Adam Felsenfeld: To produce -- the purpose is to produce high
quality finished genomes at approximately current costs in the next three years, about
25 to 50 human, and select human non-primate genomes.
And I’ll talk about quality in a few slides.
Also, we would expect grantees over time to develop more specific definition of what high
quality finished genome is, and to use state of the art methods to maximize quantity and
quality and whenever NHGRI says use state of the art methods, what we mean is we want
them to push the state of the art without actually becoming long-term technology development
centers.
So why?
For human, the reference is good but can be made better.
There are still gaps, not a lot of them, but there are still gaps.
There is incomplete representation of structural variation.
We need to move from a mosaic representation to one that represents haplotypes faithfully,
and we all know that we can better represent world populations in the reference.
When this came up at the workshop, it was considered of such high priority that we should
consider moving ahead even though costs are currently somewhat high, individually for
these.
For non-human primates, primate genomes are key to understanding fundamental questions
about human genome evolution, but the existing -- almost all the existing primate references
are not really reference quality.
They’re not finished.
They could be better.
So what is high quality?
Well, certainly well beyond the current short-read-only methods.
It’s possible to state quality in absolute terms.
I mean, you can ask for end-to-end contiguity, for example, fully haplotype resolved, and
you could ask for zero gaps.
Short of that, you could have specific lists of known difficult regions, and ask that they
be 100 percent resolved.
It’s also possible to state high quality in terms of the gain in biomedical utility,
with reference to the uses of the human reference sequence, for example.
Practical issues need to be considered because there’s a moving state of the art.
Whatever language we propose, we have in the FOA, we’ll need to ask applicants to consider
all of these things, because we don’t -- they all actually do have to be considered in any
definition of what’s high quality.
And we have to give some leeway to encourage creative proposals.
There is some relationship to other activities.
The NHGRI genome reference consortium award already funds among its activities production
of five to seven very high quality human genomes.
Some of those are expected to be essentially end-to-end contiguous, although there will
be some regions that won’t be resolved.
And any further effort we’ll need to coordinate with that, not just in terms of production,
but in terms of integration into references.
There’s no overlap from the primate genome part of this.
We are certain to need some community input regarding this selection of samples in both
cases.
We propose this as a cooperative agreement mechanism for resource and we think this will
require about $2 million a year for three years, and we would expect to make one, possibly
two, awards.
And I have to say that this amount of funds, again, comes from our best information at
the time of the July meeting, of what a current, very high quality reference genome haplotype
resolved would cost, 200 to $250,000.
But, again, I have spoken to people since then who think it can be done for substantially
less, and I hope it can be.
So I’m going to stop there, and once again, go around to the folks who I asked to take
a look at this in advance.
Lon, do you want to start?
Joseph Ecker: [unintelligible] In this case, you wouldn’t
limit the call to groups that aren’t funded under the consortium already?
Adam Felsenfeld: No, this is independent.
And this would expressly not be -- we would not attempt to make this highly coordinated
with the core GSP.
I think it’s just too much.
It needs to be an independent effort.
In the past, actually in the distant past, we had these kinds of functions together in
the same kind of grant, and actually, this kind of activity, the high quality genome
activity, needs its own focus to such an extent that I think having it be part of, or associated
with something bigger, it has to be a separate grant.
Having it too associated with something more wide ranging will detract from it.
But I don’t think that having a grant from the same institution that also has one of
the larger grants is particular bar.
It’s a very highly specialized expertise.
Lon Cardon: I don’t have a whole lot to add to that.
I think the questions on this were overlapped with other programs which you touched upon.
The cost, and the overall climate of the funding environment, you go one or two.
It was less of a scientific case, I think.
Adam Felsenfeld: Anyone on the phone?
Sorry, Carol.
Carol Bult: It’s okay.
What about annotation of the genome assemblies?
Is that out of scope for this, or would that be considered in scope?
And then reagents to actually then leverage the genome assemblies to do more experimental
work, is all of that out of scope or --
Adam Felsenfeld: What do you have in mind for annotation?
Carol Bult: Well, you could do computation gene predictions
using all the available stuff you have, or you could create CDNA libraries to get better
gene models using --
Adam Felsenfeld: Yes.
Carol Bult: -- transcripts, or RNAC, or something.
There’s a lot of additional data that you could generate that would really improve the
quality annotations of these genomes and make them far more useful, but not for this amount
of money.
Adam Felsenfeld: Yeah.
So I think that goes beyond the way I was thinking about it.
But what you said made me think not just about the utility but also it’s possible that
you could do some quality checking that way, it’s possible.
And maybe insofar as it was quality assessment, yes, but not annotation.
This is really a pretty vanilla production effort.
Carlos?
Carlos Bustamante: So it’s being done as a contract, right?
Adam Felsenfeld: No.
Carlos Bustamante: No, it’s not being done -- it’s a cooperative
--
Adam Felsenfeld: Cooperative agreement --
Carlos Bustamante: Cooperative agreement.
Adam Felsenfeld: -- for a research resource.
Carlos Bustamante: I see.
So does that mean that, you know, for example, a company that’s got an innovative technology
solution to do the sequencing couldn’t bid, or they could?
Adam Felsenfeld: Yeah, they --
Carlos Bustamante: They could.
Okay.
So we’re basically sort of putting out this RFA at two million bucks a year to buy 50
high quality genomes.
Adam Felsenfeld: In -- but there is more to it than that.
Carlos Bustamante: [affirmative]
Adam Felsenfeld: Right?
If someone says I can do it now for whatever per, that might not be as interesting as an
application that said, you know, these are the critical factors in getting this feature
of high quality, and I’m going to -- it is -- in my hands, it’s more efficient because
I’m going to use this combination of techniques.
Carlos Bustamante: Yeah.
Adam Felsenfeld: I’m not wedded to any particular method,
for example, I’m going to try these -- there should be some leeway for that.
Carlos Bustamante: I see.
I see.
But at the end of the day, because it’s not as tightly integrated with the rest of
the program, right, if an applicant or a group were to come in and say, okay, we can deliver
100 high quality genomes at this price, and here’s what we’re going to do, and --
Adam Felsenfeld: [affirmative]
Carlos Bustamante: -- you know, and that’s what we’re sort
of looking for.
Adam Felsenfeld: That’s what we’re looking for, and of
course, they should have some well thought out plans for how they’re going to pick
the individuals, what populations they’re going to come from with reference to the existing
reference, and --
Carlos Bustamante: Yeah.
Adam Felsenfeld: -- lack of representation or lack of utility,
or --
Carlos Bustamante: Yeah.
Adam Felsenfeld: -- improving utility along a number of different
dimensions.
Carlos Bustamante: It goes without saying that the diversity
component is going to be really, really critical, right?
Particularly if you want to have a bunch of age alleles and those complex --
Adam Felsenfeld: Yes.
Carlos Bustamante: -- regions.
Adam Felsenfeld: Carol.
Carol Bult: So you mentioned the GRC.
So is it anticipated that they would take stewardship of these genome assemblies?
Are they going to be properly resourced to do that task, because what they’re doing
now is extraordinarily important to the existing reference sequences.
Adam Felsenfeld: Yes.
What they’re doing now is extraordinarily important, I agree.
There will have to be an interface, because if these are good quality, I can’t imagine
that the GRC will not want to use them.
So I can also imagine that there’s some boundaries that this may go across for the
way that the GRC operates right now.
So that will have to be dealt with.
Carol Bult: Yes.
So that would be a separate -- but again, that would be a separate resourced activity
if they don’t have the sufficient resources to take these on.
Adam Felsenfeld: There wouldn’t be additional resources.
We’d have to figure out a way within the amount of money we have to get this done if
it becomes very important.
Yes.
Jay Shendure: I was going to say, I think this is a terrific
initiative, and it’s right on target.
Small investment for a big payoff.
Rudy Pozzatti: Val or David, any comments?
David Page: No, it’s a good initiative.
Val Sheffield: Yeah, this is Val.
I think it’s a good initiative as well.
Just to clarify, all these genomes would be independently assembled, is that correct?
Adam Felsenfeld: I’m sorry, Val, I didn’t --
Eric Green: [unintelligible]
Val Sheffield: Yeah, I’m sorry.
Adam Felsenfeld: I don’t know.
I think this is up to the applicant to propose what the best way is.
Val Sheffield: Of what the assembly would be?
Adam Felsenfeld: Yes.
Carlos Bustamante: If joint assembly improves the quality, then
they should be joint assembly.
Right, you know, so, whatever the best possible reference --
Adam Felsenfeld: Yeah.
Carlos Bustamante: -- that can be produced.
Adam Felsenfeld: Exactly.
Eric Green: With evidence that you’ve produced an accurate
[unintelligible]
Carlos Bustamante: Yeah, yeah, yeah.
Rudy Pozzatti: It’s all part of their application.
Carlos Bustamante: Yeah.
I think this is really, really critically important, right?
Everybody bemoans the fact that we don’t have enough really good high quality genomes.
The other sort of group that would be good to bring in is the sort of genome in a bottle
consortium, who’s been thinking a lot about these issues.
And so I think there’s a lot of complementarity between with being funded here and what they
want to do.
Rudy Pozzatti: I think we’re ready to vote.
Can I have a motion to approve?
A second?
All in favor?
Any opposed?
Any abstentions?
Thank you.
All right, Adam.
Last one --
Adam Felsenfeld: Last one.
Rudy Pozzatti: -- and again, we will not be voting on this
one.
[end of transcript]