Scientists say they can read nearly the whole genome of an IVF-created embryo

https://www.science.org/content/article/scientists-say-they-can-read-nearly-whole-genome-ivf-created-embryo

by Metacelsus • 4 years ago

81 97 4 years ago

exdsq3• 4 years ago

What’s the choke point of scanning an entire genome? Is it purely computational? Imaging? Biological unknowns?

jkingsman• 4 years ago

For IVF embryos, it's the small amount of genetic material which makes accurate sequencing difficult. For standard human whole genome sequencing (WGS), the fastest times are down to five hours[1] (although that is exceptional), for which the imaging was massively parallelized and it seems that the choke point was computational for that particular case (sequencing like this basically multiples the DNA, shreds all the copies, images each shred in a reasonably-parallel manner, and then uses longest-common-subsequence to put all the shreds back together digitally).

Average WGS times for something a person can buy for a couple hundred dollars take a few weeks, and will usually be bottlenecked by logistics (mailing things, getting it to the lab, etc.) and then the imaging (a flow cell runs the fragments over an imaging device; parallelization is accomplished by running multiple flow cells at once).

I might be slightly off on my terminology here but the idea is broadly correct, I think: Differing grades of sequencing are determined by the average depth of fragments for each base-pair -- e.g. 1x sequencing implies an average coverage of one fragment per base-pair, which could lead to mis-aligned or improperly joined samples. 30x-50x sequencing is pretty common for consumer grade WGS these days, which gives a higher number of fragments that allows you to weed out bad reads or incorrect joins of the sequence, though errors can still occur. This is usually sufficient for diploid (having two values for each base pair, one maternal and one paternal) humans, since it's important to determine if the basepair is heterozygous (different bases from each parent) or homozygous (same base from each parent). However, if you're doing cancer sequencing, a tumor may contain many many more different genes, so a massively deeper sequencing depth is required to ensure you have reasonable statistical certainty on what variations occur within the different genomes. Higher depth == more material == longer time to sequence since you have more material to image.

Note that services like 23andMe are NOT doing whole genome sequencing; they are using specialized flow cells that only examine certain specific sites on the genome called single nucleotide polymorphisms[2], which are traits or indicators that are turned on or off by a single nucleotide, hence it being much cheaper and faster to run.

[1] https://med.stanford.edu/news/all-news/2022/01/dna-sequencin.... [2]: https://en.wikipedia.org/wiki/Single-nucleotide_polymorphism

exdsq3• 4 years ago

Thanks for your response! So is it true to say every genome could be sequenced, assuming time and money isn’t an issue?

jfengel• 4 years ago

Average WGS times for something a person can buy for a couple hundred dollars take a few weeks,

I hadn't realize that we'd actually gotten the $1,000 genome. It was a big point of discussion 20 years ago, but seems to have arrived without the fanfare I would have expected. According to Wikipedia, it's been around for a few years, and claims the X-prize for it was canceled before that since it no longer looked like much of a challenge.

So we sailed right through it and are now pushing an order of magnitude below that. Thanks; I had missed it.

inciampati• 4 years ago

Different grades of sequencing are basically down to the technology and depth.

The short read sequencing you're describing makes reads that are like motes of dust in comparison to the genome.

More modern long read methods can read off sequences with high accuracy and/or length. These tend to be much higher in cost and substantially higher in the completeness and quality of the resulting bioinformatically inferred genome.

arrosenberg• 4 years ago

It's very doable, but we only know what a small amount of the genome is actually doing. Whole Exome testing hits the majority of the points people are interested in and is way less computationally expensive, since it's a fraction of the genome.

exdsq3• 4 years ago

Okay interesting - so reading the genome is basically solved nowadays and it's understanding what it's actually doing where we're working atm?

throw0101a• 4 years ago

Gattaca here we come! \o/

* https://en.wikipedia.org/wiki/Gattaca

monkeybutton• 4 years ago

Onwards to the Eugenics Wars and then the post scarcity Startrek future!

whatshisface11• 4 years ago

Directly testing people's IQ through say contrived interview questions (ever wondered why people care about leetcode[0]?) will always be more accurate than predicting it from their DNA. It is difficult to say how much of IQ is genetic, but estimates range from 50% to 80%, placing an upper bound on the effectiveness of the exact technique they used in GATTACA. (But, I want to emphasize, the more accurate way of doing it is already being done.)

[0] One objection to calling leetcode an IQ test would be that some people "grind leetcode," as in, practice at it to get better, but did you know that Raven's progressive matrices has a large practice effect? In fact, I might raise your score just by telling you that a lot of the questions are based around XORing the presence of symbols in the pictures. If companies were giving culture-free IQ tests rather than leetcode ones we'd see the exact same pre-interview behaviors, including practicing tasks that don't resemble the job being interviewed for.

[1] https://en.wikipedia.org/wiki/Heritability_of_IQ#Estimates

Flatcircle2• 4 years ago

Expecting a contrarian article in 10 to 15 years that says the IVF genome analysis is imperfect and parents have been making incorrect decisions on flawed data.

whatshisface11• 4 years ago

It only has to be better than random, right?

jacquesm3• 4 years ago

Indeed. And it could be worse.

TOMDM3• 4 years ago

Not necessarily, if the confidence of the prediction doesn't match the real odds of outcome.

Parents may make special accommodations for the needs of children with genetic difficulties that they otherwise wouldn't based on their confidence in genetic screening.

areoform• 4 years ago

The error rate for sequencing is significant and can easily lead to incorrect assumptions + decisions,

The average error rate determined was 0.24 ± 0.06% per base and the percentage of mutated sequences was found to be 6.4 ± 1.24%.

https://www.nature.com/articles/s41598-018-29325-6

topynate• 4 years ago

Won't matter for highly polygenic traits. For monogenetic disorders like Tay-Sachs, it will provide another line of defence along with conventional pre-implantation screening and pre-natal screening.

legalcorrection4• 4 years ago

Thinking about the social and political implications of this in the long run. Any society or segment of any society that isn't producing average 120 IQ babies with superior sensory perception, physical strength, dexterity, and so forth, is going to turn itself into a permanent human underclass. Eugenics is here to stay this time.

evan_• 4 years ago

Any society or segment of any society that isn't producing average 120 IQ babies with superior sensory perception, physical strength, dexterity, and so forth

Where all the women are strong, all the men are good-looking, and all the children are above average.

sweetbitter• 4 years ago

Haha, Lake Wobegon?

unsupp0rted2• 4 years ago

That particular underclass problem seems unlikely, relative to how much any 120 IQ human pales in comparison to any synthetic AGI or even domain-expert AI.

The real underclass would be humans vs. machines, which would 10x, 100x or 1000x IQ, perception, strength, dexterity... pretty much any measure.

By the time we can make 120 IQ humans consistently, we'll be able to make 120 IQ machines consistently. And a couple years or perhaps hours after that the 120 IQ machines will be able to make 240 IQ machines and so on.

ajconway• 4 years ago

The world is massively unfair as it is. Would anyone even notice already "privileged" societies becoming a little bit more privileged?

Who knows, maybe our IQ 120 overlords will be kind to make the tech available for everyone else.

legalcorrection4• 4 years ago

A 120 average IQ population would run circles around a 100 average IQ population, even starting from a much lower position. Of course, there's still the question of whether society is organized such that people of exceptional talent rise to power, and whether they have the incentive to do great things.

My main concern isn't the tech being inaccessible to poorer people or countries. International intellectual property protection has always been precarious, and I guarantee that e.g. India won't just accept having a dumber population because "oh well, an American company owns the patents and we can't afford mass licensing."

Rather, Western societies have strong anti-eugenic impulses because of 1) the Christian legacy, 2) the popular fixation on WW2 atrocities, and 3) a political taboo against acknowledging population-level differences in mental (and to a lesser extent, even physical) attributes. I could see China being much more willing to embrace eugenic technology on a shorter timescale than the United States. And that could be the death blow to the US.

ch4s3• 4 years ago

We don't have a very good understanding of the genetics of many of these traits. Intelligence is especially thorny, involves numerous genes, and is probably only about half hereditable which is actually reasonably high.

We're likely to get a bunch of tall people, until everyone remembers they die younger due to cardiovascular strain. We'll probably wipe out most single gene hereditable diseases, which will be great. We're also somewhat likely to see fads around eye color in "designer" babies. We may also get people selecting for a single gene that make for great endurance athletes.

Anything much beyond that is science fiction in the near future. The knock on effects of tinkering with more than a handful of well understood genes is going to be really dangerous.

Quick Edit* There are around 1000 genes that have some bearing on intelligence. The 22 most impactful together account for 5% of variation.

dekhn4• 4 years ago

This is sort of naive. Even the chinese have backed off from their plans on doing this, both before and after the Jiankyu debacle. https://singularityhub.com/2013/03/19/chinas-bgi-to-sequence... https://www.technologyreview.com/2015/08/20/166465/is-it-pos...

By the way, I spent about 20 years of my life pursuing this goal, and I've concluded that most cultures aren't that keen on superintelligent babies right now.

Flatcircle2• 4 years ago

IQ is overrated. If IQ mattered as much as people think, then all the jeopardy champions would be millionaires. Some of the dumbest people are willing to go up to strangers and ask them to buy something they don't need. Intelligence can get in the way more than people think. Just gotta be above the disability level. Your emotional, energetic, environmental, and cultural traits will do the rest.

legalcorrection4• 4 years ago

Yes, I agree. You should substitute a mix of cognitive attributes for my original post's simplistic focus on IQ.

postalrat• 4 years ago

Seems more efficient to clone 200 or so super geniuses and stick them in a lab.

krageon5• 4 years ago

If anything, it is liberating that this can (potentially) be achieved using editing instead of partner selection and stimulating child birth among "desirable" couples. Using editing, such things should be within reach for everyone. What's not to love?

015UUZn8aEvW• 4 years ago

Embryo selection based on genome sequencing is already being done:

https://astralcodexten.substack.com/p/welcome-polygenically-...

dekhn4• 4 years ago

Your example is "genetic" testing- it only samples a limited number of locations in the genome. This method is more like whole genome sequencing.

abcc8• 4 years ago

There really aren't that many reasons to sequence the entire genome in this context. Specific disease causing mutations in the parents can be specifically targeted in the embryo/fetus. Similarly, PRS scores don't require full genome sequencing to generate (but also aren't ready for prime time routine usage). Also, aneuploidy detection doesn't require genome sequencing. This is just a few examples.

Metacelsus• 4 years ago

This method is similar, but uses the parents' genomic data to improve predictions of the embryo's genome (since sequencing only a few cells gives low-quality data).

belval5• 4 years ago

I see a lot of comments underscoring the possible eugenics implication of this, but I am curious as to why everyone always paints it as a negative? Even in our very diversity-conscious institutions we can generally agree that some things are plain bad. You don't want a blind or deaf child. You don't want one with down syndrome or deformities that would just make their life difficult.

I wonder if the high level of opposition to this does not come from us being naturally scared of becoming irrelevant. A society capable of producing disease-less 120 IQ adults would progress faster.

Yes there are a ton of ethical concerns about building a society where hierarchical boundaries find their justification in science, but I see these arguments as myopic. Inequalities have always existed, the only difference is that now nobody would have genetic diseases.

whatshisface11• 4 years ago

now nobody would have genetic diseases.

Nobody with parents who can afford IVF would have genetic diseases. Nobody would rise from an ignoble birth to greatness ever again... or at least not in countries without universal healthcare.

thegrimmest• 4 years ago

Doesn't that just mean that the bar for "greatness" will have risen? Isn't that a net gain?

belval5• 4 years ago

Equality is great, but the situation would be no different than someone having access to healthcare/higher education/equal opportunities. After a few decades that technology would become commoditized just like everything else. It's not as if it was impossible to enforce regulations around that sort of thing.

mywittyname2• 4 years ago

Those kids would still potentially breed the normal way. If a rich kid knocks up a bunch of poor ones, those children will have similar genetic advantages.

And rich people fall from grace all the time. It's difficult for families to hold onto their wealth over successive generations. One of the keys to maintaining wealth is to keep it from being diluted, which means that some kids are going to get cut off.

workaccount21• 4 years ago

Because we have no idea how any of this works, selecting against one gene may have negative externalities that we don't even know how to measure. For example: a genetic cure for schizophrenia also dulling the creative traits it's correlated with. We cant even really understand how an emergent property like language works (see: every conlang), and you think we can engineer a civilization to be better by radically altering the balance of potential equality that we have been genetically optimized for?

A society of 120 IQ adults would probably be an insufferable hell beyond comprehension, considering the track record of intellectual movements and the proclivity of smart individuals, probably like yourself, to vastly overestimate the merits of rationality and concepts that can be limited to the mind of one human.

ALittleLight2• 4 years ago

That's a good argument for not engineering all children all at once - we don't understand the consequences. It seems like a good argument for starting to engineer a few children so we can start to learn what the consequences are. As engineering becomes more palatable to the general population we will better able to deliver good results.

belval5• 4 years ago

A society of 120 IQ adults would probably be an insufferable hell beyond comprehension, considering the track record of intellectual movements and the proclivity of smart individuals, probably like yourself, to vastly overestimate the merits of rationality and concepts that can be limited to the mind of one human.

Disregarding the personal attack (I am well aware of downsides, but it's called having a discussion), higher median IQ is not really the point, it's about giving the same chances to everyone.

We could use this to eradicate a wealth of issues that we do understand, there's no good reason to have babies born with Cystic Fibrosis, we know what genes are causing it.

whatshisface11• 4 years ago

A society of 120 IQ adults would probably be an insufferable hell beyond comprehension, considering the track record of intellectual movements and the proclivity of smart individuals, probably like yourself, to vastly overestimate the merits of rationality and concepts that can be limited to the mind of one human.

The world is full of societies of 120 IQ individuals. That would be, like... a typical office full of programmers. That's 1 in 10 people. Even 145 is 1 in 1,000. This gene stuff could only begin to surpass what you'd be able to do by holding a conference in an academic field at... 170? 180? For the foreseeable future the kinds of selection that operate on full-grown adults will greatly surpass this other kind which is limited to four or five embryos.

In so many words, more than four or five former embryos are selected between in a typical round of SWE interviews.

Scarblac• 4 years ago

Blind or deaf people would probably feel pretty bad hearing "you don't want a blind or deaf kid".

whatshisface11• 4 years ago

That's a phrasing-based argument, it disappears if you replace it with "you don't want your kid to be deaf or blind."

belval5• 4 years ago

I don't think there's anything wrong with having a blind or deaf kid. I take issue with the idea that given the technology we would refuse to fix their disability before they are born.

Try explaining to your son or daughter that they could've been able to see and hear, but you refused to avoid hurting the feelings of existing blind and deaf people...

ThrowawayP2• 4 years ago

"Blind or deaf people would probably feel pretty bad hearing 'you don't want a blind or deaf kid'"

I am legally blind. I would not want my children to have any disability whatsoever because it's difficult and miserable.

vsef• 4 years ago

Some people do choose to have deaf children: https://jme.bmj.com/content/28/5/283

There was quite a bit of outrage around that case from hearing people, but it seems no different than two parents with genetic deafness choosing each other and then not trying to use genetic testing/embryo selection to have a hearing baby.

I do think when this type of genetic manipulation becomes possible/mainstream there will be many traits chosen by parents that aren't considered universally desirable.

krageon5• 4 years ago

I am curious as to why everyone always paints it as a negative

Fear of the unknown and distrust of everyone else. This might give someone an advantage, so it must be bad for me. I view it kind of like metaphorical crabs trying to climb out of a bucket.

Gatsky2• 4 years ago

Impressive study, kudos to the bioinformaticians who did this!

This could be an option for parents with a genetic condition who don’t want to pass it on. In terms of gattaca style super people (which I find quite repugnant) the recombination events are still random at the end of the day, so you’d have to screen quite a few embryos and there would be trade-offs. If you were really serious about it, the process would start with selecting partners based on their genetic fitness, and also using young fathers.

bradleyjg3• 4 years ago

This could be an option for parents with a genetic condition who don’t want to pass it on.

Most of the genetic disorders we know about can already be screened for (those that involve a single gene).

This opens the door for polygenic screening but the underlying patterns to screen for are, in most cases, only weakly understood. We’d need to do a lot more research on adults with these diseases to get to the point where we can select against them in embryos.

On top of that the amount of selection we can do is limited by the number of embryos to choose between. In many cases that’s a very small number.

Gatsky2• 4 years ago

There are quite a lot of less severe conditions which aren’t easily testable on an embryo. That was the motivation for the research as I understand it.

The whole polygenic thing isn’t very compelling, I agree.

oneoff786• 4 years ago

I’m starting to look into this. We have a single uncommon mutation to deal with, that’s just a fairly large cancer risk. Early advice has been that it’s still pretty hard to do single gene mutation screens. Needing samples from multiple relatives with the mutation to build a reliable screen.

programmertote• 4 years ago

Coincidentally, I have a friend who is in the second cycle of this IVF procedure to select an embryo that does not carry the genes associated with polycystic kidney disease (PKD). When I heard it last week for the first time, I thought it is already an established procedure. Here, I'm learning that it is a relatively cutting-edge approach and I am now looking forward to asking my friend more about this next time we meet.

llebttam• 4 years ago

Commercial products in the space have been around for several years but can only screen for a small number of genetic diseases at a time. For example, Natera's Spectrum screens for chromosomal abnormalities (eg Down Syndrome) plus one custom genetic problem for a single condition of greatest concern. https://www.natera.com/womens-health/spectrum-preimplantatio...

Some polygenic screening services that look at a much larger number of conditions are just reaching market now (eg Orchid Health), though our ability to map genes correlated with polygenic traits to phenotype results is still in its early stages. https://www.orchidhealth.com/

WheelsAtLarge2• 4 years ago

Anyone know of any unexpected consequences of using this for IVF? It seems to me that we are falling into brave-new-world territory without really trying. I'm sure parents will do this to help their kids but I wonder what the negative issues will be? Gender selection is one but that's already being done by other means. What will this particular technology bring?

musicale• 4 years ago

The Gattaca premise sounds pretty logical but not unexpected. Presumably they will optimize for what they might view to be "favorable" genes associated with preferred traits (skin/hair/eye color, beauty/symmetry, strength, height, intelligence, disease resistance, aggression, etc.) while attempting to eliminate the others.

This will (possibly) convey an increased "genetic" advantage upon the wealthy and privileged, while reinforcing societal structures that punish and exploit those who haven't been engineered the same way.

WheelsAtLarge2• 4 years ago

Good point, people don't realize it or admit it but being born with what society defines as beautiful features gives a person big advantages in life. It's like hitting the lottery as far as advantages vs someone that's not. If you're already wealthy you'll be able to buy those advantages for your kids. It will be one of the greatest inheritance parents can give them.

0ldskool• 4 years ago

Well the governments job is to create laws to make it easier for humans to live together. Even if Gattaca style gene selection is available, laws can be put into place to prevent discrimination.

I.e. it is 100% illegal to do genetic testing for anyone other then yourself or your under-aged children. Those tests can only be done by a doctor and cannot be transferred or shared with anyone other than another doctor. Any employer or person that attempts to do a genetic test on someone can face jail-time.

ravi-delia2• 4 years ago

Check out Gwern's analysis(https://www.gwern.net/Embryo-selection) of this kind of technology. It suggests a somewhat noticeable effect, but not a particularly large or worthwhile one. That doesn't factor in new technology, but the methodology is all there so it shouldn't be too hard to plug in the new values. I haven't done that yet, but I'd be surprised if there was a big shift.

flobosg• 4 years ago

The actual paper: https://www.nature.com/articles/s41591-022-01735-0

Scientists say they can read nearly the whole genome of an IVF-created embryo

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