 Hi, my name is Melissa Harris and I'm a postdoctoral fellow in Bill Paven's lab at the National Human Genome Research Institute and today I'm going to talk to you about identifying genetic modifiers of the age-related phenotype of hair-graying. As one approach to answering the question, why we age the way we do, I have focused on genetic modifiers. Genetic modifiers are those genes or genetic variations that have the ability to subtly modify an existing phenotype. And they have really garnered increasing interest in biomedical research because of their contribution to the variability that we see in disease phenotypes. But we know that genetic background not only plays a role in disease phenotypes, but also in aging phenotypes and overall lifespan. And this is not just true in humans, but also in animal models like the mouse model that I study. And so the thought is that if we can identify what these genetic mutations or genetic variations are, then we can get at that question, more of the mechanism of that question of why we age the way we do. So one cell type to study in order to understand genetic variation in aging phenotypes is to look at somatic stem cells. And this is simply because we know that aging in part is due to the loss of the regenerative capacity of our stem cells over time. The stem cell population that I have focused on is the melanocyte stem cell. And so you can see this depicted on my left, a hair follicle has melanocyte stem cells. And these are the stem cells that are required to regenerate the color of your hair over your lifetime. If you look at the cartoon diagram on the far left, you'll see that if you lose your melanocyte stem cells, you get gray hair or non-pigmented hairs. And so I thought as a way to be able to identify genetic modifiers of aging phenotypes, we could take mice that are predisposed for hair graying, make them to mice that have different genetic backgrounds, different genetic variation, and then ask, do any of those have the ability to subtly modify that hair-graying phenotype? And we could use this as a way to identify novel genetic mechanisms involved in this aging phenotype. So let me just give you an example of where we've been successful with this. One genetic modifier of hair graying is haploinsufficiency for the transcription factor MITF. So if we take mice that are already predisposed for hair graying and reduce their MITF levels by half, and I diagram this in the RNA-seq reads at the top, wild type is in white, half of MITF or haploinsufficiency for MITF is in the red. So if we take these mice, what we find is that loss of MITF, these mice are born black, and they acutely go gray over time, as you can see in this timeline. What's even more interesting is if we isolate melanocyte stem cells from wild type mice and MITF haploinsufficient mice, what we find is that as MITF decreases, we get the up-regulation of interferon-stimulated genes. And this is exciting because this points to a novel interaction between innate immunity and melanocyte stem cell maintenance. So I hope that this example gives you an idea or underscores the relevance of assessing genetic modifiers and aging phenotypes, and we'll show you that in the future we'll be able to identify answers to that question why we age the way we do. Thank you.