 I think it's important to start with a couple disclaimers. One, I'm not a geneticist, I'm a social scientist, a lawyer and health services researcher by training. I spent nine years teaching medical students, and so I come to the Genome Institute with a very different perspective of thinking about questions. And so what I want to share with you is some questions that you may want to think about as you look at studies, particularly studies that are talking about racial differences based on genetics. So one of the things that I want to share with you is the beginning. It's in 2003, at the time of the completion of the Human Genome Project, we developed a number of challenges for the future of genomics research. And it's quite interesting that over the four years since the time of that article, that this challenge has continued to be one that I think is extremely important to the field of genetics and the field of science and will continue to be. But I think it's important to recognize that this is an issue that's a challenge and was identified as a challenge to society and as we think about these questions. So the question of understanding the relationship between genomics, race, and ethnicity and the consequences of uncovering these relationships. So as we think about this question from a societal perspective, I think it's important that we think about both history as well as the future. And so, I start with the context. And we can think about the last few weeks. We can think about the last few years. But clearly the issue of race in America is something that's very important to people in our society. And how people think about difference, how people think and discriminate against individuals. Originally when I was putting my slide show together, I thought of having a picture from Katrina or a picture of Don Imus or some other kind of picture that was fairly immediate of how race is always surfaces up in conversations within our society. But race and science often does and we can look to history as we think about that question. So as we think about how we think about difference, how we think about variation in America becomes extremely important. So, I decided to propose questions that you may want to think about as you are talking to a investigator who has just reported on their study or if you're thinking about writing a specific story or a piece that may be on TV, what are some of the questions you may always want to ask? And so I decided to present a few questions for you. And these questions are both from my colleagues within the Genome Institute but also colleagues within the public health and the medical community asking them, what would you ask if you wanted to ask about studies related to human genetic variation in race? So the first question, what was the basis for choosing the populations to study? How did the study investigators categorize or define the study populations? Is the variation peculiar to a specific group, race or ethnicity, or only more common in it? And what are the potential causes of the differences in outcomes beyond genetics? And what are the social implications of misinterpretation of the data? And finally, what is the medical significance of the variation? What does it mean for health or disease? What is so what question? So, what was the basis for choosing the population to study? And I think this is really a challenging and interesting question when we look at different populations across the globe. Is there an issue of convenience or is there an issue of known differences with regards to disease and disease prevalence? How do you think about that? How do you challenge the question of why a specific population or group was identified for the specific study is an important question. And how did the study categorize or define the study population? And this is one of the areas that I'm really interested in for my own research is how people make a determination with regards to how they're going to describe the groups within their studies. So when you think about that from the perspective of the United States, particularly in the history of how we've collected data around individuals and groups within the United States, there has been a change over time. And so I just wanted to share with you some US Census data categories that we've used over the history of this country. And so if you recall back in 1790, we only collected really in two groups. Free, white or other, and slave was how we collected information in our country about groups and populations. But then if you look in 1890, we collected groups by white, black, mulatto, Chinese, Indian, quadruun, octrune, Japanese, quadruun, think about that and think about that related to genetic studies. How do we understand? What are we trying to define? How are we trying to describe people in difference? And then more recently, you can see from our OMB categories, and here I just want to highlight the italics, where within the Census categories, it clearly stated that this is neither a scientific nor anthropological in nature. And then finally, our current categories that we have for the collection of information within our country. And you see the five racial categories, and then the ethnic category, which is Hispanic or not Hispanic. But what changed in 2000 was you could identify more than one race, which I think is extremely important with regards to how we understand people and groups within our country. So another way to kind of describe this is when you think about research studies and studies where we're looking at different populations, we really put people in bins. And we don't fit in bins. We're not all in one bin. And that's the difficulty and the challenge that we have. But that's really the only way you can really do the study. And so the question is, why did you put them in that bin? Does it make sense that they're in that bin? Can you understand that bin? And is ancestry a better bin than our OMB categories of race at times? Or is it not? Or are there other ways to do this? So the third question is, can a specific ethnic group, and I identify the HapMap populations, but this could be another group that's identified, be generalized to all individuals within a U.S. census category of people? And so it really raises the challenge, and this really ties with Larry's talk this morning, is the question of our understanding of human genetic variation and thinking about that and thinking about the level of diversity that happens to be in the continent of Africa and how does that fit with our understanding of thinking about different groups? And so many genetic studies have shown that there's clearly more variation within the continent as that only a small group of individuals left the continent to cross the different parts of the globe. And so how do we understand that when we make differences related to skin color and identification? So this is a slide from Lynn Geordie, a colleague of mine at Geneticist at University of Utah, where he does a nice job of really articulating the issue of who's an African-American. And this is based on ancestral markers. So these are individuals that self-identified as being African-American or black. And if you look at the two individuals here, you see that one of the individuals has clearly a majority of their markers that would be identified as African ancestral markers, and the other individual has a majority of markers that would be identified as European markers. I think we probably all know people like that, people who clearly come from various ancestral backgrounds but they identify their identity, their social identity, which is so important and a component of our lives as one or another group, and they make a distinction about that. My own lab is doing work around understanding of how individuals who are clearly multiracial where one parent is European background and one parent is African background perceive their identity and what happens within their clinical encounters around that identity. So this question of how we think about individuals and describe individuals becomes extremely important. But there clearly is a relationship between our self-identified race and genetics, and it's extremely important to understand that, that you can correlate, but it's often imprecise and the correlation of ancestry is clearly more informative. And so this is a challenge both for the researcher and how do you describe your groups and use racial information that can be very valuable social construct of race but also try to be very clear in the ability to communicate when you're talking about an individual versus a group or population. So next question, what are potential causes of the differences in outcomes beyond genetics? And Emily talked a little bit about this this morning and some of the questions that were raised is that we have to be careful and thoughtful. And as a social scientist, these are the issues that are most important to me, is how do we think about the social determinants and what that may make with regards to who has certain diseases, what happens with regards to disease differences and outcomes and morbidity and mortality, that the socioeconomic status issues of transportation, housing, access to service, education, income have so much impact on what happens to individuals in our society. And so when we think about who gets diabetes, clearly the genetic component is an extremely important component but the cultural component, the diet, the issues of access to general healthcare services can be also very important to those issues. So how do we interpret and communicate that to the public? I think it's a challenge for researchers and it's likely a challenge for you. So I wanted to identify one study that was published a couple years ago that you may or may not be familiar with which was published by the Institute of Medicine called Unequal Treatment. And it's really been a profound study in our understanding of health disparities and really raising issues and providing a consensus of data that there's difference in treatment that people receive within our country that is related to the race and ethnicity that has nothing to do with the genetic basis but has to do with how they are treated within a system can have equal insurance but where there's differences in how they're treated. And what does that mean related to health and illness or may not mean related to health and illness? But the importance of understanding that the society and the influence of some of that with regards to what happens with individuals and their health is extremely important. So I wanna share with you a study that was published by Richard Cooper and a group of researchers that I think does a nice job of just kind of raising the case study of why we all have to be thoughtful. And this was a study related to blood pressure in populations of European versus African descent. And specifically, he was looking at the question of hypertension which is often identified as African-Americans and individuals who are self-identified as black as being greater risk generally throughout populations across the globe for hypertension. And so he wanted to look at that from a perspective of whether trying to tease out what may be the differences in different populations. And this figure from the article identifies a number of different population groups. So you'll see here where U.S. blacks are a little over 40% prevalence of hypertension and Nigerians a little bit over 10% and Jamaicans about 25% but you see the highest is from Germany. And so the question of challenges of understanding environment and diet and culture become extremely important in this question. And so it's really a question of challenge that we need to think about all of the issues with regards to how we understand disease and difference within our society. And so that this article is just an example of challenging us to make sure that we don't over focus on the genetics but that we also look at the environmental and the social issues that are extremely important. So the next question is, what are the implications of misinterpretation of the data? And I think that there are a number of examples from history that we can look to but I just wanna give one example that I wanna share with you. And this is from an Ebony magazine in 1966. And I just wanna highlight this article because it described sickle cell disease and it talked about sickle cell disease as a Negro disease. And clearly within the United States the prevalence of individuals with sickle cell disease would be identified as black or African-American. But if you think and now our knowledge that we clearly have across the globe, if you're in Greece or in Saudi Arabia or other parts of areas of the world where there was a high malaria possibility at one time, there are a number of individuals who also have sickle cell disease or sickle cell carriers. And it raises those questions. So this is from JAMA in 1947. And I know this is from 1947 and it's always nice to have 2020 hindsight and to be able to look back. And I think that's the challenge that we all have as we move forward. But in JAMA, 1947, the most significant feature of sickle cell anemia is the fact that it's apparently the only known disease that is completely confined to single race. Well clearly that's not true. And so how we think about this question and I think sickle cell disease, even though it's a single gene disorder, is a great case study of issues of misinformation, of discrimination against a group, of stigma against individuals who may be at risk for something but not have a disease that we can learn from when we think about society, the United States, and race, genetics, and disease. So the next question is, is the variation peculiar to a specific group or only more common in it? And I think this is an extremely important question as we talk about differences in groups related to potential genetic variants. And how does the investigator respond to you as a reporter when you ask that question and are able to interpret their results? So how is variation distributed between populations? Larry talked about this earlier, but again this slide from Lynn Geordi does a really nice job to show that the green bar that most of the variation is within a population group. And so the differences between populations is really very small when you look at the variation that occurs within populations and between populations. And what is the medical significance of the variation? What does it mean for health and disease? It's the so what question, so often for clinical researchers, what impact is this gonna have on the health of my patients? And I just wanted to kind of give you a context on a couple of things. One is an issue that I think has been a milestone but probably a milestone for the wrong reasons. And it gets talked about a lot in genetic and genomic conferences. And it really wasn't a genetic or genomic study whatsoever, even though it raised some questions about potential genetic variation. And that's the issue of the first drug that's been approved by the United States for a specific racial group, which was by-deal. And this is the indication in usage directions where it says by-deal is indicated for treatment of heart failure as an adjunct to standard therapy and self-identified black patients to improve their survival. But the challenge is who is self-identified black? And how do you understand that? And what does that mean from a clinical care perspective? And really are there other things that are going on that we need to learn and understand that may make by-deal very valuable for a lot of populations that would not identify as self-identified black or for individuals that clearly are self-identified black where it has no benefit to. And the question that I'm just really raising for you is that from a clinical perspective, we have to always be thoughtful of the challenge of what does this really mean to improve the health of people in a society, the people that may read your articles, people that may see your TV pieces, or the scientists that interpret others' studies. And so it becomes important that we're thoughtful about these questions. So I'm gonna end on a couple, I'm gonna share a little data from some work that I'm doing, research that I'm doing about how physicians think about these issues, what do doctors think when we think about human genetic variation and genetics and race. And I'm just gonna share with you two quotes from some focus groups that we've done with general internists across the country that I just think are nice illustrative points of the issue. So the first quote is, so I think we clearly know that biologically there are different chemicals and different functional processes going on in African-Americans versus white patients. You have to take that into account. They're going to respond better to one drug more than another, perhaps. This is a physician in Detroit, Michigan. Second one, race is a social construct. It's useful given the historic context. I would not let anybody not refer to me as black, as a black woman. However, I actually do believe that there's no biological basis for that and science proves me out. So we are entering into an exciting period of better understanding the genetic components of disease. And then how does that translate both to society and the public and how does it translate into clinical care becomes extremely important. And I just want to end with a quote from a piece that Francis Crick did in 2003 as part of the celebration of the completion of the Human Genome Project and the anniversary of their identification of the structure of DNA. And Francis Crick made this statement. It was a very powerful but short interview that he did. He was ill at that time. But he made this statement that I think it's important for all of us to remember. In biology, a new world is expanding in front of our eyes. May we learn to use it wisely? Thank you. So we'll start with questions. I got everybody quiet. So actually, so I mean, I actually have a question. Okay. So I want to start sort of biologically at the biological level of the gene, is there a distinction between blacks and whites? Blacks and whites? So no. So I guess the issue is that what is black, what is white? And that there's clearly information and data that supports ancestral differences. And so you can see human genetic variation across the globe that is ancestry link that may have some links with also skin color and other features and traits that you identify individuals from a social construct of race. But our social constructs of race are that, they're social constructs, but they may have valuable information to describe different ancestral backgrounds that are important to understanding human genetic variation. As we go forward, you know, we're gonna be hearing about studies. We've heard the studies on obesity. We're gonna hear some studies coming out shortly about height and from what I gather when this is not unreported information at this point, so this is just for your information. The distribution of that trait about height when you look at the hat map populations is different. So it's different and it's not as prevalent in Asians who are shorter than Europeans who are shorter than the Europeans who are the North African samples or the Western Africa sample. So I mean, what are we supposed to do? How do we interpret that? What are we supposed to do with that information in terms of discussing how these traits that are not diseases vary across the populations across the face of the planet? I think that's a perfect example. And if you think about the continent of Africa and the hat map populations you're above, which is from Nigeria area, so the West Coast. But if you think about the continent of Africa and the height of individuals from the continent, it changes dramatically. And so there are certain tribes and ethnic groups from Southern Africa that are very, very short and from Eastern Africa that's very, very tall. I mean, that's a perfect example that you then couldn't say that individuals who are quote African American or who are black are gonna be taller or shorter or this. So I think that's a great example to show the variation that occurs within different areas of the globe and within one continent. Yes? Years ago, I read and heard of a theory that partly explaining hypertension in American blacks. And I think it went like the blacks in the slave ships who could, many, many died, but the ones who could retain salt the best survived, if I've got that right. And they brought those genes to this country and that explains why American blacks have more hypertension than African blacks. Is that, was it ever true? And is it still true that there? So I'm gonna look to my colleague, Dr. Brody, and to give a perspective on this. Pleasing story. Although I've not seen any data that would suggest that it's true. The other issue is that to change allele frequencies, to change frequencies in population takes a lot, a lot of selection. And as horrible as the passage was, it may not have been a strong enough to selective force to actually change the frequencies in populations. If you think about the passage over the slave trade, it occurred over hundreds of years drawing from different regions. So I haven't seen published information that says this is what happened and this is why this might be true. And as you saw, the range of blood pressure varied. It is almost a continuum, almost without regard to continent. So if there are some documented differences, I don't know about it in the genes. And clearly, the environment changes quite radically across Vince's profile from Nigeria all the way to Germany. I don't know if Elaine or Francis has ever seen any scientific publication that said that this might be the... No, because at the moment, we don't have any good examples of genetic variations that have been validated as showing a strong association or even a weak association with hypertension. Those have been pretty frustrating to come by. And at such time as such variants appear, I suppose this could finally be a testable hypothesis by looking at the gene pool in African-Americans compared to West Africa, where the slave trade primarily was conducted. And you could see if there was any shift. I like you, I'm quite skeptical that that will be found, but it's testable. But why wouldn't it have been enough time? If there were a strong pole for a certain genetic type of individual to survive and the others not, why wouldn't that be enough time? It actually comes down to the math of selection and replacing genes or different flavors of genes. In order to get total replacement, it either takes a long, long time of drifting slowly, so little bits of selection over a long, long time, or massive amounts of selection over a short time. Short time in this case would be hundreds of years in that in order to get full replacement so that you had a big shift in the frequency, you may have to have 95% mortality. And the mortality was awful, but it wasn't that high. Once you have people over here and then you no longer have the selective force, it's really easy to have all the wills maintain a frequency. It also fits with the myth of how you could get rid of recessive disease by eliminating the people who are affected. There are lots of recessive diseases that are lethal and people don't reproduce, but there's this huge pool of people who are heterozygotes who aren't affected who continuously replenish that disease population. So in large populations, allele frequencies don't change radically unless selection is occurring over a long, long time, or selection is extremely intense. And there's one example that's been published over the last year in the ability to metabolize lactose. And that's the story where there's an example. In human population, it looks like some populations have acquired the ability to use milk for nutrition as adults, which not everyone can do. And the signature in the genome looks like that that trait is a recently evolved, recently selected for trait. But those are relatively few and far between those examples. One of the things that we're trying to do is use this HAPMAP type data and whole genome association data to look for other signatures of selection in the genome. But there's not a lot of them at this point. Sickle cells, another one, or anything that affects hemoglobin in malaria-ridden areas is another one. But we'd run out of examples very quickly if we went through them. You know, just to put another perspective on that, we do a lot of modeling of population genetic selection in the 150 dog breeds because we do see excess as a particular disease as in one breed or another. So if you're a Scottish Terrier, your chances of getting bladder cancer are 30-fold higher than if you're any other breed of dog. And so we look at exactly these sort of selective pressures and selective sweeps and what breeders were selecting for and what got dragged along with. And the pressure that you have to put on to really change the allele distribution is absolutely dramatic. When we see something actually change, we often see a population that, for instance, bottlenecked during World War II down to maybe 20 dogs, of which maybe only three or four were stud dogs that were still breeding, contributing to the gene pool. We know of examples in the Lee and Burgers where they bottlenecked down to about eight dogs. And so the pressure that the population drops enormously, the number of individuals in the population contributing to the gene pool drops enormously. And then there's a very, very strong selective pressure applied to those remaining individuals. Then you can start to see changes in allele frequency in a population, but it almost takes the constellation of those three events to see some meaningful change. It has to be really quite dramatic. I have a question for that regarding Ireland. The first light-hearted, when will Irish Catholic make it into the OPM category for HapMap? Because I didn't like that when I wrote that in for my SATs many years ago. But regarding folklore and Ireland growing up, we had always grown up hearing that because of the famine and because of the famine years and because of forced emigration and starvation and mortality that the tallest and the strongest were selected to go out on the coffin ships to go and live in Australia and New Zealand and America, that the families chose those who were going to make it. So when you look at the population now in the Republic of Ireland, the stature, the physical stature of the men is less tall and big than today's NFL linebacker. So I've always thought it was an interesting question and certainly never has been, as far as I know, explored scientifically, but I think it would be an interesting area for study. Well, the whole issue with the salt retention and the migration. I mean, if you follow back the articles and really look at the articles, you'll see that this is a hypothesis that there's been no empirical data. But I know that recently there was a popular TV show that had a piece on this. And so this is one of the challenges of how do we understand where the science is today and how we understand some of these differences. Issue a little bit. I collaborate with folks in Ireland and spend a fair bit of time talking to them and visiting. And so I've picked up a little bit the famine statistics. And it's another case where the famine, again, was awful and there was a huge efflux from the population. But the numbers, again, didn't have the selective pressure that we need to actually push allele frequencies. And even if they did, even if you selected all of the tallest, if you remember the slide I showed about the distribution and height, a generation of breeding, for lack of a better term, will essentially have that start to regress to the mean because we're talking about lots of different genes and different combinations. And so on average, tall parents tend to have children that are more similar to the average than they are to themselves to a certain degree, although there's a strong genetic component. The population of Ireland is still not what it was in the famine, but the number of Irish individuals in the world is roughly 10 times the population of Ireland. And my guess is that you won't find significant differences between the 40 million Irish that are outside of Ireland and the five or six million that are there. In forensic medicine, how is it that we're able to identify the so-called race of the victim? Are we latching onto so-called characteristics of curly hair? And do we even know the genome that well that we can identify the gene responsible for this or that? So for answers, you want to start that one out? So as Vince told you, most of genetic variation is shared amongst groups, but the frequency of a particular variant may be different depending on where your ancestors came from. I remember Larry's picture of those colored circles migrating out of Africa and particular variants therefore turning out to be more frequent in Asia or Europe than they might be across the continent of Africa because of a founder effect or just drift, which is another term geneticists use for the fact that the frequency will, especially in a smaller population, not stay constant just by random sort of stochastic change. And if you look across all 10 million snips in the genome and you look carefully, you can find some where the frequencies of a variant are really quite different depending on whether that person's ancestors came from Europe or Asia or in the case of HapMap, the Yoruba in West Africa. And that means that if you simply sample those that are particularly ancestrally relevant with a mere 20 or 30 of those snips, you can make a prediction about a DNA sample whether that person's ancestors came from one of those three parts of the globe. And you'll get it right as long as you're not looking at Tiger Woods. I'm gonna say the exact same thing if you stumble on that person. Right, so if you're given a limited number of options, you should be able to make a pretty good prediction about ancestral geographic origins. To say nothing about whether that is a predictor of race because race is such a murky, baggage laden term that in this instance, I think one should be careful about what you're determining and what you're not. You're really determining ancestral geography of that person's predecessors. And certainly that is being used in some instances in forensics to try to take a guess at what the origins might be of somebody who has left a DNA sample at the scene of a crime, even if you don't have a match, maybe it'll help the authorities in their abilities to try to prioritize who might be the culprit. And they're at least one celebrated or not celebrated depending on your perspective case in Louisiana where that was done. That's quite controversial because certainly, given the fact that many people don't have all of their ancestors from just one part of the world, and certainly when you look at the group that we call, for instance, Hispanics or Latinos, there's a very different kind of ancestral history if you happen to be from Puerto Rico as opposed to Mexican-American, as opposed to somebody who grew up in the country of Spain and yet we would call all of those Hispanics. So maybe this tells more than it should. But of course, this has turned into quite an industry of how people can send in a DNA sample and be told where their origins came from, right down to in some instances, the village in Africa where your ancestors came from, which is quite fanciful since, of course, Africa has not been static over the course of all this time either. And so some of that is people actually making bucks on making predictions that are really not well supported, at least not to that level of precision. One of the things we're anticipating, though, is that as we get more and more information about how genetic variation not only correlates with ancestral origin, but actually we identify variations that are associated with appearance. And you heard about one from Elaine, this gene that's associated with skin color. It's not unimaginable that in the next five or 10 years we'll also identify genes that play a role in facial structure, craniofacial features. And hair texture and hair color and eye color will, if not already getting glimpsed, get better and better so that a sketch of the individual derived solely from their DNA sequence might get better and better. And then that really is going to, I think, turn things upside down in terms of forensics and in terms of privacy issues about who has access to your DNA and what do they do with it.