Shamini Bundell
Welcome back to the Nature Podcast, this week: a first draft of a human pangenome...
Nick Petrić Howe
...and the latest from the Nature Briefing. I'm Nick Petrić Howe...
Shamini Bundell
...and I'm Shamini Bundell.
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Shamini Bundell
2001 was a landmark year for science with the publication of the first draft of the human genome, in papers in Nature and Science. For the first time, scientists around the world were able to peruse over 90% of the human genome, opening the door for a new era of genetics research. Over the years, researchers have worked hard to fill in the gaps, releasing new versions and sequences with the first genome to have no gaps at all being published only last year. All this honing and sequencing has created evermore accurate reference genomes, the genomes used as the baseline in comparative genetic studies, but they still have an issue: diversity. The current reference genomes are based on DNA from a very small number of people, so they don't represent the vast amount of genetic variation known to exist across human populations. But things might be beginning to change. This week, Nature is publishing the first draft of a human pangenome. The latest results from a consortium that aims to encapsulate a greater diversity of people in it sequences. To find out more reporter at Benjamin Thompson spoke with Michelle Trenkmann, a Senior Editor here at Nature, who handles a lot of the genetics and genomics papers published in the journal, she started by talking through the issues with the existing reference genomes.
Michelle Trenkmann
So, the current human reference genome, the draft of which was published in 2001, is a mosaic of several people's DNAs. About 70%, contributed by a single individual, so this reference genome does not represent the diversity. And this gap free new genome that was published last year, this also represents only a single individual.
Benjamin Thompson
And what sort of biases could that introduce into genomics research, for example?
Michelle Trenkmann
So we know that specific genetic variants occur more often in some populations than others. And so if we're using only one reference, we basically create a bias towards calling that particular person DNA reference, even though in a different population, that might not actually be a reference. So, it's really important that we have a more representative genome that includes as many populations on the globe as possible, so that we can also serve other communities better both in basic research and in health science research.
Benjamin Thompson
And so enter a suite of new papers published in Nature this week that have looked at take a step towards making a reference genome that maybe does encapsulate more of the diversity in human populations around the world. And these papers are from the Human Pangenome Reference Consortium. So, for someone not familiar, what is a pangenome?
Michelle Trenkmann
A pangenome is constructed of multiple genomes. And by doing that, you get a representation of all of these different genomes that have contributed to the pangenome, at an equal level. And so you get a much better idea of how diverse the genetic sequences are in those different genomes. And then you can do analyses that show you where are these genomes practically the same? And where do these genomes really differ?
Benjamin Thompson
And in terms of this work then, what have they actually done? How many genomes have they included?
Michelle Trenkmann
This draft human pangenome included 47 genomes, so 47 volunteer donors have contributed their DNA. So we have 94, haploid genomes — because humans, we have two copies of each chromosome. And these individuals that were sequenced for this pangenome they come from across the world. And so, of course, 47 is still not representative of the whole global population, but it's a start. And the consortium have also chosen to call it a draft human pangenome on purpose. It's supposed to indicate it's a work in progress.
Benjamin Thompson
And was this a difficult thing to accomplish?
Michelle Trenkmann
Yes, certainly, the technological advances of the last 10, 15 years have definitely been hugely important for achieving this. For about this time, we've had now a sequencing technology called long-read sequencing, which means that in a single read, you get very long pieces of DNA. And, of course, if you have very long pieces of DNA, you have fewer puzzle pieces, and so it's easier to put together these puzzle pieces in the right orientation. But this is still not a fully automated process. And the sequencing technologies are still evolving, they're still getting better, they're still getting more accurate. And so we have to remember that the genomes that contribute to this draft, they are not yet gap free. So you know, there's still some way to go.
Benjamin Thompson
And one thing that struck me reading about this project was trying to get a sense of what it actually looks like. Because if you think back to the genome that was first published in 2001, you can kind of use the book analogy, right, you start on page one, and you could read the DNA in a linear manner all the way to the end. But this is kind of a book that also contains 47 books at the same time. So what does it look like?
Michelle Trenkmann
So what the researchers are working on is something that is called graph representation. And one can imagine that a little like an underground map, where different lines meet in an important hub — say, a train station — where you have five, six different lines coming into the train station, but then they leave in different directions, although some of them might still meet again, in another train station. And the pangenome is similar, where sequences that maybe are shared between all of the genomes, they are just a single line, and then they split off into their different sequence paths. And then a few of these might meet again, somewhere, and make a joint line again. So this is the idea of a graph representation.
Benjamin Thompson
And you said the researchers behind this work are calling this a draft pangenome, and if the ultimate aim of this project is to be representative of humanity — of Homo sapiens, across the world — I guess the genomes of 47 people from different populations needs to be expanded upon, where does the project go next?
Michelle Trenkmann
There is a subgroup within this human pangenome project that works, especially on that question: how do you make sure that diversity is really represented in this genome? At the moment, the plan is to increase the number of contributors to this pangenome to 350 individuals. And the project is working not just on identifying the populations that could contribute, but they're also working on reaching out to those communities and building collaborations and making sure that such contributions happen in an equitable manner and within an ethical framework.
Benjamin Thompson
And here we are then at the start, so this pan genome draft has been published, what do you think that it could ultimately be used for in the future?
Michelle Trenkmann
So, I think one important application is definitely going to be in medical research and in translational research. For example, in a genetic diagnostics when you're using a reference that is more representative of the population that your patient belongs to, then you have a better chance of actually identifying the gene that might make them sick.
Shamini Bundell
That was Michelle Trenkmann talking with Benjamin Thompson. To read more about the draft human pangenome, look out for the links in the show notes.
Nick Petrić Howe
Coming up, get ready to update your textbooks as there's a new organelle in town. Right now though, it's time for the research highlights, with Dan Fox.
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Dan Fox
A new semi-transparent sensor allows a wearer to 'see' infrared light that is normally invisible to the human eye. Researchers made the wearable device by layering carbon-based molecules with materials used in some light emitting diodes. When stimulated by infrared light, the layers generate charge carrying particles that can be collected to produce a visible image. The authors say that their device outperforms previous systems which produced lower resolution images. The team tested its material in a wearable screen that sits on the face and showed that it could be used as an anti-surveillance device to spot infrared light from facial recognition cameras. You can spot that research in Science Advances.
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Dan Fox
You might think that vultures have a fairly predictable diet, whatever dead wild animals they come across, but researchers studying griffon vultures from two populations in Spain have found a surprising amount of variation. Using GPS trackers and field observations, the team recorded several thousand feeding events. In both populations, males were more likely than females to eat foods linked to humans, such as rubbish in landfills. This behavior comes with risks, including exposure to poisons, pharmaceuticals, and live power lines. But the two vulture populations also turned out to have different culinary cultures. Vultures from northern Spain tended to dine on predictable food sources associated with humans, such as livestock carcasses and rubbish from landfills. Whereas vultures living in the south often opted for wild animal carcasses. Even in locations where the two populations overlapped, vultures tended to stick to the ways of their home group suggesting that diets are culturally determined. The authors say the area of overlap could be important for vulture conservation because it contains a rich variety of food sources and supports multiple vulture cultures. Pick over the bones of that research in Proceedings of the Royal Society B.
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Nick Petrić Howe
Finally, on the show, it's time for the Briefing Chat, where we discuss a couple of articles that been featured in the Nature Briefing. Shamini, what have you got for us this time?
Shamini Bundell
This week, we are delving into fruit fly intestines—
Nick Petrić Howe
—Oh—
Shamini Bundell
—a place I'm sure you've always wanted to go. And it's quite cool, some scientists have discovered some new possible organelles in cells in the fruit fly intestines. And this is a news article in Nature about a paper also in Nature.
Nick Petrić Howe
Oh right, and when you say organelle, as well, these are things like, you know, mitochondria, endoplasmic reticulum, that sort of stuff.
Shamini Bundell
Yeah, yeah, exactly. So almost acting like mini organs inside cells, I suppose, in a way—
Nick Petrić Howe
—organelle—
Shamini Bundell
—organelles yep! Complex structures with membranes. And this new one seems to be involved in phosphate and probably storing phosphate acting like a reservoir, maybe helping to regulate the levels. And that's quite important, because phosphate is vital for growth is really important for animals, plants, bacteria. But in animal like tissues and cells, it's not so well studied in terms of its sort of specific functions and what's going on with phosphate inside animal cells.
Nick Petrić Howe
And so does this give us a better insight into what is going on with phosphate?
Shamini Bundell
Well, yeah, they certainly found something that's going on with phosphate. So, I think that is what they were sort of setting out to look at. And they decided to look at fruit flies, so Drosophila. So they did a couple of experiments, which basically sort of limits the amount of phosphate that's going into the cell. So either by giving the flies food with less phosphate in, or in one experiment, they gave the flies a particular type of acid, which inhibits the absorption of phosphorus, the element in phosphate, and looked at what happened. And the interesting thing that they noticed, was in the fruit flies guts in their sort of intestinal lining, the lack of phosphate seemed to be leading to a spike in cell numbers. So the cells were suddenly growing, dividing more.
Nick Petrić Howe
But that seems kind of counterintuitive. You're like limiting them from something, but then they're actually growing more of themselves, what's going on?
Shamini Bundell
That's kind of what I thought, when I first read this, I was like, huh, isn't that... does that make sense? Is that the opposite way around? But they do have a sort of theory about it. So they looked into it a bit more deeply as well. And they looked at a particular gene, there's this gene called PXo, and they know in mammals that this is involved in sort of phosphate sensing. So they looked at that in these fruit flies. And they saw that when there was less phosphate, when they sort of deprived the poor little flies of phosphate, there was less of this genes expression. And when there was less of this gene expression, it seemed to cause the cells to start to divide more. And on the opposite way around, when they kind of tweaked the gene to overexpress and make more of this particular protein, then the cell division slowed down. So this seems to be kind of key to the relationship between, giving the flies phosphate and having this multiplication of cells in the intestines. And it was this that led them to this organelle, because then they put a fluorescent tag on the PXo protein and saw that it was associated with these like oval like shaped structures in the cells, which they looked at. And they thought those aren't any of the organelles that we know about.
Nick Petrić Howe
I think it's fair to say the fruit fly is pretty well studied, how have scientists sort of not noticed that there's this organelle here before?
Shamini Bundell
I know, it's funny, isn't it? And this article talks about how phosphate is really important, but people didn't really know a lot about what was going on in animal tissues with it. I think it's just another example of this sort of area of biology where, you know, we might think we've got it all covered, but there's so much left to explore. And you know, there's a quote from the in here that says it's opened the door to many other questions. And basically, they said it highlights how much there is still to learn about cell physiology. The lovely quote is, "the beauty is there, it's just waiting for us to discover it."
Nick Petrić Howe
Oh, that's really nice. I do love that about science, every time you scratch the surface, there's always more underneath—
Shamini Bundell
—more work to do—
Nick Petrić Howe
—always more research—
Shamini Bundell
—keep going, yup—
Nick Petrić Howe
—and speaking of keeping going for my story, this week, I have been reading, in Nature, about a ancient pendant that researchers have been able to get DNA from, to sort of identify who the pendant belonged to.
Shamini Bundell
Oh, this is sort of tracking people down via their lost ancient jewelry. How ancient are we talking about? Where's this pendant from?
Nick Petrić Howe
There's certainly a lot of like forensic science sort of vibes in this because it's very much getting DNA from objects to try and track people down. So, this object — this pendant — is from around 20,000 years ago, and it was found in the Denisova Cave, which you may be familiar with. It's a cave in Siberia, where lots of human artifacts have come from because it seems that many different humans — and different hominids even — lived in this cave over several 100,000 years. But this one appears to be from a Homo sapiens. And also we can tell because of the DNA that was extracted from it from a woman.
Shamini Bundell
Oh, but wait, how... you said it's a pendant? You know, I've heard a lot about them extracting ancient DNA from bones from remains, how do you forensically get this DNA from an object, like a pendant?
Nick Petrić Howe
Well, that's been the real difficult thing and a lot of what this paper is about is how exactly you could do that. So, the pendant is made from an elk tooth, and this material is quite porous, so things can get into it. So what they believe happened was maybe some body fluid from the person who's wearing the pendant, or maybe even making the pendant, managed to get inside of it. And then that's been preserved over this long period of time. But to actually get this DNA out, what they did is... it's our pal phosphate again — phosphate is getting a lot of coverage in this week's Briefing Chat — they used a kind of phosphate bath to bathe the pendant in and by slowly increasing the temperature and doing many sort of washes with this, they're able to basically gently cajole the DNA out of the pendant, and then take it out for sequencing.
Shamini Bundell
Wow, okay, so that so you can actually get some DNA from someone who was touching this pendant, and you said, they're human, they were a woman, is there anything else you can tell about this ancient person from their DNA?
Nick Petrić Howe
There is. So, they compared the DNA that they got from this pendant to other ancient DNA samples that have been sequenced in the past. And they were able to determine that this woman was from a North Eurasian population, which actually previously have only been identified to be much further east than where this pendant was found. So it's unclear what that means at this point. But it's very interesting that it's so far away from where we've previously done it. And as I said, they're not sure whether this was the person wearing it, or the person who made it. So—
Shamini Bundell
—It could've been traded, I suppose, all that way, couldn't it?
Nick Petrić Howe
Potentially, yeah. Like we just don't know, at this point. But it's just really interesting. And, you know, some of the people interviewed with article were really impressed that this was a technique that we can do, because whilst these artefacts are very rare, like these sort of bone artefacts, DNA is even rarer, so to be able to get DNA from it, is really impressive. And also, in the past, when we've wanted to associate artefacts with particular people, we've just seen where they're buried, and like, oh, this person was buried near this, so probably this was their tool or something like that. Whereas this gives us a much more specific relationship between a tool and a person.
Shamini Bundell
Well, I was going to sort of say, Oh, well, is this a whole new tool for archaeologists to be able to... a new place to find DNA. But yeah, as you said, these particular items aren't terribly common. But when they do pop up when they are discovered, that could be an exciting extra insight.
Nick Petrić Howe
No, definitely. But there are some caveats to this approach. So in the paper, they actually tried to get DNA from a bunch of different artefacts, but we're only able to get from this one. And one of the big reasons for that is us. Us modern humans, we have our DNA sort of throwing it around everywhere. So there's quite a nice quote in a sort of Research Briefing, which has an associated article that the author wrote to go along with this, where they said, "it seemed as if we had developed an extremely elaborate method of recovering modern DNA contaminants from ancient bone artefacts." So they were quite, it seemed, frustrated at first, but then they actually got it to work. So going forward in the future if we were looking to use this technique — and this is already done in a lot of modern archaeology, but maybe not so much in the past — is to really be careful use gloves, use masks and things and really try and prevent any contamination. As soon as a new artefact is uncovered.
Shamini Bundell
So this is again, getting more and more like a forensic scene with your archaeology. Brilliant. Well, thanks very much for telling us about that. And if anyone wants to find out more about either of these two stories, we'll put links to these in particular, in the show notes and also a link to where you can sign up to the Nature Briefing.
Nick Petrić Howe
And that's all we've got time for. Just before we go, don't forget you can keep in touch with us on Twitter, we're @naturepodcast, where you can send us an email to podcast@nature.com. I'm Nick Petrić Howe.
Shamini Bundell
And I'm Shamini Bundell. Thanks for listening.