 Next up is Jen, right? Okay, Jen Troyer is going to give us the presentation on the concept non-human primate developmental G-tex. Go ahead, Jen. Okay, so for those of you who don't know me, I'm Jennifer Troyer. I'm a program director in the division of genome sciences, and I'm presenting this for a group from both NHGRI and NICHD that has been working on thinking about the areas in developmental genomics that we all have a common interest in. And I would also like to thank my colleagues throughout ERP and our division directors for many helpful comments in preparing this. For the purpose of non-human primate developmental G-tex is really to study gene expression patterns for multiple reference tissues across stages in different non-human primates and compare these to gene expression patterns in humans. This will allow us to determine common developmental networks and pathways as well as ones that are primate and human specific. It will establish data sets and samples for comparative developmental genomics and inform model selection for functional follow-up and studies of particular developmental processes. This follows on several other genotype tissue expression projects, G-tex, that was mentioned in Eric's director's report and is a successful common fund program that is now completed and recently as Eric highlighted, published on 838 post-mortem adults, 49 tissues, DNA and RNA seed methods, and this is a highly used and utilized resource that has helped us understand tissue specific gene expression profiles as well as really pioneered the field of EQTLs. Jodi came to you last year with a proposal for developmental G-tex, which is a collaborative project between NHGRI and ICHD and some of the institutes and centers interested in the development of brain. And this is a project that is now under review and plans to collect tissues from 120 post-mortem infants and children and again provide DNA and RNA seek as well as some single cell RNA data. Again, to further our understanding of tissue specific expression at different developmental stages and that are developmentally regulated as well as some single cell type specific expression and to really further our understanding of the impact of variation on development. So what I'm proposing today is an addition to that looking at developmental pathways in non-human primates. This will allow comparable and parallel data sets in experimentally tractable laboratory animals and allow us to extend this knowledge to prenatal as well as postnatal stages of development as well as building on our knowledge that has been obtained over the years from model organisms. Just to touch on that, there's a vast array of resources and knowledge that's been obtained from looking at development across many different organisms and as well as the developmental genomics. If you start with worm and sea urchin where there are detailed cell faint maps from single cell to adult stages moving onto fruit flies and zebrafish that have given us understanding of the regulatory networks that lay down complex body patterning for organisms and then into frog and mouse where we have more understanding of specific organs and their development and stages throughout. So now we're proposing to continue these studies into non-human primates. These are our closest relatives and if you look the closest organism where we have detailed information is really the mouse which evolved 800 to 100 million years ago from us. And if we move into non-human primates we get closer with 40 million years ago for new world monkeys, 25 million years ago for old world milk monkeys. In addition to being closer relatives importantly they have similar developmental trajectories to humans with more development occurring postnatally particularly for things like behavioral processes and immunity. Many of the things are used as model systems. In addition primates have genomic diversity even in the captive populations that are used in biomedical research have a high level of diversity that makes them good models for human population studies. They are used as biomedical models for many things from as I said immune system to morphology to brain development and drug sensitivity and so they're understanding their similarities and differences from humans in these processes is quite important. And they provide comparative genomics particularly touch points between some of the model organisms and humans. So what we're proposing today is that we fund one to two centers that would be responsible for collecting expression data and I'll go a little more into that in the next slide. These would be funded at approximately 3.5 million per year over five years would collect data from multiple developmental stages tissues and species. They would be responsible for making the data available and usable to the community and we would ask that they use opportunistic and bank samples wherever possible. What would this look like. So we're asking for samples to come from a minimum number of species for us at least two old and new world monkeys at at least six developmental stages that would span prenatal and postnatal 12 animals per stage that would have a balance between males and females and again at least 30 tissues per animal. The data that would be generated again would be the whole genome sequence for the animal and then expression data for each of the tissues. Certainly other assays could be proposed and there would be a data management component that would involve QC some basic analysis and then submission to the appropriate resources. Standing this up from scratch would be quite a big endeavor but we would assume that applicants will leverage the non human primate resources that are already funded through the primate Resource Center Consortium. There are seven of these centers supported by the Office of Research and Infrastructure Programs and these have colonies from 10 different primate species, all of which have genomic resources. They maintain the level of dynamic diversity, the relatedness of the animals. They maintain high ethical standards for primate research and many of the animals have behavioral and phenotypic data available. Both the primate Resource Centers and others have extensive banked tissue sample collections that may be appropriate for some of these studies. And their ability to leverage the high quality reference genomes that NHGRI funded as part of the reference genome program. The other part of this is not only should they collaborate and be talking to the non human primate resources but also to the human developmental GTECs. As I said these are under review right now but it's proposed that there will be tissue procurement centers and data analysis and coordinating center that will be performing essentially analogous tissue collections and data generation and analysis that will in humans that would be now proposed to do also in non human primates and so it would be important that these groups are working closely together for protocol standards and interoperability. As with any program there are considerations of balance and certainly here there's multi dimensional data with many axes this different stages individuals tissues assays species. And then anytime you're generating this amount of data there's the question of providing it as a resource and developing new or integrating with existing resources and potentially the need for new data analysis methods. So, we're going to ask councils input on this concept and I've asked Len Panaccio and Steve Fodor and Mark Craven to lead us off on the discussion. We welcome comments and any part of this proposal. But the questions I'm particularly going to pose to you to start off as is this balance right, and how do we make sure that if we're producing this resource for really maximizing the benefit of these tissues, and are there additional resources activities going on in the community that we might not know about that we should be coordinating with and thinking about. And so, when do you want to Sure, you know this resonated with me I mean I have mostly reiteration of things that you said like the timeliness is great with the human developmental GTX. I thought the human non human primates made a ton of sense as an out group versus trying to go to other more distant vertebrate models since we're interested in humans. I also saw the opportunity to get tissues you couldn't get from humans during development as a real bonus, especially from non human primates. I thought that this is a pilot project that could potentially be expanded and so this is something that hopefully will be successful. Having only one or two centers makes that a little more tractable so I thought not expanding it to three or four or beyond I mean ideally you probably want to not one but it seems like the right scale for kind of you know it's not a pilot but something that is a relatively new part to part of this. So overall I didn't have any concerns I mean you just brought up again the data analysis component which I'm not real clear on how much comparative GTX or this kind of QTL type of analysis tools exists but it's outside of my area expertise so there's probably development that needs to happen there or be called out in the applications themselves. So again, overall I thought this was something that didn't really see any major issues with. Thanks. Thanks Len and I think you bring up a good point about sort of the scope and is this a pilot what we're seeing this as really is a baseline of what NHGRI will support but we are talking to other institutes and centers across the NIH about whether there are parts of it that they're interested in and interested in building out on to and you could see how the bank tissues and the data could be co-opted to additional projects in the future so that's part of making sure that we're we're planning this in such a way that it can be built upon. So I go next please. Yeah, so I, you know, I think I agree this is a really important program and I also agree with many of the comments that have already been made. It's important both as a program and a resource in an area where, you know, samples are scarce and precious. And although these aren't human, they're still scarce and precious. And to that end, you know, as I understand it, the sample collection from great apes and so on won't really be supported through this. But instead the leveraging of samples that may be used for other purposes, or banked and so on will be preferred, I guess. That's one of the questions I wanted to talk to you, George, just ask you a little bit about. But with that in mind, in my sort of two comments are, you know, there's been a, you know, gene expression is a big field these days. And there's a lot of new advances. You did mention that emphasis on things like single cell would be emphasized. I think that's really good. But with precious samples, you know, that there's certainly the spatially resolved single cell type stuff. I think that would be very useful. In addition, you know, a lot of recent work on RNA modifications, implications of development and so on would also be good. And so, you know, there's a lot to be thinking about what your standards of data should be in this instead of sort of the old days where we just ground up everything. And got a pot parade, it'd be nice to get higher resolution on these if possible. And that kind of goes along with the value of the samples also is to be very thoughtful about how to use them. The other general question, and this is just food for thought, is can a program like this be used to sort of inspire some technology development, you know, such as non invasive, or maybe non lethal sample acquisitions. Especially in, you know, these areas where you've got a lot of ethical concerns. So that's kind of food food for thought, but I'm very supportive of the program. Thanks Steve know those are great ideas and great things to think about. And so I don't think there was a real question there but I'm going to go back to this question of sort of the banked samples for versus freshly collected and I, and I think that that is a really important point and one of the reasons we say, at least two as you could even for some of the grade eight somebody has been these samples from past studies that might provide really relevant data. And it would be use it not doing anything invasive. Certainly, I think we'd be very open and could think about building into the RFA some ability for people to do non invasive sampling as well. Or I guess it would be invasive but as you say non lethal. Thank you so I very excited about the program as well. And I think my major comment had to do with the, the parameters of sampling so as you describe the ideas you look at two species and six developmental stages and 12 animals at each I think and 30 tissues and as I, as I indicated in some email I guess I think it'd be worth thinking about letting having the center's proposed experimental designs. Right so that that, you know, in this parameter space as the data is being gathered it could also be driven by power calculations or other analyses, indicating where you're going to get the most informative sampling at as you go. And, and I guess I had questions also about whether the samples were coming from the tissue banks or opportunistically from animals that die or whatever because that also might suggest some kind of adaptive type procedure where you're also deciding what what to say depending on what opportunities to present. So that's just one area for thought. One really minor comment is, is that in the concept there's a mention that in later years, you will be soliciting proposals for statistical methods to analyze the data, and I would just encourage you to broaden that language to statistical and information or something that's just a little more encompassing. And then I also had a question which is that for developmental GTX there are more institute partners and mental health I think and, and, and I and DS. And so are there possibilities to get more partners beefing up this project here. Yeah, I'll answer that part first which is, yes. So, and I see HD has expressed some enthusiasm and we're talking to both mental health and and and I and DS. And also, the Office of Research Infrastructure programs. I'll also be presenting a similar thing to the trans NIH non human primate working group to try and see if other ICs are interested as well and I think they might be. Okay, Tray. Yeah, so I to am very supportive of the idea of a developmental GTX. In fact, I was thinking of multiple times in the past six months, where I've been on some research conference call and someone pipes up, you know wouldn't it be great if we just had GTX for development. You know, and so, so I think it's it's very much needed. And of course there are some resources that overlap but nothing of the ambition you propose. Given the sort of armchair interpretation of what you're proposing it seems to have not one but several more dimensions than GTX. So it's not just across tissues that was the key thing that you know that GTX of course did, but now you're adding to that species component and a time component. So it's, it's certainly more complex. Could you just give us your analysis of how these, these extra dimensions reflect on the budget and scope of this versus the original GTX. Maybe cutting something that the original GTX did, or else this budget's going to have to be much larger, or you know the scope it's going to have to be larger. So how do you think about that. That's a really good point and that is sort of this balance of if you increase by one dimension you have to increase decrease by others if you're going to stay. So could you compare against GTX, I guess. So this here really a sample number. So both for developmental GTX and humans what's proposed and now what we're proposing in the non human primates, we're really looking at pretty small numbers of individuals, where as GTX have that 900 and could do some important statistical analyses and I think that in these smaller studies, we're really honing in on large differences between your stages and between your tissues, and not going to be have subtle effects. And in addition, it's sort of the exploratory space to say where do we want to look deeper. Yeah, just out of curiosity, was the original GTX scope 900 samples it was fewer was it not. Is or Jody is able to speak to that I don't know what was originally scoped out for the original GTX. Does anybody on who can speak to that Jody. Yeah, I don't know what the original I know that the final was 906 they recruited 965 donors and collected over around 53 tissues. The original original aim was 1000. So they came close. So sorry, Simone has has piped in the pilot was 180 and then they expanded it to the close to a thousand. Okay, Jonathan. But on that point tray, I just also wanted to note that the other dimension that's that's advanced I think from the original GTX program is relates to Steve voters part about the most recent assays sort of the type of, you know, assays and analysis that you can do is becoming a little bit more expansive as well and yet another dimension on top of sort of GTX which had the strong focus on bulk RNA sequencing. Go ahead Jonathan. So, two comments one. One is that I, I would look at this is this this is a pilot this is essentially exploratory can this actually work and I would hope that if it does that it could then be expanded because the sample sizes are are small so you know let's hope it works and that we can get more data because the amount of data that's going to come out of this while it could be really really useful I'm sure people are going to come back and say, but we really, you know, we could use five times as much right and then, you know, then then you have to worry about the budget. The other I think I wanted to follow up I think was marked that that made the comment about the statistical and computational analysis it was that that that was going to be down the road a little bit I worried that if that if if people aren't thinking about the study designs are made that it can have an impact on on on how things are done. This goes back to the classic problem with anyone who does biostatistics and they're brought into the game late, and then they have to try to figure out how to analyze data that was not designed the study design was not good for any any sort of analysis I would just encourage maybe maybe it's not a grant per se but clearly the analytical part of this needs to be thought of early in the game. Very good point and I think some language to that effect can be put in the RFA. Any questions or comments for this concept. Okay, can I get a motion to approve the concept. And a second second all in favor raise your hands five four, three, two, one anyone opposed or abstaining. Great. Thank you very much. Thank you, Jen.