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October 30, 2024 14 mins

Welcome back to the new series of the Oxford Sparks Big Questions Podcast! We are here to answer weird and wonderful questions about our world, with the help of science. And we’re starting with a very big question! How do you sequence the genomes of 70,000 species?

 

Dr Liam Crowley, from the Department of Biology, tells us about the ground-breaking Darwin Tree of Life project, which aims to sequence the genomes of over 70,000 species in Britain and Ireland. Discover the challenges and technological advances that make this monumental task possible, and explore the potential applications in fields like conservation genetics and evolutionary biology.

 

Tune in to find out how this project could revolutionise our understanding of biodiversity and the future of life on Earth!

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Episode Transcript

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>> Emily Elias (00:08):
A genome tells us the genetic building blocks of
what makes something something. It took
over a decade to figure out the human genome, and now
a group of researchers are thinking
bigger. On this episode of the Oxford
Sparks big Questions podcast, we are asking,
how do you sequence the genomes of
70,000 species?

(00:34):
Hello, I'm Emily Elias, and this is the show where we
seek out the brightest minds at the University of Oxford, and
we ask them, the big questions. And last time
we spoke to this researcher, it was about bed bugs.
So, hopefully, this time around, there will
be less anxiety and creepy
crawlies on your skin.

>> Liam Crowley (00:53):
Hello. so, I'm Doctor Liam Crowley, and I am a
postdoctoral researcher, in the department of biology at the
University of Oxford. And I, am working on a
project called the Darwin Tree of Life project.

>> Emily Elias (01:05):
What is the Darwin Tree of Life project?

>> Liam Crowley (01:07):
So, the Darwin Tree of Life project is a very
exciting, ambitious project, which is a
collaboration between lots of different institutions,
including universities, but also, museums
and botanic gardens. And we have
the ultimate aim of trying to sequence the full
genome of every single species of eukaryote in
Britain and Ireland.

>> Emily Elias (01:28):
That sounds like a lot of species.

>> Liam Crowley (01:30):
Yeah, ambitious is definitely, a good word to describe
the project. So, based on our current list, of
what we expect there to be in, Britain and
Ireland is more than
70,000 species of animal,
plants and fungi and protist.

>> Emily Elias (01:46):
Maybe we should start from the basics. What exactly
is the genome that you're sequencing?

>> Liam Crowley (01:52):
So, the genome is all of the genetic
material held within the cells of these
organisms, so as well as everything inside the
nucleus. Ah, with all the chromosomes, it's also
everything outside the nucleus. So there's some DNA held
in things like mitochondria. So we want to take every
single sequence of those four bases that make
up DNA. Adenine, thymine, guanine,

(02:14):
cytosine, the order of those bases
across all of the millions
of base pairs that comprise that
genome.

>> Emily Elias (02:22):
But why would you want to do this?

>> Liam Crowley (02:25):
Well, it's a very good question. So
the first way you could kind of answer that is actually just to say,
because we can. Because actually,
this is the first time in all of human history where
something like this would even be feasible.
And the first genome that we did, one of the first genomes that
we produced was our own genome, the human genome. That

(02:45):
took about a decade and
billions of dollars to do just one genome,
but actually that revolutionized all sorts of different
fields of research and medicine. So now it's the
turn of everything else. The rest of biodiversity. We want
to try and eventually sequence all of the DNA on
the planet, and it will give us a much greater
understanding of all these different species. But also there's

(03:08):
loads of different applications for genomic science.

>> Emily Elias (03:11):
You're into insects. How would you
apply this, then, to an insect? What sort of
thing would you be able to take away?

>> Liam Crowley (03:19):
Yeah, that's right. I'm an entomologist. I am,
focusing on trying to find all the different species of
insects, that we have at whiteon woods. So then we can then
repair those specimens, extract the DNA, and sequence them.
And there's lots of different things we can do from this. So I categorize it
in two different ways, the first of which
I would describe as discovery science. So

(03:40):
we don't know what we don't know. So, actually, just by looking
at all this data, we can start to find
patterns and interesting things going on with the genomes
themselves. And we can also see how
these different species are evolving and how perhaps they're
related to other species and how they're evolving as their convergence,
or their unique mutations and adaptations
that are arising within specific genes or gene families

(04:03):
in these genomes. Then the other thing
that we can do is what we like to call enabling
science. So we have this really kind of
grandiose sentence that we can say that genomes are
fast becoming an essential component of a 21st
century biology toolkit, meaning
that more and more genomes are becoming

(04:23):
a fundamental prerequisite to then allow
us to do a whole range of different other,
scientific inquiries. So, a really good example of
this would be for conservation, and conservation
genetics. So, if you want to see how
related a, vulnerable or isolated population is
to each other or to different populations, we can
do, various sequencing to kind of see that genetic

(04:45):
diversity. But before we can do any of that, we need to
actually have that original reference genome so we
know what part of the genome m to look in to sequence,
because we can't sequence an entire genome every single time, but
we can very quickly and easily sequence just very small
snippets. So it's all about knowing where to look.

>> Emily Elias (05:02):
How long does it take to sequence something? I mean, the
human genome took, what, like, 13 years to do.
So, like, I can't imagine this is a
quick turnaround.

>> Liam Crowley (05:12):
Yeah, that's right. the first few, because we were kind of figuring out
the process did take a very long time, but actually,
both the time it takes and the cost it takes
have, decreased beyond exponentially, which is
really quite impressive. We can sequence a genome
very, very quickly because this is all happening at scale.
It's hard to say how quick one particular genome

(05:33):
might take. But with whole batches of genomes
going through this process, best case scenario, we could
actually go from collecting a beetle,
from a log in Whiteham woods to actually
publishing a full, high quality genome
within a matter of weeks, potentially.

>> Emily Elias (05:49):
That's insane.

>> Liam Crowley (05:50):
Yeah.

>> Emily Elias (05:50):
So we've gone from years down to weeks. Is that like, the
power of AI, or is it something else at
play?

>> Liam Crowley (05:56):
It's to do with how we actually sequence it. So
find out the order of those bases and then the
software and the. The programs and the way that we
put those sequences together. It's a little bit like doing a jigsaw
puzzle. If you had a jigsaw puzzle with a few large
pieces, it's a lot easier to put it back together
than if you had one with lots and lots of small pieces.

(06:17):
So new modern sequencing technology is called long
read sequencing. And that's exactly what we're doing, where we actually,
starting from larger, original fragments of DNA. And
that's really helpful because DNA is actually really repetitive. So
it's really difficult to know, actually, which bit
of DNA, which cell, that bit of DNA actually originally
came from. So it's like doing a jigsaw with loads

(06:37):
and loads of pieces where they're all gray and they've all been shoved into one
giant bag, and you're trying to work out what on earth goes where.

>> Emily Elias (06:43):
So I guess that you're kind of in the process of making this
giant library of genomes.
What would be the hope that somebody would
be able to do with it? Would it be like, oh, I'm really curious. In this
beetle. Let me go take out the beetle book
and see what's been happening with these guys.

>> Liam Crowley (06:59):
Yeah, absolutely. So one of the big pillars of this project
is it's all completely open and available at
every single stage. So all of the draft
data and everything is all made
available, kind of with the caveat that, yes, it's not finished. There may
be mistakes. Hopefully, the finished project will be brilliant.
And so far, the quality has been unbelievably
good. It's almost like we're building a

(07:22):
library and we're putting the books onto
the shelves, and then anyone around the world
can come and they can take these books and they can do
whatever research they want to do from that. So
we already have examples of people using our
genomes, mostly in genomic science,
but also in other fields as well, where some really exciting

(07:42):
projects.

>> Emily Elias (07:43):
Do you have any examples of what people have done when they take
those books off the shelf and what they're using it
for?

>> Liam Crowley (07:49):
Yeah, so, there's actually some really nice examples, from the
insects, particularly in conservation genetics.

>> Emily Elias (07:54):
Oh, you would say that you love your insects.

>> Liam Crowley (07:56):
Yeah, not that I'd buy it at all, but, there's
this one, insect, a butterfly. It's called the large blue
butterfly and it actually went extinct in the UK and then
there was a reintroduction from, some swedish
individuals. And, it's now doing really well thanks to some
quite intensive conservation efforts. And it's actually
spreading. But because you have these kind of meta
populations across these areas and they're potentially quite

(08:18):
restricted, it's really important that we know how related they are
and actually do we need to intervene? Perhaps we could translocate
individuals or just kind of look after healthy genetic diversity
for these populations, but we won't be able to do any of that
conservation genetics before we have that original reference
genome. So, yeah, we worked very hard and managed
to get permits and permissions in place to
take a, couple of individuals to sequence,

(08:41):
which would have no impact on the population there taken from
one of the sites where it's doing best. And we are now
producing that genome. So as soon as that's finished, we have a
direct application of people ready and raring
to go to then do some really important
conservation genetic work.

>> Emily Elias (08:56):
And how do you produce a genome? Like, do you
just send it to the genome factory and then
it spits it out like a box of
crackers? Or how does that work?

>> Liam Crowley (09:07):
Yeah, so, the one word answer to this would be teamwork.
So we have a huge team and process which we have
been perfecting over the last four or five years. But
essentially you have someone like me, who goes out and finds the species,
identifies them and then preserves. So everything
is flash frozen at -80 to preserve that high
quality DNA. That then goes to the Sanger

(09:27):
institute in Cambridgeshire, where they
essentially break open all the cells, and extract that
DNA. That DNA can then be checked for quality.
and then if it looks like it's good, then it can be loaded
onto the sequencing machines. They then determine the order of
those bases and then all of that data goes
onto, the assembly step, which is bioinformatic

(09:47):
processes, which then reconstruct the jigsaw, and
then there's various kind of post assembly
checks of quality. We have other techniques going on at the same
time to make sure that all the scaffolds and some of
the high level structures of the genome, are all being put together
correctly. And then we're even doing some,
annotation. So actually sequencing some of the rna
alongside with the DNA to see where

(10:10):
the genes are. And actually, can we label genes
on the genome and try and have some work related to
that? So it's, yeah, a lot of different people
in part of this big pipeline. but there's
seems to be a very good process where we're kind of trying
to link back to each other and make sure we keep track of
specimens and everything is working all to a very high

(10:31):
quality.

>> Emily Elias (10:32):
Okay, so you guys have got a goal of
70,007 0
hour. Where are you at in that process?

>> Liam Crowley (10:42):
yeah. Ah, it's a big number. And the first thing to say
is, actually, at the start of the project, we didn't even really know how many
that is. So that's kind of our best guess, because
actually, we've had hundreds of years of
taxonomy and natural history
in Britain and Ireland, and we still
haven't named every single species we think is here.
And we're finding there's new cryptic species, or

(11:04):
perhaps we got some stuff wrong in the past. So it's a
big ask to kind of complete taxonomy for a
nation, but, we're doing pretty well. we have
collected more than 10,000 species in the
initial phases of the project. and we have
been sequencing a large number of these and we've released, more
than 1300 genomes so far.

(11:25):
But that rate of new genos coming out is going up all the
time.

>> Emily Elias (11:28):
I hate to be that guy, but, like, what does this
mean for the future? If you are able to sort of,
like, perfect this process, get
all of this information, build up this
massive library of books
that species books that we don't even know how big it could
be. What could this mean?

>> Liam Crowley (11:47):
Well, at our launch meeting back in
2019, Professor Mark Blackstar, who's one
of the lead, investigators for the project, kind of stood up
at this internal meeting and said, this project is
going to change biology. And, at the time I thought,
oh, that's kind of just trying to tee everyone up and get
everyone enthusiastic. But actually, as it's gone on, there's
more. I kind of agree, actually. This is revolutionary.

(12:10):
So, as I alluded to before, there's a whole range of different
investigative techniques which, are
unlocked. We kind of can call it genome
enabled research. So there's all these various different
things from sorting out taxonomy and resolving
phylogenies to study of evolution
and how genomes themselves, as well as the organisms and
genes and gene families are evolving. And then there's the

(12:33):
actual applied, applications like the
conservation, genetics and even potentially
biodiscovery. Again, we don't know what we don't know. There could be all
sorts of amazing biological compounds
held within the organisms which are all encoded
within the genomes. So having that
is really exciting and is really important step.
And the ultimate goal is, yeah, we want to sequence everything on the

(12:54):
planet, particularly in the face of the mass extinction
event and unprecedented biodiversity loss,
it becomes even more important. And, you know, if there's even potential
science fiction applications kind of thing in the future with
de extincting species. Although that's a whole
other tangent.

>> Emily Elias (13:10):
We'll save that tangent for another day.
This podcast was brought to you by Oxford Sparks from the
University of Oxford with music by John Lyons and a
special thanks to Liam Crowley. Tell us what you think about this podcast.

(13:31):
We are on social media at oxfordsparks. Or
you can go to our website, oxfordsparks dot ox
dot ac dot. It's a pretty cool website.
I mean, it's got stuff on it. I'm Emily
Elias. Bye for now.
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