 Hello, my name is Justin Rubio, and I'm here today to tell you about a study we've conducted on the leucine rich repeat kinase 2 gene or LARP2, which has recently been accepted for complication in human mutation. Now, genetic mutations in LARP2 are the most common known cause of Parkinson's disease, and this underpins its selection as a drug target. Genetic studies have shown that LARP2 is actually associated with other human diseases. And consequently, that variation in LARP2 might have plyotropic effects. And this suggests that potentially, LARP2-based treatments could be used in the future to treat other conditions beyond Parkinson's disease. Now, to address this question, we sequence the LARP2 gene, the entire LARP2 gene, or 51 protein-coding axons, in 14,000 people that comprise 12 different non- Parkinson's disease conditions and some population controls. Overall, we identified 739 single-nucleotide variants. That's one every 20 base pairs. And of these, 316 are novel exonic variants, including five nods of mutations and 210 nods of anonymous variants. Among individuals of European origin, we observed that 62% of these variants are private to a single individual. Now, this detailed study of LARP2 is actually part of a larger study of 202 prospective or current drug targets. And in relation to those drug targets, LARP2 was not particularly differentiated. However, as a collection, these drug targets were differentiated compared to other human genes. Like the other genes that we sequenced, we observed that LARP2 is under purifying selection. That is, selection is acting to minimise the occurrence of potentially damaging variants in this gene. We also observed, through comparison of amino acid sequences across 14 different malignant species, including humans, that the central region of LARP2 is actually more conserved than the flanking regions. Now, this is important because the central region of LARP2 includes the enzymatic domains, one of those being the kinase domain, which is currently where LARP2 inhibitors are having their compound target interaction. So, we observed increased evidence of conservationists in this area across species. And we also observed evidence in humans of increased effect of purifying selection on the central region. Now, this goes some way to explaining why pathogenic mutations that cause Parkinson's disease in humans tend to cluster in the central region. So, we identified, we didn't identify any statistically significant genetic associations with the 12 diseases that we studied the LARP2. However, we identified 17 carriers of pathogenic mutations that can cause Parkinson's disease. But none of the individuals that carried these mutations actually had Parkinson's disease at the time they were clinically obsessed. It's possible they have Parkinson's disease now. What was particularly interesting among these carriers of pathogenic mutations was that six of them carried a mutation that has only previously been observed in Asia. And this suggested to us that potentially, because we were looking at Europeans, that potentially, carriers of this mutation, this mutation in particular, may have originated independently in Asia and Europe. So, to look at this in more detail, we used genome-wide SNP data, components to map the geographical origin of these individuals. And we found that they all originated from north-western Europe, which was suggested that our original premise that this mutation occurred has occurred more than once in Europe and in Asia independently was actually correct. So, in conclusion, we've conducted the most detailed genetic characterization to date of LARP2. All the variants we've identified have been submitted to DVC and are provided as supplemental information for this manuscript. We hope that they will be a benefit and used to future genetic studies of LARP2. And while we did not identify any novel genetic associations that might suggest LARP2 therapies in the future might be beneficial for treating other diseases beyond Parkinson's disease, we did, using a number of different approaches, show how next-generation sequencing can be exploited to reveal fundamental characteristics of clinically important genes such as LARP2. Thank you, and I hope you enjoy the manuscript.