo becomes master of its own destiny? We hypothesise that formation of a transcription-competent, three-dimensional (3D) nuclear structure triggers zygotic genome activation and predicts developmental trajectory.
Using cutting-edge genomics techniques that capture nuclear structure, we will test our hypothesis in zebrafish embryos. We will also use live imaging of zebrafish embryos and individual cells as they undergo genome activation, to observe visible changes in the nucleus as genes are switched on. Our overall aims are, (1) to discover the transcription-permissive 3D nuclear structure underpinning zygotic genome activation, and, (2) to disrupt 3D nuclear structure and determine the consequences for zygotic genome activation.
Our research will provide the first evidence for how a 3D nuclear structure places an animal under the control of its own genes for the first time, and will determine how important nuclear structure is for gene activation.
Determining how the zygotic genome is at first held inactive, and how it rapidly becomes activated, will provide new insight into the very beginnings of life.
Why do inbred males fire blanks? Unravelling the relationship between inbreeding and infertility
Dr HR Taylor
Inbreeding negatively affects a wide range of life history traits in taxa as diverse as humans and plants. Mitigating the effects of inbreeding depression has been a key focus in animal husbandry and horticulture for millennia and, more recently, inbreeding has become a key topic in conservation science.
It is well known that inbreeding negatively affects male fertility across a variety of taxa, but this phenomenon has rarely been examined in species where males are the homogametic sex (e.g., birds), or in the wild.
While several sperm quality traits are known to be depressed by inbreeding (sperm morphology, motility, and DNA fragmentation) the interplay between these traits remains unexplored. The common fragility of male fertility suggests inbreeding disrupts a conserved set of genes across taxa, but these genes are yet to be unidentified.
We will use a novel combination of genotyping by sequencing, computer assisted sperm analysis, and DNA fragmentation assessment to conduct a comparative study of inbreeding depression of male gamete quality in New Zealand's birds – the first such study in any wild system. We aim to elucidate the relationship between inbreeding and sperm quality, and identify candidate genes that might be responsible for infertility in inbred males.
Do glaciers drive diversity? Using ancient DNA to retrace the history of New Zealand’s biodiversity
Dr NJ Rawlence
Scientists have long been intrigued by the biological effects of glaciation in New Zealand and beyond.
Glaciers are traditionally seen as destructive forces for ecosystems, with ice sheets having eliminated biodiversity across extensive regions of the globe. By contrast, new evidence emerging from temperate mountain systems, including New Zealand’s Southern Alps, suggests glaciation may be a key evolutionary force structuring biodiversity along mountain chains, with speciation driven by isolation in narrow refugia.
This research programme will test for ‘real-time’ range-shifts and diversification events associated with New Zealand’s Last Glacial Maximum (34-18 kya), using ancient-DNA of iconic species from multiple unique time-series of sediment cores and sub-fossil bones.
Broadly, this study will use state-of-the-art tools to track phylogenetic, ecological, demographic and biogeographic shifts across recent glacial-interglacial cycles. This multi-disciplinary approach combines a wealth of sub-fossil samples, sediment cores and genomic resources - a unique system that will reconstruct the recent evolutionary history of NZ’s iconic biota.
Parasitic Puppeteers – How do They Pull the Strings?
Professor NJ Gemmell
Parasites can profoundly affect the animal hosts they invade, manipulating host biology with exquisite precision to enhance host-to-host transmission.
One of the most extraordinary of these host manipulations is the water-seeking behaviour that some nematodes and hairworms induce in their hosts so that the worms might exit the host and reproduce.
The process is the stuff of science fiction; the worm hijacks the host’s central nervous system forcing it to seek water. Once water is found, the adult worm, often many times the size of the host, emerges, sacrificing the host.
This amazing alteration in behaviour is induced by parasitic worms spanning two phyla (Nematoda and Nematomorpha) and is observed in a variety of arthropod hosts, notably crickets, weta, earwigs, and sandhoppers, leading us to hypothesise that a common and conserved mechanism is being utilised by the parasites to induce this behaviour in their hosts.
Here we propose to couple field and laboratory studies of two phylogenetically distinct hosts and their parasites, with powerful genomic and bioinformatic comparisons to elucidate the trigger and genetic cascade through which these parasitic puppeteers elicit this highly conserved, yet astonishing behavioural response.
In vivo gene editing with CRISPR to define estrogen feedback in the brain
Professor AE Herbison
Circulating levels of the ovarian hormone estrogen act on the brain to control fertility. A group of brain cells called the gonadotropin-releasing hormone (GnRH) neurons are responsible for controlling fertility in all mammals including humans.
At present, the cellular pathway through which estrogen modulates the activity of GnRH neurons in unknown. This project intends to determine precisely which brain cells are responsible for detecting estrogen levels in the blood and transmitting this information to the GnRH neurons.
We will use a novel application of CRISPR-Cas9 gene editing to delete estrogen receptors from GABA, glutamate or kisspeptin neurons located in two specific brain regions of the mouse.
This research will develop world-leading in vivo gene editing technology for neuroscience within New Zealand and elucidate the mechanism of "estrogen feedback" to the GnRH neurons.
This information will underpin the development of new strategies for helping infertile couples as well as the development of safer contraceptive agents.
Silencing unwanted expression in molecular circuits using naturally evolved solutions
Professor CW Ronson
Synthetic molecular circuits can be assembled that carry out novel reactions and process simple computations.
However, assembling complex circuitry presents significant hurdles, as stochastic biological fluctuations (noise) can activate molecular switches in the absence of stimuli. Furthermore rapid protein inactivation is critical for dynamic circuits to function correctly, and if proteins are slow to degrade, the circuit may slow down or stop functioning altogether.
Currently there are very few ways available to inactivate regulators once they are expressed. We have discovered a novel “antiactivator” protein, QseM, that tightly suppresses activation of a natural quorum-sensing circuit through binding and inhibition of two distinct transcriptional activators, and is impervious to noise.
We will solve the 3D structure of QseM and characterise its antiactivation mechanism against the two targets using in vivo and in vitro approaches. ‘Proof of principle' for the utilisation of QseM in synthetic biology will be demonstrated by both constructing artificial antiactivator targets from components commonly used in synthetic circuits, and by constructing a synthetic and controllable genetic toggle switch based on quorum sensing activators and their cognate antiactivators.
Epigenetics and Evolutionary Theory
Professor HG Spencer
Epigenetic changes do not affect the DNA sequence of an individual. Rather, a variety of removable chemical mechanisms temporarily mark the genome, thereby modifying expression of the genes.
Appropriate epigenetic markings in different tissues at different life stages are critical in the correct development and function of every individual organism.
Intriguingly, we have recently discovered that, instead of being reset every generation, some epigenetic marks can be passed on unchanged from one generation to the next. Moreover, individuals in a population may differ from each other in their epigenetic markings: just as natural populations exhibit genetic variation, so do they harbour epigenetic variation.
This project asks how we can explain this transgenerationally inherited epigenetic variation in natural populations and what might be the consequences for evolution.
The researchers will construct and analyse new mathematical models to investigate these matters, validating these models with data from real examples, and using the models to make novel predictions about the properties of epigenetic variation in nature.
Thus, this research will lead to a significantly improved appreciation of a fundamental feature of evolution and a more accurate description of inheritance in all its forms.
The genes of life and death: a role for placental-specific genes in cancer?
Professor MR Eccles
Invasive cancers are hard to treat. If we determine how cancer cells become invasive, then we will discover new strategies for early diagnosis or treatment.
Good models for cancer invasion in humans are rare, but remarkably, the human placenta could be an excellent model for cancer because of its invasive features. The placenta invades the adjacent uterus, like cancer erodes into surrounding organs. It also takes hold of the immune system to prevent rejection of the fetus, just like cancer controls the local immune response.
Intriguingly, placental and cancer cells share a genetic phenomenon that we do not understand - they fail to silence virus derived DNA sequences, known as retrotransposons, that are normally silenced in healthy tissues.
Retrotransposon unsilencing is usually associated with gene disruption, sometimes causing cancer. However, in the placenta, retrotransposon unsilencing creates new genes that are essential for placental function. We have evidence that these placental genes are activated in cancer, and believe retrotransposons may offer powerful perspectives on cancer prevention and treatment.
By using the placenta as a model for malignancy, we aim to determine the implications of retrotransposon activity in cancer and expect to identify new genes that control cancer invasion.
Bones under pressure. How does the skeleton sense gravity?
Professor SP Robertson
The human skeleton responds to force and movement by building stronger bone. How these forces are sensed at a cellular level and translated into a biochemical response that results in stronger bones is unclear.
We have discovered that mutations in two genes subvert this mechanism resulting in excessive bone formation indicating that they connect to form this biological mechanosensor.
Using genetic, animal model and biochemical approaches we will describe the architecture of this force transducing apparatus that is key for the maintenance of bone health over the lifespan.
Uncovering the physiological roles of the multiple NDH2 in bacterial genomes
Dr Yoshio Nakatani
A fundamental feature in the adaptation of bacteria to different environments is the ability to generate energy from variable sources and to sustain metabolism. A key enzyme in this adaptation is the type II NADH dehydrogenase (NDH2) that catalyzes the transfer of electrons from NADH to various quinones.
This enzyme has important roles in energizing the electron transport chain and maintaining a NAD+/NADH balance for cell metabolism through NADH oxidation.
Multiple ndh2 genes exist in bacterial genomes, but the reasons for this remain unknown. The project will use the intracellular pathogen Listeria monocytogenes as a model system to uncover the physiological roles of each NDH2 in both the extracellular and intracellular environments, genetically, biochemically and structurally. Such understanding could provide new rationales for targeting NDH2 for antibiotic development.
The Marsden Fund Was established by the government in 1994 to fund excellent fundamental research. It is a contestable fund administered by the Royal Society of New Zealand on behalf of the Marsden Fund Council. Read more about the Marsden Fund.