The Human Genome an Imperative Discovery Tool
Rhodes scholar Pardis Sabeti graduated with her medical degree from Harvard Medical School in 2006, earning the school's highest honor - the third woman ever to do so. She's also the lead singer and songwriter of the band, Thousand Days, who uses her music to make science appealing to children, especially, girls. As a graduate student at Oxford University in England, Sabeti developed a way to detect natural selection at the level of individual genes. In Eric Lander's lab at the Broad Institute, she scanned the entire human genome to figure out which genes have changed within the last 10,000 years and which have spread rapidly in the human gene pool due to natural selection. With these tools, geneticists can study how cultural and environmental changes have affected the evolution of the human genome. Now Sabeti is applying this technique to her true passion: understanding the interplay between humans and the pathogens that cause diseases like malaria, tuberculosis, and leprosy. Her work - published in December 2007 - revealed genes involved in drug resistance and in evading the immune system, giving researchers potential targets for new therapies and vaccines.
Pardis Sabeti: Well, so it’s basically a method by which you can look in the human genome and let it-- It’s a discovery tool. Right. You look in the human genome and you see what has emerged, what’s been- become really common and prevalent and therefore must be important for our survival, and the things that you find are interesting. A lot of them we like to say are very-- it’s skin deep so a lot of them is to do with pigment. When you look in Europe and Asia it’s the lighter skin.
Those are things that have become very common. It looks like hair in Asia so hair and sweat glands in the Asian population have been under evolutionary pressure. So a lot of things that just allow you to interact with the environment that seem to be under potential pressure and then lactose tolerance is another big one so the ability to drink milk. Again it’s an effect as our nutrition, as our sources of food change, our metabolism changes and how we use those resources. So those are the kinds of things that we find but one of the- to me the most interesting with my background in- sort of clinical background and MD is that the other thing that’s very strongly under selection is things that are known to protect from malaria and things that seem to be involved with infectious disease.
So it makes sense that as we’re moving to different environments and climates we’re changing our sort of skin and our sweating patterns to deal- to thermoregulate and deal with the sort of summery pressure. As we change our- domesticate plants and animals we are changing our metabolism and what we’re using as nutrient resources and as we deal with lots of infections so parasites, bacteria, viruses that are interacting with us all the time we need to survive. And so when I was looking through the genome I kind of honed in on-- Originally, I saw- I was developing the test looking at genes that were protected from malaria, seeing these kinds of patterns, and then as you look through the genome the things that protect from malaria seem to be evolving.
This is all very preliminary but it looks like a bunch of genes that are involved with Lassa hemorrhagic fever, which is a hemorrhaging fever that people get, also seem to be under evolutionary pressure. So it’s kind of pointing me to pathogens are a very important evolutionary pressure to humans and what’s very interesting is that what’s so interesting about pathogens is they are themselves changing so rapidly. So we see how we evolve and adapt to them but they are also continuing to evolve and adapt to us so it’s this moving target and their genomes are much like ours and we can study them in the same way and see how they survive.
Question: How does this help humans?
Pardis Sabeti: So as we look in the human genome we look to see what’s evolving and what’s protected from- and the things so far that we’ve identified important in infectious disease we’ve-- Malaria is when we understand a lot so we can see where those genes that protect from malaria seem to be under strong evolutionary pressure, and the kinds of things that we see is in the gene hemoglobin, the sickle cell mutation, G6PD deficiency.
You see a lot of things that are involved in immune response or T-cell response and so you see both red blood cell because malaria invades the red blood cells so both receptors on a red blood cell and things that are important in the constitution of the red blood cell under strong evolutionary pressure and also things important in the immune system. So-- And one of the other genes is CD36 which is a receptor on endothelial cells so we see how both the immune system and the red blood cell are very important in malaria pathogenesis and that genes that are within those- sort of within the immune system and red blood cells are often under natural selection for protection from malaria.
Question: How do you distinguish between natural selection and randomness in gene mutation?
Pardis Sabeti: So that’s the process by-- So what’s nice is that we have a lot of candidates that we already know to be functionally important. Right. So we can look around those and that’s originally when I was developing the test I was. I was looking around genes that I already knew that were protected from malaria that we’d have an expectation that they would be under natural selection. Right. So they cause resistance to malaria and malaria’s been around for a long time and that you might expect to see them rise through the population. So that’s basically the test that I was working on is about that.
It’s about distinguishing just a random event and a random mutation that’s common in the population versus something that was sort of became prevalent too rapidly to happen by chance alone. So what we do is we go through and we look across the genome and we look for things that are very prevalent and things that are very young and we have a way- a threshold of saying this is too young to have become this prevalent by chance. And so it hasn’t been around long enough that it just sort of randomly got to this prevalence.
Question: Why do some people contract malaria and die and others not?
Pardis Sabeti: Well, we do know part of-- We do-- We know part of the story as to why some people get malaria and live and some people get malaria and die so there are-- Like I said, malaria is a very complex organism and the way that it invades and affects and it causes lots of different symptomologies like cerebral malaria or severe malarial anemia. There’s a lot of interactions that are going on with the host, with the human, and so we don’t understand every aspect of the disease but we do know some of the mutations that allow people to survive and we understand partly how that works. And again those have to do with things that are expressed in red blood cells or they’re important for red blood cells and things important in the immune system.
Well, actually I have a great group already. I have some-- I-- Harvard is a great place. There’s a great community around and I was already at- between MIT and Harvard at the Broad Institute so I had a lot of connections so I already have a very good core group of students and staff working with me, and essentially kind of-- one of-- We talk about what are the core principles that the lab does and what does everybody know, what are the core fundamental information that they have, and our lab is just based around methods, methods for understanding natural selection and important things in the genome.
And so what we work on is we work on developing better methods to study natural selection in humans and in malaria and other pathogens and better ways of understanding relationships between physical traits that we see and the genetic variation in the genome. So basically everyone in my lab is very method driven. How do we do this better? How do we understand this better? But then the things that we study is we do study human evolution so we continue to look at the human genome in different populations and see what’s important. And then we study the malaria genome s well and understand both how it evolves but also just trying to get the scope of what is the diversity out there in the malaria population, what’s going on, how well will our drugs work, how different are the different parasites in different populations, what is the evolutionary pressure for facing it. So essentially building is methodology and applying it both to humans and to pathogens.
And then the last one- the last kind of area of the group is this new thing, Lassa hemorrhagic fever, that we’re just recently studying, but it all ties in the same. Basically, it’s a very deadly infectious disease and it appears to be- have been in human populations for a very long time and have genes that are being spread through human populations to protect against it. So we’re investigating that right now and broadly investigating Lassa fever since it’s a very-- Who knows whether or not it’ll bear out, this-- these signals that we’re detecting for that pathway and for those genes that are important in the pathway, but regardless it just sort of pointed me to this disease that’s very understudied. So millions and millions of people are infected with it yet hardly any research funding is going towards it.
Recorded on: June 29, 2008
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