Friday, July 13, 2012

Whole-genome sequence from 10 to 20 human cells

See 2021 update:  Review article prepared for the book Genomic Prediction of Complex Traits, Springer Nature series Methods in Molecular Biology. Genotyping from few cell embryo biopsy is now routine.

This new Nature paper describes a genotyping technique that can be performed using only a small number of human cells. One implication is that we are close to non-destructive sequencing of human zygotes. For example, parents participating in IVF can potentially genotype fertilized eggs before deciding which to implant.
Accurate whole-genome sequencing and haplotyping from 10 to 20 human cells (Nature) 
... we describe a low-cost DNA sequencing and haplotyping process, long fragment read (LFR) technology, which is similar to sequencing long single DNA molecules without cloning or separation of metaphase chromosomes. In this study, ten LFR libraries were made using only ~100 picograms of human DNA per sample. Up to 97% of the heterozygous single nucleotide variants were assembled into long haplotype contigs. Removal of false positive single nucleotide variants not phased by multiple LFR haplotypes resulted in a final genome error rate of 1 in 10 megabases. Cost-effective and accurate genome sequencing and haplotyping from 10–20 human cells, as demonstrated here, will enable comprehensive genetic studies and diverse clinical applications.
See this earlier post Maxwell's Demon and genetic engineering:
... The amount of variation in intelligence within a particular family is almost as large as in the population as a whole, mainly due to the diploid nature of our genomes (half of the genes come randomly from each parent). Thus, as Fisher noted, superior characteristics do not "breed true" ... It is unlikely for a particular descendant to inherit most of the positive variants from both the mother and the father. If loci with positive effect on intelligence were identified, and selection performed on gametes (or zygotes), one could ensure offspring with many more advantageous alleles than normally obtained by chance. We would obtain the best from the set of possible offspring of a given mother and father. A process of this type can be thought of as a Maxwell's Demon of reproduction -- it suppresses fluctuations of the wrong sign.


JustinLoe said...

Why not use a computer with sufficient capacity to select the set of advantageous intelligence alleles such that all offspring, i.e. of all parents, possess the highest members of the intelligence allele set? Such as the posited computer in A.C. Clarke's City and the Stars. Of course, in some sense, these offspring would not be true children of their parents as they would possess genes that there parents would not have.

stat squatch said...

Unfortunately human women are not salmon so it will take a
while to get your super geniuses. With IVF
you are lucky to get 10 viable embryos.
Using the model from your slide deck, what is the chance that one of
them had 39 (68) fewer deleterious genes, which corresponds to a 1 (2) SD
improvement in intelligence, than their parents average of a 1000? Using binomial variation I get 34%
(0.2%). If you use a different distribution, say a normal
with mean 1000 and SD 39, it gets better at 82% (21%). Either way, it will take decades. This will give the angry peasants plenty of
time to light their torches.

steve hsu said...

You can't make the leap all at one for obvious reasons (e.g., a +6 SD genotype is still +6 SD improbable until direct genetic manipulation becomes possible), although keep in mind that more than 10 eggs can be extracted over multiple cycles, frozen, and then fertilized at a later date.

Imagine what a couple might pay to ensure that they get the best out of 10 or 50 possible offspring, optimizing over their choice of heritable attributes. You might compare this with the cost of a Harvard education or K-12 private school tuition. The cost of an IVF cycle is down to a few thousand dollars and could go even lower.
Genetic prediction at high accuracy will probably be possible once of order millions of genotype-phenotype data pairs are available for analysis. I predict about 5-10 years. The advance in the Nature article makes me confident that the necessary reproductive technologies will also be available.
I imagine progressive governments will make this procedure free for everyone. The benefits from increasing economic output, decreasing welfare and criminality rates, etc. far outweigh the cost of what I have described above ( = few cycles of IVF + running my algorithms dirt cheap licensing rates ;-)

Robert Sykes said...

Once you get down to one cell, the problem of chimeras arises. How do you know the actual source of the cells sampled?

LondonYoung said...

I hope that progressive governments will make this procedure free for everyone." Hmmmm, this option is so "in the money" that it is almost impossible to imagine that a govt willing to institute a one-child policy would not also make such selection mandatory - "increased economic output, decreased welfare and criminality rates" being goals primarily of the state rather than the individual. Blair Underwood's job in Gattaca will be a government position.

steve hsu said...

They'll have the genotype of both parents in all likelihood, so trivial to check that the cell comes from their zygote.

steve hsu said...

On the other hand some governments will be slow to adopt (even legalize) this technology, so in those countries only the rich will have access.

There's a part of the Blair Underwood (genetic counselor) scene in Gattaca that was cut in which he asked Ethan Hawke's parents whether they want genetic enhancement for Hawke's little brother -- e.g., alleles for music or math ability that aren't present in the parental DNA. But the director left this out -- possibly because it changes the nature of the future world the movie is set in. If that kind of enhancement were possible the engineered people (with whom Hawke competes for the space navigator job) would be inconceivably superior. There would be essentially no overlap between the distributions for engineered and non-engineered people, whereas in the film it is clear there is still substantial overlap. I think you can find this clip on YouTube.

gwern0 said...

Well, of course you could do that - but it would be a *lot* more difficult to take a random embryo and rewrite all couple thousand alleles or whatever, and do so for every embryo. In contrast, this procedure is just 'generate a bunch of embryos, sequence each, and implant the one that scores highest', and you don't have parents wigging out about their kids not being theirs and mutants.

Richard Seiter said...

That scene appears on the DVD as "Eighth Day Center (Original Version)". The parents declining the enhancements because they cost an additional $5K made a very definite point. The scene ended by discussing the disposal of the unused embryos (not at all surprised that part was cut). I was unable to find the video on YouTube (had to pull out my DVD ;-). If someone has a link please post.

Here is the theatrical version:

A brief description of the deleted scenes appears at
For anyone who hasn't seen it, I like the deleted "Coda" scene:

LondonYoung said...

some governments will be slow to adopt (even legalize) this technology" - well, then, so the future is "Space Seed" rather than Gattaca. Only, as we know, Khan is gonna win the first time out ...

LondonYoung said...

Richard - never seen the Coda - and I know this movie so well - much tks

JustinLoe said...

Yes, but the long term future will be true genetic engineering, to the extent that it is possible, in which children maximize sought after traits that may not be in their parents.

stat squatch said...

A couple of thousand for IVF? Maybe that is the cost in
Mumbai. In the USA it will set you back $15K. So that close to $60K
to get 50 embryos and you still may still only have a 2% chance of getting +2
SD on your offspring. On the other hand you can greatly lower the odds
that your kid has ride the short buss.

Let me give you some advice before you file your med.
device 501K in the US: focus your development and marketing on the far left
hand side of
the bell curve. It is controversial to say genius is genetic but for some
reason it is OK to say retardation is. The FDA has a lot of discretion
and it will be easier for them to license a device (or ignore an unapproved
use) if you say you are selecting against “autism” than for genius. Good

steve hsu said...

You can't use US numbers for real medical costs -- our system has huge distortions. Few $K is the cost in Taiwan or Korea and success rates are if anything higher there. That's not even factoring the economies of scale that would arise if a large fraction of couples wanted it.

Who says the US is the first market for this?

David Coughlin said...

I am with gwern0, the natural outcome is that there is a specification of 'best' and all the kids will get it. Really, people aren't going to stop with IQ, they are going to order the top of the line model, and there will be a generation of kids floating around that are genetically identical. Who is going to roll the dice that they might end up with a redheaded kid. It won't be viewed any differently [by some|most] than plastic surgery.

JustinLoe said...

What's more interesting to me, though, is that if we assume that all of this is feasible, and given the size of the known universe, there are probably many, many species who all have greater than 6 s.d. IQs (equivalents in their alien minds). Interesting.

Richard Seiter said...

One question I have with respect to both embryo selection and genetic engineering is will the traits selected for "breed true"? How many of the desirable genotypes will turn out to be heterozygous? (Tay-Sachs comes to mind in the intelligence context, Sickle cell anemia is another possible example, how many more are there?) Another question is how often will genotypes turn out to be tradeoffs (e.g. I have a strong immune system but am somewhat more prone to autoimmune diseases)?

Once we go down the path towards human genetic engineering will it become undesirable (in the sense of outcomes worse than pre-genetic engineering) to have babies the "old fashioned way"? It seems like we could end up in a situation similar to F1 hybrids where their offspring are on average much worse than the parents (of course, a cynical person might say that is exactly what a genetic engineering industry would want since it would guarantee customers).

I think the idea of a "best" genetic profile is hard to justify. "Best for a given goal and environment" is somewhat more reasonable (if I live in a malaria-prone area I want that single Sickle cell allele), but trying to reduce human genetic complexity to a single dimensional number is IMHO dangerous.

To be clear, I do agree with your analysis and with "there will be a generation of kids floating around that are genetically identical" given the caveat "in many ways".

JustinLoe said...

Ultimately, there's a real philosophical question (at least for me), which is that to the extent that the potential of children are engineered in accordance with their parents' preferences, are those children pre-programmed to fulfill the wishes of the parents'? Should children be engineered to fulfill the ambitions of their parents?

I tend to favor genetic engineering to fix disease and improve intelligence, but I wonder about engineering traits such as ambition in combination with intelligence and other characteristics such that the wishes of the parents' may be fulfilled.

Perhaps a life and a world that has less freedom and variety, and a world in which everyone is a genius is less interesting. I won't be here to see it, so it's idle speculation.

David Coughlin said...

Those questions are the essence of the science still out there, I think. If I had to pick some likely tracks, though, someone is going to speculate [either the wealthy with their money, or the government with there regulatory power] about what constitutes 'best' and slap a label [a brand?] on it. Then it will become the standard until there is reason to believe otherwise. Steps forwards and backwards, not one step at a time.

LaurentMelchiorTellier said...

It appears that the clip indeed had not been uploaded yet. So I uploaded it.

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