The Irish DNA Atlas, a study of Irish genetic history and diversity led by researchers at the Royal College of Surgeons in Ireland (RCSI) and the Genealogical Society of Ireland (GSI), has recently published in findings into the genetics of Ireland in the Nature Publishing journal Scientific Reports (The Irish DNA Atlas: Revealing Fine-Scale Population Structure and History within Ireland). The Irish DNA Atlas is a cohort of individuals with four generations of ancestry from specific regions in Ireland, recruitment is organised and managed by Seamus O’Reilly at the GSI. Mr O’Reilly helps potential recruits finish, or double-check, family history and pedigree charts for the recruitment process, and mails out sample kits and paperwork for their return to RCSI.
The researchers, led by Professor Gianpiero Cavalleri at RCSI, have found; i) different groups of Irish individuals, clustered by genetic similarity alone; ii) the genetic differences between these groups are incredibly small, iii) members of each of these groups share ancestries from similar regions in Ireland (see image below); iv) a migration event(s) is observed in the north of the island of Ireland that dates somewhere in the 17th and 18th centuries and is from Britain; v) a number of genetic barriers within in Ireland, notably; in the north, and between Leinster and Munster; and finally vi) a significant level of Norwegian-like genetic ancestry throughout Ireland is observed for the first time and this is associated with a genetic migration into Ireland around the turn of the first millennium.
Using the Irish DNA Atlas in conjunction with a dataset of British individuals with regional ancestry (the People of the British Isles Study) the project was able to clusters 2,103 individuals from Ireland and Britain based on genetic similarity as 30 distinct genetic groups (see image 1 for clusters within Ireland). People within the same group are more genetically similar to each other than they are to individuals in other groups. When each Irish individual is colour coded by the group and is placed on a map based on where their great-grandparents were born, we generate a map shown below. Shown to the left are the geographic spread of the identified clusters and on the right a map of Irish kingdoms that represent proto-Provinces circa 800AD.
Analysing the Atlas, the broadest groups within Ireland are either; nearly 100% made up of Irish/Northern Irish individuals (i.e. from the island of Ireland), or are a mix between Irish and mainland British individuals. In the case of the latter, this suggests that those (Irish and mainland British) individuals have shared Irish and British genetic ancestry. The Irish individuals within these mixed groups are mainly from the north of Ireland (predominantly those who are blue crosses in the image above), and the British members are predominantly from the north of England and the south-west of Scotland.
These groups/clusters of near 100% Irish membership are interpreted as mainly ‘Gaelic’ Irish, and the genetic differences between these groups are incredibly small. The groups/clusters are grouped geographically and most are remarkably faithful to the boundaries of the Provinces in Ireland (shown on the left map). We compare these clusters and kingdoms from around 800AD in the above image for illustrative purposes. The reflection between the genetic and historical groups suggests that these Provinces and the kingdoms they represent have subtly impacted the genetic landscape of Ireland. Of particular note is within Co. Clare, which has historically been both parts of Munster and Connacht. Individuals with ancestry from Co. Clare reflect this by showing a mix of genetic groups found within both Munster and Connacht.
In addition to identifying different genetic groups within Ireland, the research sought to investigate whether previous migrations into Ireland had a detectable genetic impact on the genetics within Ireland. Having already identified groups of Irish individuals mainly in the north of Ireland who appeared to a mixture of Irish and British genetics, the researchers tested whether this could be due to a specific event creating these mixed groups. They estimated that these mixed groups are from a number of admixture events in the past, dating around the 17th and 18th centuries.
As well as migrations from Britain, the researchers asked whether evidence of migrations from wider afield, i.e. from continental Europe, could be found. A surprisingly larger amount of Scandinavian – specifically Norwegian – looking ancestry in all our Irish clusters was detected (see below image). This image shows along the horizontal axis each of the 30 genetic groups identified in Ireland and Britain. Along the vertical axis is the average proportion of the genome that’s the closest similarity is found in each of the 10 reference European populations. Ireland and Wales share a lot of French-like ancestry, but Ireland shows a lot of Norwegian-like ancestry compared to England or Wales. In fact, in this Norwegian respect, Ireland shows a similarity to Orkney.
This similar pattern of elevated Norwegian-like in Ireland and Orkney is interesting as Orkney is a region with strong evidence of Norwegian Viking genetic migration and mixture. Therefore the researchers investigated whether this Norwegian ancestry in Ireland was due to a mixture event dating from the time of the Viking activities in Ireland. They dated the ancestry to sometime around 1000 AD, which agrees with a ‘Viking Hypothesis’. This result was perhaps the most surprising using the Irish DNA Atlas, as previous work with Y-chromosomes found no evidence of Norse genetics within Ireland. However now, with whole-genome data, the extent of Norwegian mixture within Ireland is able to be shown.
This research has been funded through a Career Development Award from Science Foundation Ireland. RCSI is ranked among the top 250 (top 2%) of universities worldwide in the Times Higher Education World University Rankings (2018) and its research is ranked first in Ireland for citations. It is an international not-for-profit health sciences institution, with its headquarters in Dublin, focused on education and research to drive improvements in human health worldwide. RCSI is a signatory of the Athena SWAN Charter.
Cystic Fibrosis (CF) is a progressive, genetic disease that causes persistent lung infections and limits the ability to breathe over time. CF is caused by mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene which encodes a chloride channel responsible for helping conduct chloride and other ions across epithelial membranes. Loss of functional CFTR channel disrupts ionic homeostasis resulting in mucus production that clogs the lungs and results in a vicious cycle of chronic infection/inflammation. There are almost 2,000 different variants in the CFTR gene and 70 % of CF patients contain a mutation at position 508, which results in the loss of Phe508 and disruption of the folding pathway of CFTR. ΔF508 CFTR is a trafficking mutant that is retained in the endoplasmic reticulum (ER) and unable to reach the plasma membrane and function correctly as a chloride channel. The Coppinger research lab is focused on understanding the basic mechanisms of CF disease with a focus on the ΔF508 mutation and translating these findings into diagnostics/therapies. We are particularly interested in two areas of research 1. Using basic science technologies to identify novel signalling pathways in CF to discover new CFTR corrector therapies in ΔF508 CF models. We have recently discovered the PI3K/Akt/mTOR signalling pathway to be dysregulated in CF models and a possible therapeutic avenue worth further exploration in CF. Additionally, we are interested in 2. Investigating how diminished ΔF508 CFTR activity leads to heightened inflammatory cell recruitment and CF airway pathogenesis. Exosomes are nanovesicles (40–100 nm) actively secreted by cells and are crucial mediators of intercellular communications. We hypothesised that exosomes may be released from ΔF508 CF patient bronchial cells/fluids and play a role in regulating immune cell function. Preliminary data has confirmed this hypothesis and also indicated exosomal signatures may possibly serve as markers of disease progression in CF. These studies are in collaboration between several groups at the National Children’s Research Centre, Royal College of Surgeons in Ireland, Beaumont Hospital University College Dublin, Cystic Fibrosis Unit, St Vincent’s Hospital.
Last week was another superb week for circadian research in the Molecular and Cellular Therapeutics Department. The Curtis Laboratory published our first big paper on the immune body clock in Nature Communications. This study originated back in 2013. I was still a postdoc in Prof. Luke O’Neills laboratory at Trinity College and was intrigued by some of the studies that showed that multiple sclerosis (MS) was affected by the circadian disruption. A key study showed that teenagers who work shift work before the age of 18 are more susceptible to multiple sclerosis in later life. I wondered if we would see any differences in multiple sclerosis if we disturbed the immune body clock. I approached Prof. Kingston Mills also at Trinity College, who is one of the world leaders of multiple sclerosis and has a key mouse model that recapitulates certain features of MS, called experimental autoimmune encephalomyelitis (EAE). The first experiment we conducted was to see if a mouse which does not have the molecular clock in macrophages was more susceptible to disease, and low and behold it was! This project was driven by one of the most talented researchers that I have ever had the pleasure of working with, Dr. Caroline Sutton, who is a senior postdoctoral fellow in Prof. Mills lab. This project is a great example of collaboration between multiple labs, Mills, O’Neill and my own new group here at RCSI.
And if that wasn’t enough! We also hosted the circadian expert Prof. Qing-jun Meng for our second institutional seminar series on Thursday. Prof. Meng is a world expert on clocks in the musculoskeletal system at University of Manchester. I met Qing-jun in 2013, and have followed his research intensely. He has made seminal discoveries on the impact of the clock on cartilage and invertebral disk function and how this leads to diseases of ageing, such as osteoarthritis and lower back pain. He had the audience enthralled for an hour with his rhythmic images of cells glowing with 24-hour rhythms, and his use of Google searches. It was an absolute pleasure to have Qing-jun with us for the day, and I hope that we can have him back again in the near future.
Some news features on the article can be found here:
I have had an immense passion for science since I began my secondary school journey, which would be five years ago, now! I became engrossed in the subject, and intrigued in all there was to learn from it. I knew it was what I wanted to pursue as a career and that it would be a major part of my future. I couldn’t be more eager to continue on my path of science and see what it has to bring.
So, as you can imagine, when I received word of a lab safari experience in RCSI, I was ecstatic and jumped at the chance to improve my knowledge in the field of molecular and cellular therapeutics, meet new people, both those with a similar ardent spirit of science and interest in the field like myself and those who have incredible stories to share of their journeys in the field. I was also especially keen to get a glimpse of the college itself, as it is a college that really stood out to me, as a lover of science and I have followed its successes and path for years now.
Arriving outside RCSI with my mother, I was filled with joy and overwhelming adrenaline as I was about to enter the college. Upon our entrance, we were shown to a room where we received our introduction talks. We first met Tracy Robson who spoke of her role as head of the department of molecular and cellular therapeutics in RCSI and her inspirational path into the area of science and focuses on the research of cancer. Her talk had to be my most enjoyable part of the whole experience as she expressed that passion for the field is what got her to where she is today, and also going out and discovering opportunities and having the courage to ask questions. It gave me motivation and encouraged me to take all opportunities that may come my way, which will benefit me as I begin my adventure into the scientific world!
We were then introduced to Avril Hutch, head of equality and diversity at RCSI. We did an exercise in which we were shown pictures of workers in the science field and we had to guess which profession they held. It gave us a glimpse at the topic of unconscious bias, particularly in science, and as a female in science myself I greatly respected her and her focus on equality in RCSI.
After being divided into our groups, we put our goggles and lab coats on and began our safari. We firstly arrived at the station of Claire McCoy who informed us of her work, targeting miR-155 activity in macrophages to promote an anti-inflammatory function for multiple sclerosis. The work she does is fascinating and it captured my attention as she explained. She was extremely polite and helpful and all questions I had, she was more than delighted to answer.
Then, moving on we met a team who thought us all about genetics, we even got to do experiments to determine what genetic traits we had ourselves and compare within our group, which I tremendously enjoyed. Lastly, we greeted Olga and John who explained the research in biomarkers for neuroblastoma. It was an extremely gripping topic to learn about and after that sadly, it was time to leave the labs.
Following the tour of the labs, fun experiments completed and brains full of new, amazing knowledge we all received certificates and colouring books of the brain, which I absolutely loved!
Overall the experience was so special to me and every bit of it was wonderful. I feel like I’ve learned so much and can use my new-found knowledge along with my journey in science. I would like to thank RCSI for holding such an event because it is greatly appreciated by those who want to adventure it to the scientific field and those who are unsure, and I hope there will be many more like it in the future. After this whole experience, I am even more certain and passionate about working in the world of science!
As some of you know, I have joined RCSI as a StAR research lecturer in June. My plan is to establish a lab on ‘MechanoVascular Biology and Microscopy’. What do I mean by this?
The first part ‘MechanoVascular Biology’ sets the scope. I am interested in how cells in the cardiovascular system use mechanical forces to achieve their tasks. As mechanical and chemical cell functions are tightly related, both play important roles in health and disease. Most research has focused on one or the other aspect, but not both. The novel research field of ‘mechanobiology’ takes an integrative approach to better understand how physical forces co-regulate chemical processes on the molecular level. In my previous work at ETH Zurich, I have studied how fibroblasts sense matrix stiffness and respond to it. Here at RCSI, I want to study platelets in the context of thrombosis and, over the years, investigate their interplay with endothelial cells.
The second part ‘Microscopy’ highlights one of the major working horses in my lab. Following the credo ‘seeing is believing’, watching cells can tell you a lot about how they do things. I use microscopy to test hypothesis but also to discover unexpected behaviour. Over the years, I have developed several new microscopy techniques to look at sub-second dynamic processes, directly measure cellular tractions, or determine the nanoscale architecture of multi-protein structures. These are great tools to better understand how the processes starting from platelet activation and ending with the consolidation of the thrombus are regulated in space and time. For this we will use in vitro models, but I am keen to move in the future towards in vivo imaging.
By now, you may have noticed from my scientific viewpoint and my enthusiasm for technology that my background is in physics. I studied physics with a specialization on biophysics at the Technical University Munich. My PhD work at the Max Planck Institute of Biochemistry focused on electrical stimulation of neurons with extracellular electrodes. After a short postdoc at the Ludwig Maximilians University Munich where I studied bi-molecular binding kinetics in living cells, I moved to ETH Zurich in Switzerland. That’s where I have started with mechanobiology and super-resolution fluorescence microscopy, which I know bring over to RCSI.
A long way is lying ahead of me to cross the bridge towards clinical research. I look forward to having many inspiring discussions with you, already thank you for the ones we had so far, and hope that I can make a valuable contribution to the research here at RCSI!
Looking forward to seeing you at MCT Research Talks on 16th October 2017 at 12.00 TR4!
Last Monday while in Amsterdam with my Mam and two sisters, a friend of mine sent a text to let me know that the 2017 Nobel Laureates in Physiology and Medicine were Hall, Rosbash and Young. They were awarded the Nobel for their work in identifying the key genes that create circadian or body clock rhythms in the fruit fly. My feet literally were stuck to the ground, it was thrilling to know that these gentlemen would get the recognition that they so deserve, but also what this will mean for the field of science that I am so passionate about. The body clock is the molecular timekeeping system that exists in practically every organism on the earth and in every cell in our body. Simply put, it allows the cell to tell what time of day it is. Why is that important? We live on a spinning planet and because of the earth’s rotation to the sun, all life on earth has been subjected to daily periods of light and heat, dark and cold. The body clock allows us to anticipate and respond to these 24-hour predictable environmental changes and synchronises our physiology to it. For example, the body clock increases cortisol levels in the body ahead of awakening, this helps us to become active once we wake. The body clock also increases expression of digestive enzymes in the intestinal tract during daylight hours (this is why curry chips at 3am is never a great idea!).
Back in the 80’s Hall, Rosbash and Young independently isolated a gene called Period, they showed how the gene encodes a protein PER that builds up in cells at night and degrades during the day. This daily rise and fall of PER essentially allow the cell to track time of day. How thrilling it must have been for them to observe this daily change in the mRNA levels of Period gene (Figure 1- black line), all that is changing along the x-axis is the time of day.
So what does this mean three decades later? We have made great strides in understanding how the molecular clock works. We now know that the clock keeps time by a series of transcriptional-translational feedback loops. We also know that the clock controls 40% of all coding genes within the body. The body clock controls all aspects of our physiology from metabolism to immunity.
Many diseases, such as osteoarthritis and cardiovascular disease, are highly time of day dependent. Moreover, it appears that disruption of our body clocks, caused by our non-stop 24/7 lifestyle and exposure to artificial light at all times of day, is partly responsible for the increase in chronic inflammatory diseases. Unfortunately, most cell culture systems are not synchronized with the time of day, and this, in my opinion, is one of the main reasons that many researchers unknowingly neglect this field. Finally, we are making great strides in attempting to time specific treatments to the right time of day, an area called chronotherapy. Therefore, it is my hope that this increased awareness of the body clock will bring more researchers into this fascinating field. If we don’t fully understand how our body clock controls physiology and disease we will certainly be left in the dark.
Annie Curtis is a Research Lecturer and runs the Immune Clock laboratory at MCT and is fascinated by all things body clock related.
Cystic fibrosis (CF) is an inherited chronic disease that primarily affects the lungs and digestive system. CF is caused by mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene, a chloride channel responsible for helping conduct chloride and other ions across epithelial membranes. The loss of a functional CFTR channel disrupts ionic homeostasis resulting in mucus production that clogs the lungs and pancreas and results in a vicious cycle of chronic infection and inflammation as the disease progresses.
There are almost 2,000 different variants in the CFTR gene and 70 % of CF patients contain a mutation at position 508, which results in the loss of Phe508 and disruption of the folding pathway of CFTR. ΔF508 CFTR is a trafficking mutant that is retained in the endoplasmic reticulum (ER) and unable to reach the plasma membrane. Efforts to enhance exit of ΔF508 CFTR from the ER and improve its trafficking are of utmost importance for the development of treatment strategies. Clinically, progress has been made in recent years identifying therapeutics that target CFTR dysfunction in patients with specific mutations. However, small molecules that directly target the most common misfolded CFTR mutant, ΔF508, and improve its intracellular trafficking in vitro, have shown modest effects We performed a study aimed to identify new therapeutic targets that will help address the unmet clinical need for CF patients homozygous for the ΔF508 mutation.We aimed to understand the protein interactions regulating CFTR transport using mass spectrometry-based proteomics. Using mass spectrometry based protein interaction profiling and global bioinformatics analysis we revealed mammalian target of rapamycin (mTOR) signalling components to be associated with ∆F508 CFTR. Our results showed upregulated mTOR activity in ΔF508 CF bronchial epithelial cells. In addition to a well described role in several cancer subtypes, excessive activation of the mTOR pathway has been reported to be involved in age-related misfolding diseases. There are a range of inhibitors that target the PI3K/Akt/mTOR pathway and after screening a selection of inhibitors, we identified 6 different inhibitors that demonstrated an increase in CFTR stability and expression. Mechanistically, we discovered the most effective inhibitor, MK-2206 exerted a rescue effect by restoring autophagy in ΔF508 CF cells. These findings highlight this pathway as a possible therapeutic avenue worth further exploration in Cystic Fibrosis.
We aimed to understand the protein interactions regulating CFTR transport using mass spectrometry-based proteomics. Using mass spectrometry based protein interaction profiling and global bioinformatics analysis we revealed mammalian target of rapamycin (mTOR) signalling components to be associated with ∆F508 CFTR. Our results showed upregulated mTOR activity in ΔF508 CF bronchial epithelial cells. In addition to a well-described role in several cancer subtypes, excessive activation of the mTOR pathway has been reported to be involved in age-related misfolding diseases. There are a range of inhibitors that target the PI3K/Akt/mTOR pathway and after screening a selection of inhibitors, we identified 6 different inhibitors that demonstrated an increase in CFTR stability and expression. Mechanistically, we discovered the most effective inhibitor, MK-2206 exerted a rescue effect by restoring autophagy in ΔF508 CF cells. These findings highlight this pathway as a possible therapeutic avenue worth further exploration in Cystic Fibrosis.
In keeping with the strategic objective of further increasing our international profile in the research domain, Professor John Waddington (Emeritus, MCT) has recently returned from the World Congress of Biological Psychiatry, Copenhagen, where he was invited to organise, Chair and speak in a symposium on ‘Psychosis is disrespectful to diagnostic boundaries: Nosological and pathobiological implications of psychoses beyond the schizophrenia spectrum’. He was also invited to Co-Chair and speak in a second symposium on ‘Beyond unitary models of psychosis: Confronting complex aetiology and dimensionality’. This reinforces the high standing in which our investigators are held in the international scientific community.
Dr Rebecca Coll is a Research-Industry Fellow at the University of Queensland, studying innate immunity and novel anti-inflammatory drugs. Rebecca received her PhD in Immunology in 2013 under the supervision of Professor Luke O’Neill at Trinity College Dublin and moved to Associate Professor Kate Schroder’s group at the Institute for Molecular Bioscience in UQ in 2014. Over the last five years, her research has focused on inflammasomes – protein complexes at the heart of inflammation and disease – and how these complexes can be targeted therapeutically to prevent damaging inflammation.
Rebecca led the biological characterisation of MCC950, a small molecule inhibitor of the NLRP3 inflammasome and an exciting prospect as a new therapy for treating patients with NLRP3-mediated diseases. In 2016, Rebecca received the Research Australia Discovery Award for her work on MCC950.