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Interviewer: DNA tells the story of a 40 million year long battle between primates and deadly pathogens. Up next on The Scope.

Announcer: Examining the latest research, and telling you about the latest breakthroughs. The Science and Research show is on The Scope.

Interviewer: Post-doctoral fellow Matt Barber and Nels Elde, assistant professor of human genetics at the ÈËÆÞÖгöÊÓƵ of Utah, published a paper in the journal Science, documenting an incredible battle for survival between infectious bacteria and primates that has been raging for 40 million years. I'm joined today by Dr. Barber.

Why do you think knowing this story is important?

Dr. Barber: Well, when we think today about emerging resistance of bacteria to antibiotics and we're sort of losing our arsenal of drugs and therapies that we can use against some of these pathogens, and so understanding these sort of new weapons we can use against them I think is really important

Interviewer: I think we're all familiar with the immune responses that our bodies normally mount to fight off infections-- we sneeze, we have to blow our nose. But your story focuses on a different type of response.

Dr. Barber: Right, so what we're talking about here is often referred to as nutritional immunity, so the idea here is that, primarily it's been focused on iron. So iron is an essential nutrient not just for us but for also cellular microbes that inhabit our bodies: so bacteria, fungi, all these guys. So one sort of passive means of immunity is to effectively starve bacteria of nutrient iron. So iron in our body is almost entirely bound by chaperone proteins or other factors that effectively hide this nutrient from potential invading pathogens.

Interviewer: And scientists have actually known about this nutritional immunity for a long time, but I think what your story does is show how important it really is.

Dr. Barber: So what our story is really telling is that really, for at least the last 40 million years of primate evolution and probably in human populations today, is that this battle for iron between bacteria and primates has been a determining factor for our survival as a species.

Interviewer: So how did you go about figuring this out? What was your first clue that this was important?

Dr. Barber: So our story primarily focuses on a primate gene called transferrin. So this is a protein that floats around our blood steams, and it's been known for the last 50 years as the iron transporter in our bodies. So transferrin in the bloodstream binds free iron, transports it throughout the body and delivers it to our cells. But it turns out transferrin is also an abundant source of iron for pathogens.

So we sequenced the transferrin gene from 21 related primate species. So this represents about 40 million years of primate evolution. And then we can use statistical analyses to say, "Are the actual amino acids in this protein rapidly evolving across different species?" And it turns out 16 of the 18 amino acids that we identified were all in this C-lobe of transferrin which really suggested that there was something interesting happening in that part of the gene.

Interviewer: One of the most striking things to me in your paper is this picture of the bacterial protein reaching for iron that is being bound by the transferrin protein, and where these mutations happen is right at that interface, it's like, "Wow, we've got to protect this one spot."

Dr. Barber: Right. So when we have this signature of rapid evolution that leads to the question of what's driving it. Why do we see this at all? And we have some information from the literature that bacteria that steal iron from transferrin, they encode these surface proteins, these receptors called TBPA. This is a receptor that is used by several important human pathogens, so nicera meningitis which is the positive agent of meningococcal disease.

Haemophilus influenzae is a pathogen, if you have kids, they've probably received the Hib vaccine, so this is a potent pediatric pathogen, as well as neisseria gonorrhea which is the causing agent of gonorrhea. So a lot of these important human bacterial pathogens utilize TBPA receptors. What we saw was that, when we mapped the sites that were rapidly evolving in transferrin, all 16 of those sites in the C-lobe under selection were interacting with TBPA.

Interviewer: So you know that these mutations accumulate in one particular spot, and so how do you know that they're really important?

Dr. Barber: I think that the strength of the study came from merging that evolutionary approach and using it as a guide for an experimental biochemical approach. And so what I did was purified transferrin proteins from several different primates. So, for example, we made a single mutation that represents one of the few changes between human and chimpanzee transferrin and that single amino acid, which is also under selection when we look across all primate lineage, that single amino acid was able to block this interaction. So this suggests this is functional genetic differences between humans and chimps, presumably related to bacterial immunity.

Interviewer: You can make some of the mutations you saw in these different primates, you can make them in the lab and show that they actually had an effect.

Dr. Barber: Yes. Exactly.

Interviewer: That must have been kind of a "Eureka" moment for you.

Dr. Barber: That was one of my favorite experiments I've probably ever done in my scientific career.

Interviewer: And of course bacteria aren't going to take this lying down, right?

Dr. Barber: Right. And if we look at the genes for this transferrin receptor, TBPA, across many different bacterial pathogens, it turns out that they also show these signatures of rapid evolution, and it's specifically in the interface of the protein that binds to transferrin. So, this is sort of what we think is seeing the flip side of the arms race from the bacterial perspective.

Interviewer: This story still plays out in the DNA of people alive today.

Dr. Barber: Exactly. Turns out that actually for several decades we've known about variation in the transferrin gene in humans. And so there's a variant of the gene that's called C2. It turns out that the C2 transferrin variant is very abundant. In a room of a hundred people, several people are going to have at least one copy of this gene. And the C2 variant comes down to a single polymorphism, a single amino acid change in transferrin.

And what's really interesting is that C2 transferrin cannot be bound by a receptor from haemophilus influenzae, but it could from some of the neisseria pathogens, like gonorrhea. And so, this was also the start of appreciating some of the underlying genetic variation on the side of the bacteria, that some could not see this human variant and some didn't care.

Interviewer: And I think it's fair to say that if you were just to look at the human DNA sequence, you wouldn't necessarily appreciate kind of the history of what has been going on.

Dr. Barber: That's right. And again, that's maybe another reason why this hasn't been picked up before is that, if we consider studies of human genetic variation we're looking on time scales of maybe thousands or tens of thousands of years. And when we look back, there's potentially no strong signatures of rapid evolution in transferrin within humans, to separate the fact that we see variability. Whereas if we overlay that with 40 million years of primate evolution that we can look at and understand, this sort of gives us a broader perspective on what might be driving some of these interesting changes.

Interviewer: And do you think if we were to do a similar analysis, that our DNA might have other stories to tell?

Dr. Barber: Absolutely. Some other work that I'm doing in the lab is applying the same approach to think about asthma susceptibilities. So for example, people have looked at genes that are different between humans that relate to the ability to develop asthma. And many of these genes are involved in immunity, and if we again look instead of within human populations, if we look across primates, many of these genes appear to be rapidly evolving. So I think this is the tip of the iceberg.

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