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Personal Genomics

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ancestry Just got my results back from AncestryDNA. I’ve done autosomal ancestry tests with 23andMe and Family Tree DNA, in addition to analyzing the raw data myself. When I first got the results the Y and mtDNA results were totally expected; R1a1a and U2b respectively. Those are typical South Asian lineages. But what surprised me was how East Asian I turned out to be. This is really obviously in ADMIXTURE and PCA, but curiously 23andMe, even in speculative mode above, gives a relatively low fraction. Below 10%. You can see in the AncestryDNA results that in fact I’m a lot more East Asian than that, as well as a Melanesian-like element. I suspect that the latter is due to Austro-Asiatic admixture, in particular from my mother. ftdna Family Tree DNA gives similar proportions.

The differences don’t invalidate the robustness of admixture analyses. It’s just that these results are always carved around the joints and reifications which are human-digestible, and humans are the ones who pick the specific parameter values and data inputs around which the models are constructed. The companies have different reference populations, and these reference populations are the data inputs around which individuals are constructed as linear combinations. 23andMe uses a sophisticated system that looks at haplotype blocks, but it seems quite clear that finely admixed people are sometimes difficult for them to resolve (because of the uniqueness of their blocks in comparison to their reference populations).

• Category: Science • Tags: Personal Genomics 
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23andme_logo If you’re not sleeping under a rock, you know that today 23andMe has rolled out its plan to provide government (FDA) approved medical results. In the generality I knew this was in the offing. I asked contacts within the company, and they pretty much signaled this was imminent, though they didn’t detail the specifics. This is a big deal because for a lot of people the medical results are big reason you’d get the service. Certainly I have friends who have been waiting for years, who kept asking when this would happen, as then they could the pitch to family to get typed.

But there’s a minor hitch: you’ll be charged more for fewer results. They’re going to be jacking up the price to $199 from $99. Arguably the results they’ll be giving you are more robust than the older full suite, but basically 23andMe is increasing prices, while giving customers a leaner deal than many of us were used to before the FDA clampdown (also, carrier testing is provided pretty much free for many people with insurance if you are going to have a child).

The question then emerges for the rationale behind this price increase. After all, in the tech sector it’s not the norm to charge more for less after users have become used to a particular price point. My own hunch is this: with well over 1 million customers they’re going to aim to squeeze more information out of their current user base than gain more customers. From what I had heard, 23andMe was basically losing on customers in the initial years to grow their data set. But recently SNP array have become cheap enough that on paper they’d actually be making a profit by pushing their product for $199 if you just took the array price into account.

I’m a little disappointed in the particular turn of events, though overall I stand by my assertion from two years back that these bumps in the road will be little in the long run. The future is coming at us, at varying rates of increase or decrease, but always with a positive velocity.

• Category: Science • Tags: Genomics, Personal Genomics 
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Giant study poses DNA data-sharing dilemma:

Next month, the group is expected to release a project plan. Observers are eager to learn its answer to a key question: how much information about disease risk, especially genetic data, will the project share with participants?

That issue is the subject of much debate. Dishman and others say that participants should at least have the option to see all their personal data so that they can investigate their own health, just as he did. But some specialists in the field say that showing participants their data is irresponsible, because the information is challenging for people to interpret and its significance is often uncertain.

Most genetic variants linked to disease increase risk only slightly, yet people who discover that their genome holds such a variant might worry excessively or seek unnecessary medical tests. Or they might do nothing: the limited research on how people react suggests that, far from causing panic, information about common variants of small-to-moderate effect does not seem to motivate people to make recommended long-term behavioural changes to lessen risk. “Unless you give people the tools and the skills to deal with the raw data, I don’t see how you could give them the raw data,” says Brian Van Ness, a geneticist at the University of Minnesota in Minneapolis.

Years ago I had a short conversation with Mike Snyder where we discussed the fact that for human genomics to become useful there had to develop a culture of openness and ubiquity of data. That is, you need huge sample sizes and lots of information on those samples. Several years ago I elaborated some of my views with an essay in Genome Biology, co-written with my friend David Mittleman, Rumors of the death of consumer genomics are greatly exaggerated. The point is that the gains to genomics, and what is now being called “precision medicine”, is really going to occur when there is widespread adoption of sequencing and comfort among the populace with analyzing the intersection of the sequence data with phenotype data. That is, there are returns to scale. But all this sounds very “Brave New World” to people, and they are not comfortable with it. Yet. One way to make people more at ease is to give them some “ownership” of the process. They may never analyze their raw data, but they’ll have it, forever. Or, they may analyze it with third-party tools such as Promethease. Ultimately personal genomics needs to be personalized, and if you lock the data behind gates, that totally undermines the message.

Second, I think on normative grounds one can say that it is not ethical and right for researchers to withhold your own sequence when they are attempting to do research with your data. After all, they are making gains career wise with your own information, your raw data. It strikes me as unjust that they’d withhold that data because you might not do the right thing with it. That it’s up to them to decide when you can see information on your own body. There is perhaps a place for paternalism on some issues, but in the generality this is not one hill that I think many geneticists will die on. Those who stand athwart history are going to look foolish in hindsight.

• Category: Science • Tags: Personal Genomics 
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Citation: Estimates of Continental Ancestry Vary Widely among Individuals with the Same mtDNA Haplogroup

Citation: Estimates of Continental Ancestry Vary Widely among Individuals with the Same mtDNA Haplogroup

A new paper in The American Journal of Human Genetics, Estimates of Continental Ancestry Vary Widely among Individuals with the Same mtDNA Haplogroup, tells you something which should be obvious:one marker tells you only so much about individual ancestry. In other words, the history of one gene can only tell you so much about the whole genome. Because mtDNA and Y chromosome* does not recombine you can treat it as one long genetic marker. On the coarse grain they can tell us a great deal. Both mtDNA and Y confirmed that it seems the modern human populations seem to be diverged from a group with an African origin. Genomics, even using the whole genome, has confirmed this. Additionally, non-recombining regions of the genome are more tractable for a coalescent framework. They are actually trees.

But Richard Lewontin’s insight that a great deal of human genetic variation is not partitioned across populations, but within them, applies to mtDNA and the Y chromosomes as well. Where Lewontin’s insight misleads is that using just a few more markers one can obtain relatively robust phylogenetic trees which reflect well the population structure and history of a given species. One can see this when one considers mtDNA and Y chromosomal lineages jointly. If someone tells you that their Y chromosomal lineage is R1a1a you can infer that their ancestry is anywhere from Central Europe all the way to South Asia. But if they add that their mtDNA is U2b you can be confident that they are South Asian. U2b spans South Asia, as well as parts of the Middle East. But in the latter zones R1a1a is very rare.

Though the phylogeographic import of mtDNA for a given individual is often questionable, that’s true of any marker. Because mtDNA is amenable to phylogenetic modelling it is still quite useful, especially when making very geographically coarse inferences. But the paper’s argument that the geographic inferences of DTC tests is questionable based on the fact autosomal SNP-chips are the same framework used within the paper to test the informativeness of mtDNA.**

* The NRY

** Disclosure, I have done consulting for Family Tree DNA on their autosomal tests.

• Category: Science • Tags: Personal Genomics 
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23andMe_Logo_blog23andMe just made a huge deal with the biotech firm Genetech. You’ve probably heard about the details elsewhere, but if not, Matt Herper has an excellent lowdown:

A deal being announced today with Genentech points the way for 23andMe, the personal genetics company backed by Facebook billionaire Yuri Milner and Google Ventures to become a sustainable business – even if the company’s discussions with the U.S. Food and Drug Administration stretch on for years.

According to sources close to the deal, 23andMe is receiving an upfront payment from Genentech of $10 million, with further milestones of as much as $50 million. The deal is the first of ten 23andMe says it has signed with large pharmaceutical and biotech companies.

Such deals, which make use of the database created by customers who have bought 23andMe’s DNA test kits and donated their genetic and health data for research, could be a far more significant opportunity than 23andMe’s primary business of selling the DNA kits to consumers. Since it was founded in 2006, 23andMe has collected data from 800,000 customers and it sells its tests for $99 each. That means this single deal with one large drug company could generate almost as much revenue as doubling 23andMe’s customer base.

From what I know 23andMe has been losing money for on the sales of kits. They were loss leaders. And 23andMe isn’t a non-profit. Though “insiders” have been talking for years how 23andMe has wanted to start selling its huge database to pharma/biotech, even if you were a casual consumer you could connect the dots and assume that there’s a reason they were collecting data on your traits and pestering you to fill in all sorts of personal details on your profile. It’s a business. And businesses try to work the angles to make a profit.

Nevertheless, some people are outraged. My question is simple: is there something about genetic and medical information that privileges it and makes it more precious than the enormous cloud of data private firms already have on you? I don’t think genes are magic, so I’m not convinced, though there are some real issues like life insurance risk for those with highly penetrant disease variants.

Years ago I had a discussion with Mike Snyder about the utility of genomic information for practical ends such as in personalized medicine. The problem to me seemed to be that sample sizes for most academic and even industry studies were just too small. Everything was too under-powered to really find much new and interesting. The real juice would be squeezed by enormous sample sizes on the order of hundreds of thousands, as well as whole genomes at reasonable coverage, intersected with non-genetic data. Yes, health history, but also various lifestyle factors. All of this requires a level of permeability across what are today information silos, and also a comfort of individuals with their information swelling the massive data cloud. The upside on the individual scale is a yield of new results. Of course the problem is that this system encourages “free riding” from those who wish to receive the benefits of the research, but do not want to “opt-in.” They get the benefits of science without sacrificing their privacy. 23andMe has at least shown that this isn’t an insurmountable problem, as it has convinced hundreds of thousands to opt-in to its research. The question is whether this was done transparently.

• Category: Science • Tags: 23andMe, Personal Genomics 
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Razib's daughter's 23andme Chromosome Painting

Razib’s daughter’s 23andme Ancestry Composition

Everyone knows that I think 23andme provides a great service. But I’ve had some criticisms in the past. Several years ago I thought it was rather strange of them to limit their chromosome painting feature to only a few ancestral components when it produced strange confusing results (e.g., many East Africans being mostly European in ancestry). Over the past few years they’ve nicely expanded their ancestry components, addressing this concern. But at this point my own inclination is to say that they’ve gone too far. For example a friend who is ethnically Japanese from Honshu gets these results: 76.1% – Japanese, 3.5% – Korean, 19.7% – Nonspecific East Asian, 0.4% – Nonspecific East Asian & Native American and 0.3% – European. I can give you reasonable explanations for these proportions, but it’s going to be confusing for many Japanese to be told they’re only 3/4 Japanese genetically. The issue is the scope of their reference population. It’s not capturing the diversity of the whole population of Japan.

But this is a minor concern in comparison to something else I’ve noticed. Here are some ancestral proportions from my family:

French & German British & Irish
Razib’s daughter 14.0% 8.0%
Razib’s wife 5.8% 1.6%
Razib’s father-in-law 5.2% 2.4%
Razib’s mother-in-law 3.0% 3.1%

I’ll tell you right now that I don’t have any European ancestry according to 23andMe, so my daughter’s elevated French & German and British & Irish have nothing to do with her paternal lineage. In addition I can look at the chromosome level ancestry. Most of my daughter’s chromosome 3 and all of chromosome 6 are French & German (at least the ones obviously inherited from her mother). But there is no French & German ancestry for my wife on these chromosomes (either copy). There is one recombination event from her maternal chromosome 6 and three for chromosome 3, but I don’t think that should have such a large effect.

So hypotheses? My own hunch is that clusters like French & German are somewhat artificial, insofar as they cover a very large geographic area (though granted Europe from the Bay of Biscay to the Elbe is definitely relatively genetically homogeneous). People of mixed European ancestry, like many American whites, often may resolve strangely because the methods used have a difficult time distinguishing mixed ancestry from populations which are composed of mixed ancestry (like many American whites the “French” have diverse ancestries from different regions of Europe, so many Americans may look somewhat “French”). A friend from Guatemala who is ethnically mestizo of many generations has 20% unassigned ancestry, presumably because so many recombination events have intercalated Amerindian and European segments, making it impossible for 23andMe to give a correct assignment. My parents and myself have unassigned proportions of nearly 10%, likely due to ancient admixture between our South and East Asian components, which dates back over 1,000 years in the past.

Personal genomics services are great, and I heartily recommend them. But people should be careful about taking all the results at face value. It’s like with anything else, be an informed and cautious consumer. It can be great for some things, like Dan MacArthur’s South Asian ancestry, which literally jumped out of the genetic background. But the finer you get in the grain, the more confusion will result.

Update: In the comments 23andMe scientist Eric Durand asked if I’d enabled split view. The reason he asks is that 23andMe phases the genotypes (reconstructed each physically linked segment of chromosome of the pair) before assigning ancestry along a segment. If you don’t have family information you have to use population based information. But more powerful are parental trios, since offspring simply have mixed & matched segments of their parents. And yes, I do have split view enabled, and checked it. Same weird result:



• Category: Science • Tags: 23andMe, Personal Genomics 
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Credit: Cryteria

Credit: Cryteria

Happy Thanksgiving (if you are an American)!

It’s been a busy few days in the world of personal genomics. By coincidence I have a coauthored comment in Genome Biology out, Rumors of the death of consumer genomics are greatly exaggerated (it was written and submitted a while back). If you haven’t, please read the FDA’s letter, and 23andMe’s response, as much as there is one right now. Since Slate ran my piece on Monday a lot of people have offered smart, and more well informed, takes. On the one hand you have someone like Alex Tabarrok, with “Our DNA, Our Selves”, which is close to a libertarian cri de coeur. Then you have cases like Christine Gorman, “FDA Was Right to Block 23andMe”. It will be no surprise that I am much closer to Tabarrok than I am to Gorman (she doesn’t even seem to be aware that 23andMe offers a genotyping, not sequencing, service, though fuzziness on the details doesn’t discourage strong opinions from her). An interesting aspect is that many who are not deeply in the technical weeds of the issue are exhibiting politicized responses. I’ve noticed this on Facebook, where some seem to think that 23andMe and the Tea Party have something to do with each other, and the Obama administration and the FDA are basically stand-ins. In other words, some liberals are seeing this dispute as one of those attempts to evade government regulation, something they support on prior grounds. Though Tabarrok is more well informed than the average person (his wife is a biologist), there are others from the right-wing who are taking 23andMe’s side on normative grounds as well. Ultimately I’m not interested in this this argument, because it’s not going to have any significant lasting power. No one will remember in 20 years. As I implied in my Slate piece 23andMe the company now is less interesting than personal genomics the industry sector in the future. Over the long term I’m optimistic that it will evolve into a field which impacts our lives broadly. Nothing the United States government can do will change that.

Yet tunneling down to the level of 23andMe’s specific issues with the regulatory process, there is the reality that it has to deal with the US government and the FDA, no matter what the details of its science are. It’s a profit-making firm. Matt Herper has a judicious take on this, 23andStupid: Is 23andMe Self-Destructing? I don’t have any “inside” information, so I’m not going to offer the hypothesis that this is part of some grand master plan by Anne Wojcicki. I hope it is, but that’s because I want 23andMe to continue to subsidize genotyping services (I’ve heard that though 23andMe owns the machines, the typing is done by LabCorp. And last I checked the $99 upfront cost is a major loss leader; they’re paying you to get typed). I’m afraid that they goofed here, and miscalculated. As I said above, it won’t make a major difference in the long run, but I have many friends who were waiting until this Christmas to purchase kits from 23andMe.

Then there are “the scientists,” or perhaps more precisely the genoscenti. Matt Herper stated to the effect that the genoscenti have libertarian tendencies, and I objected. In part because I am someone who has conservative and/or libertarian tendencies, and I’m pretty well aware that I’m politically out of step with most individuals deeply involved in genetics, who are at most libertarian-leaning moderate liberals, and more often conventional liberal Democrats. Michael Eisen has a well thought out post, FDA vs. 23andMe: How do we want genetic testing to be regulated? Eisen doesn’t have a political ax to grind, and is probably representative of most working geneticists in the academy (he is on 23andMe’s board, but you should probably know that these things don’t mean that much). I may not know much about the FDA regulatory process, but like many immersed in genomics I’m well aware that many people talking about these issues don’t know much about the cutting edge of the modern science. Talk to any geneticist about conversations with medical doctors and genetic counselors, and they will usually express concern that these “professionals” and “gatekeepers” are often wrong, unclear, or confused, on many of the details. A concrete example, when a friend explained to a veteran genetic counselor how my wife used pedigree information combined with genomic data to infer that my daughter did not have an autosomally dominant condition, the counselor asserted that you can’t know if there were two recombination events within the gene, which might invalidate these inferences. Though my friend was suspicious, they did not say anything, because they were not a professional. As a matter of fact there just aren’t enough recombinations across the genome for an intra-genic event to be a likely occurrence (also, recombination likelihood is not uniformly distributed, and not necessarily independent, insofar as there may be suppression of very close events). And this was a very well informed genetic counselor.

Additionally, there are the two major objections to 23andMe’s service which some on Twitter have been pointing me to. First, they return results which are highly actionable. The FDA explicitly used the example of a woman who goes and gets a mastectomy due to a 23andMe result. I don’t think this is a very strong objection. No doctor would perform a mastectomy based on 23andMe results. So that’s not an issue. Then there are those who allude to psychological harm. This could be a problem, but 23andMe has multiple steps which make it so that you have to proactively find out information on these sorts of diseases. Call me a libertarian if you will, but I object on principle to the idea that medical professionals necessarily have to be involved in the dissemination of information about my own genome as a regulatory matter. Obviously when it comes to a course of treatment they will be consulted, and no doubt there will be replications of any actionable results. But I don’t trust the medical sector to be populated by angels. To illustrate why I don’t trust medical professionals to always behave out of the goodness of their hearts, consider that deaths from hospital infections started dropping sharply when Medicare stopped paying for treating these infections. Workers in the health care sector do care about patients, but even here incentives matter, and the human cognitive budget is such that they can shift the outcomes greatly by reminding nurses and doctors that washing hands is going to impact the bottom line (the reality is that hospitals probably instituted much stricter measures). What does this have to do with personal genomics? You are our own best advocate, and one of the major reasons that those in higher socioeconomic strata have better health outcomes is that they are so much less passive as patients. The more detailed the information you have on your own health, the better you can advocate and be involved in the decision-making process. And the reality is that with dropping prices in sequencing, and the ability to design software to do interpretation, without draconian measures there’s almost nothing the United States government will be able to do to prevent anyone with a moderate amount of motivation from getting this sort of information.

A second objection is that the SNPs returned are of small and very probabilistic effect. This is embedded in issues regarding the “missing heritability” and the reality that most complex diseases are due to many factors. Because of the small effect size, and until recently, small sample sizes, this literature has been littered with false positives, which passed arbitrary statistical thresholds. The argument then boils down to the reality that 23andMe in many cases is not really adding any informative value. If that’s the case though then why the urgency to regulate it? Horoscopes and diet books do not add informative value either. This problem with small effect SNPs is widely known, so bringing it up as if it is revelatory is rather strange to me. Additionally, as Eric Lander and others have pointed out the locus which helped us discover statins is of very small effect. As long as they’re not false positives, small-effect SNPs are likely a good way to go in understanding biological pathways for pharmaceutical products. But that doesn’t speak to the risk prediction models. I think there the possibilities are murkier even in the long run because complex traits are complex. Even if we have massive GWAS with sample sizes in the millions and 100x whole-genome coverage (this will happen), the environmental factors may still be significant enough that researchers may balk at definitive risk predictions.

Ultimately where I think personal genomics is going is alluded to in the Genome Biology piece: as part of a broader suite of information services, probably centralized, filtered, and curated, by a helper artificial intelligence. What cognitive science and behavioral economics are telling us is that individuals operate under mental budget constraints. Dan MacArthur is probably right that personal genomics enthusiasts overestimated how involved the average person on the street was going to want to get in terms of their own interpretations of returned results. The reality is that even genetic counselors can barely keep up. Someday the field will stabilize, but this is not that day. But overall the information overload is going to get worse and worse, not better, and where the real upside, and game-changer, will be is in the domain of computational tools which helps us make decisions with a minimum of effort. A cartoon model of this might be an artificial intelligence which talks to you through an ear-bud all day, and takes your genomic, epigenomic, and biomarker status into account when advising you on whether you should pass on the dessert. But to get from here to there is going to require innovation. The end point is inevitable, barring a collapse of post-industrial civilization. The question is where it is going to happen. Here in the United States we have the technology, but we also have cultural and institutional road-blocks to this sort of future. If those road-blocks are onerous enough it doesn’t take a genius to predict that high-tech lifestyle advisement firms, whose aims are to replace the whole gamut of self-help sectors with rationally designed applications and appliances, will simply decamp to Singapore or Dubai.

Personal genomics is a small piece of that. And 23andMe is a small piece of personal genomics. But they are not trivial pieces.

(Republished from Discover/GNXP by permission of author or representative)
• Category: Science • Tags: Personal Genomics 
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nap First, download your 23andMe raw results now if you have them. If you don’t know what’s going on, the FDA has finally started to move aggressively against the firm. Unfortunately this is not surprising, as this was foreshadowed years ago. And, 23andMe has been moving aggressively to emphasize its medical, as opposed to genealogical, services over the past year. But this isn’t the story of one firm. This is the story of government response to very important structural shifts occurring in the medical delivery system of the United States. The government could potentially bankrupt 23andMe, but taking a step back that would still be like the RIAA managing to take down Napster. The information is coming, and if there’s one thing that can overpower state planning it is consumer demand. Unless the US government wants to ban their citizens from receiving their own genetic data they’re just putting off the inevitable outsourcing of various interpretation services. Engagement would probably be the better long term bet, but I don’t see that happening.

(Republished from Discover/GNXP by permission of author or representative)
• Category: Science • Tags: Personal Genomics 
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The last week has seen a lot of chatter about the slapping down of the diagnostic patent by Sequenom, Judge Invalidates Patent for a Down Syndrome Test:

A federal judge has invalidated the central patent underlying a noninvasive method of detecting Down syndrome in fetuses without the risk of inducing a miscarriage.

The ruling is a blow to Sequenom, a California company that introduced the first such noninvasive test in 2011 and has been trying to lock out competitors in a fast-growing market by claiming they infringe on the patent.

Sequenom’s stock fell 23 percent on Thursday, to $1.92.

The judge, Susan Illston of the United States District Court in Northern California, issued a ruling on Wednesday that the patent was invalid because it covered a natural phenomenon — the presence of DNA from the fetus in the mother’s blood.

The existence of intellectual property is a utilitarian one. That is, these are institutions which are meant to further the cause of creativity and innovation. Is there going to be an abandonment in this domain of the push toward technological innovation? Coincidentally in the last week of October Sequenom put out a press release which heralded some advances in its panel:

…The MaterniT21 PLUS test will begin reporting additional findings for the presence of subchromosomal microdeletions and autosomal trisomies for chromosomes 16 and 22, in addition to the previously announced additional findings for sex chromosome aneuploidies involving an abnormal number of the X or Y chromosomes. These additional findings complement the MaterniT21 PLUS test core identification of trisomies for chromosome 21, chromosome 18 and chromosome 13. With this expansion, the MaterniT21 PLUS test is the first-of-its-kind noninvasive prenatal technology (NIPT) to provide these comprehensive results from a maternal blood draw.

Sequenom Laboratories will begin reporting on these select, clinically relevant microdeletions, including 22q11.2 deletion syndrome (DiGeorge), Cri-du-chat syndrome, Prader-Willi/Angelman syndrome, 1p36 deletion syndrome, as well as trisomies 16 and 22 the last week of October. Results from a method validation study….

It seems that the firm’s main path to profit and riches is going to be to innovate faster, gain market share, brand recognition, and economies of scale. This seems as if it is a greater good for the public than its rents extracted through intellectual property monopolies.

(Republished from Discover/GNXP by permission of author or representative)
• Category: Science • Tags: DTC personal genomics, Personal Genomics 
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This isn’t the face of the future

I was in the audience when Anne Morris, co-founder of GenePeeks, gave a presentation to outline the services that they are aiming to provide at the Consumer Genetics Conference. Honestly my biggest reaction was, “Oh, this is 2013, I suppose. And boy, Lee Silver has a lot of energy” (he kept bouncing around the back of the conference room). From what I can tell the “technology” is the sort of brute-force “subtlty” only feasible in our era because of the intersection of sequencing and computation. After the presentation it looks like GenePeeks is revving up its marketing engine (as promised). From a lengthy BBC story which reads more like a press release with caveats:

Ms Morriss’s business partner, Prof Lee Silver, a geneticist and expert on bioethics at Princeton University, New Jersey, told BBC News: “We get the DNA sequence from two prospective parents. We simulate the process of reproduction, forming virtual sperm and virtual eggs. We put them together to form a hypothetical child genome.

“Then we can look at that hypothetical genome and – with all the tools of modern genetics – determine the risk that the genome will result in a child with disease. We’re looking directly for disease and not carrier status. For each pair of people that we’re going to analyse, we make 10,000 hypothetical children.

The process will be run for the client and each potential donor one by one, scanning for some 600 known single-gene recessive conditions. In this way, the highest-risk pairings can be filtered out.

In general I’m moderately skeptical of patents for these sorts of analytics (in particular, the non-obvious parts). Though to be fair I’m skeptical of patents in general due a long-standing Grusification of my attitudes in this domain. I suspect in the near future you’ll have R packages which can do this sort of thing on the cheap.

GenePeeks’ core consumer segment are women who need to make recourse to sperm donors, so this isn’t going to be mass-market. And, they’re focusing on recessive disease probabilities. But it is obvious that extensions of this model could be much more ubiquitous and societally impactful.

And, GenePeeks’ consumer strategy is a hint at what the face of the cutting-edge of modern personal genomics is going to be. It won’t be traditional conservative families who multiply fruitfully and early. Rather, a disproporionate number of consumers will probably be couples such as Anne Morris and her wife, Francis Frei, who you might know from extensive coverage in an article on women at the Harvard Business School. Educated women who delay childbearing and expect to have two children at most, many in “non-traditional” personal arrangements. This is why the constant focus on eugenics and Nazis strikes me as unhelpful. The past and the present really have little to do with each other, but that’s partly because the present is changing our expectations almost imperceptibility. So the easiest course is to yammer on about Hitler while the single female professional down the street takes her own reproductive chocies into her own hands (so to speak).

Finally, I do need to enter into the record that there are probably limitations to any algorithm which computes the phenotype of offspring. GenePeeks and its competitors are going to focus on large effect high penetrance variants which are causal in Mendelian diseases because that’s doable, and also not as ethically controversial. But the genomic architecture of quantitative traits such as height and intelligence are going to make prediction using sequence data less useful (the best prediction is probably going to be parental phenotype for a while). And of course what may be “good” in one generation may not be good in another. W. D. Hamilton, an avowed eugenicist, admitted reservations about the prospect of genetic optimization in The Narrow Roads of Gene Land mostly for this reason.

At the end of the day I agree that a broad-based discussion of the ramifications of personal genomics is useful and necessary. But the conversation ends when someone brings up the N-word.

(Republished from Discover/GNXP by permission of author or representative)
• Category: Science • Tags: Personal Genomics 
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Matter has a very long feature by my friend Virginia Hughes, Uprooted, on how personal genomics is changing, and sometimes disrupting, family relationships. I sat in on one session at the Consumer Genetics Conference last week, and an audience member expressed worry about how genetic results might cause family disruption. This individual was actually a faculty member who wanted to introduce personal genomics into the classroom as a way to educate, but was wary of these sorts of side effects. Even neglecting the reality that paternity uncertainty is likely far less pervasive among the sorts whose parents would be enrolling their offspring at universities in the Boston area, these worries always have to be predicated by the fact that even dodging this ethical gray zone in the specific case only delays the near-future inevitable. Unless medical authorities ubiquitously and invariably selectively shield this sort of information from the relevant parties the widespread adoption of genetic analysis as a consumer product will result in exposure of this sort of information. Though it may seem crazy preemptive testing of all offspring to ascertain biological relatedness of putative parents may simply be the best way to head off this issue, which will be like a ticking time bomb.

(Republished from Discover/GNXP by permission of author or representative)
• Category: Science • Tags: Personal Genomics 
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Vanessa L. Williams
Credit: Tabercil

The website The Root often has a Q & A with various African Americans, famous and not so famous, about their genealogy in relation to personal genomics. In most cases these tests tell you what you already know, but for African Americans there is often actually value-add in terms of greater specificity and precision, which would otherwise be lacking for obvious historical reasons. Despite its objective scientific patina the processing and interpretation of the resultant information can be rather subject, and illuminating. Recently they sat down with actress, and the first black winner of Miss America, Vanessa L. Williams, to discuss her results. There were two passages which I think were particularly interesting, so I’ll quote them below:

What did you find out about your DNA?

My DNA breaks down as follows: I’m 23% from Ghana, 17% from the British Isles, 15% from Cameroon, 12% Finnish, 11% Southern European, 7% Togo, 6% Benin, 5% Senegal and 4% Portuguese.

Now, I can’t wait to go to Ghana and Cameroon and Togo and Senegal — it’s a great opportunity to see why the customs resonate with you. I love to travel and I love to explore, and I have to admit that I was always jealous of people who knew their cultural background. Both my family and myself came out with light eyes, so obviously there is a recessive gene here. Not knowing what that was just made me very curious.

How did your family react to all this information?

They loved it. They really can’t wait to go on our world tour of where we’re from. The biggest surprise was Finland. How did that happen? Who is Finnish? That is definitely going to be one of my trips coming up. It’s all surprising, really interesting and it’s really incredible.


First, note that Williams highlighted her African components as particularly noteworthy. She did not say she can’t wait to go to Finland. Not surprising, but it emphasizes that people are looking for specific things, not objective truth. On that Finnish ancestry, perusing what I can find about the AncestryDNA service it seems that this a Finnish-like component, not necessarily Finnish. This sort of confusion is common, and I hope that ancestry services will work on greater awareness of the best way to interpret their results in the future.

(Republished from Discover/GNXP by permission of author or representative)
• Category: Science • Tags: Personal Genomics 
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Credit: Robert Payne

The British media is blowing up today about Prince William’s Indian ancestry. Here’s a representative headline: Hunt is on in Gujarat for a distant cousin who shares Prince William’s Indian blood. The science here is straightforward. Apparently some British researchers found third cousins of Lady Diana Spencer. These individuals, like Diana, are descended from a woman named Eliza Kewark. This woman, William’s great, great, great, great, great grandmother was an ethnic Armenian who was resident in India. She was also the housekeeper of William’s ancestor Theodore Forbes, a Scottish merchant. At some point he sent his children by this woman to be educated in England, and there William’s ancestress married into native British lineages. Since Diana’s cousins share the same unbroken matriline as she does they by definition share an mtDNA lineage. As it happens these individuals carry haplgroup R30b, a very rare lineage found only in South Asia. But that’s not all. Diana’s cousins also are 0.3% and 0.8% South Asian on their autosomal genome. The intersection of these two facts does convince me that William’s genealogical ancestress, Eliza Kewark, did have South Asian ancestry (not totally surprising even in notionally ethnically distinct groups like Armenians or Parsis who have been long resident in India). But please note that I said genealogical ancestress.

Observe the large variance in ancestry of Diana’s two third cousins presumably derived from Eliza Kewark (though there is always the chance that these segments come from different South Asian ancestors, the typically South Asian mtDNA match across the two reduces the probability of that being the answer in this case). Beyond eight generations the chance of a genetic segment being passed from an ancestor down to a descendant is small. Diana’s cousins are seven generations down from Eliza Kewark, so it isn’t totally implausible that a segment should get passed down. But William at eight is at the boundary, and he may carry no segments (in fact, Diana may have carried no segments). Of course I did note that their mtDNA is likely to be passed down, because there is no element of chance in that. You have your mother’s mtDNA. But one can debate whether mtDNA, which is not present in the nucleus, really counts as ancestry. I believe that heritable genetic material is heritable genetic material. Assuming the lines of descent are as they are recorded I accept that we know for a fact that William likely has South Asian mtDNA. But we most certainly do not know if he has any South Asian autosomal DNA.

But in the end how much does this matter? People will make of it what they will. And yet there is an important aspect to note: this seems like another instance of the firm BritainsDNA hyping genetic findings to increase their profile. You see that the screenshot of their website shows that they’re promoting the story about William’s ancestry, and, they’re also claiming that they are offering the world’s most advanced genetic ancestry test. First, I have to observe that their price points are very high, and second, if they are going to claim the most advanced test in the world they should actually do a point-by-point comparison with other services, which they don’t seem to do.

Perhaps more importantly this outfit now has a history of getting caught up in, and frankly stoking, hype. I don’t begrudge anyone their livelihood, or financial success, but scientists do have an implicit and explicit honor code. Jim Wilson has been involved in some interesting work, which is what I knew him from. But a third time will be a trend, and Wilson shouldn’t be surprised if rather soon he becomes thought of as a ‘tabloid geneticist,’ rather than a scholar who popularizes serious science to the broader public.

Prime Minister of the United Kingdom, 1812 – 1827

Addendum: For American readers I should make it clear that it isn’t totally surprising that the British upper classes and gentry have some Indian ancestry, because so many of them have had ancestors associated with the British Raj. The book White Mughals explores this period and people in extensive detail. For some specifics, recall that Robert Jenkins, later Lord Liverpool, and Prime Minister of the United Kingdom for 10 years, 1817-1827, was 1/8th Indian by ancestry. The British actress Nicollette Sheridan is also 1/8th Indian. And finally, my friend Dan MacArthur clearly has South Asian ancestry, due to the same historical circumstances as the individuals above. This is perhaps the British equivalent of “Native American ancestry.”

(Republished from Discover/GNXP by permission of author or representative)
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Guess what, we’re related! Credit: Wapondaponda 

This is a public service announcement. If you are a user of direct-to-consumer personal genomics services, please do not pay any attention to your mtDNA and Y chromosomal haplogroups. Why? Because they hardly tell you anything about your individual ancestry. What do I mean by this? Your mtDNA comes down from your mother’s-mother’s-mother’s-mother… and similarly for your Y chromosomal lineage if you are a male. These few individuals are not any more likely to contribute to your ancestry than all those multitudes and multitudes who do not contribute to your mtDNA or Y lineages; also known as almost all your ancestors! What you should pay attention to are your autosomal results. Inferences made from most of your genome. These results may be more difficult to parse, but difficulty is no sin, and elegant ease is no virtue, in this case. That’s because you are interested in your ancestry, not a convenient interpretable story.

Of course I am not saying that mtDNA and Y chromosomal haplogroups are useless. They are useful for population scale phylogeography. But please don’t make inferences about yourself from one data point. At least in most cases.

(Republished from Discover/GNXP by permission of author or representative)
• Category: Science • Tags: D.T.C. Personal Genomics, Personal Genomics 
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Update: Feature was always there. Just hard to find.

23andMe did a site redesign. Most of it is user interface clean up, but there one particular cool function: if you have an individual’s pedigree up to grandparents you can see which allele they inherited. Just select “Family Traits” under “Family & Friends.”

You then get a pedigree you can fill out. A few weeks ago my wife inferred that my daughter did not carry the allele for an autosomal dominant disease which I exhibit (treatable, don’t worry!) by looking at the segments inherited. On the chromosome in question there were no recombination events and the whole chromosome was from my father. Since I received my copy of the gene which results in the disease from my mother logically my wife was able to conclude my daughter does not carry it.

The new feature makes it much easier. You can population the tree with individuals who have been typed, and enter in the gene code. It tells you which maternal and paternal grandparent the alleles come from. This is useful because many times you might be carrying a high penetrance Mendelian disease allele which happens to not be on a SNP chip. Or, there haven’t been many GWAS studies done on this disease in any case, so though the likely genetic region is known, the candidate variants are still a mystery. But if you have phenotype information you don’t need that research (I have it in my mother’s disease state).

Another reason to get your whole family typed.

(Republished from Discover/GNXP by permission of author or representative)
• Category: Science • Tags: Personal Genomics 
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I have put 1 million markers (from a combination of Illumina SNP-chips) of mine online. I’m also going to put my sequence online when I get it done. Why? What do I gain from this? Hopefully I don’t gain anything from it. By this, I mean that the only major information that is actionable in a life altering sense is likely to be disease related. Though I’ve been contacted about possible loss of function mutations through imputation, so far my genotype has not illuminated any more risk susceptibilities. Rather, I am trying to make it clear by my openness that your genetic information has more power when pooled together with that of others, and small one step in creating that vast pool of information is to demystifying sharing it, and practicing what you (that is, me) preach. My soul is not in my genes, and certainly my genotype reflects me with far less obvious fidelity than a photograph would. By this, I mean that there are many traits that one could predict about me, but many one would be at a loss to predict.

To me this is a coordination problem. The more genetic and phenotypic information researchers and analytic software have, the more correlational juice one might squeeze out of the vast cloud of data. But the temptation here will be to free ride, and keep one’s own genome private, while one benefit from the openness of others (to some extent, this is what happens when you have medical research subjects, whose results are used for the gain of the public, which pays, but does not participate). I can see why someone would not want to divulge their health information. A list of venereal diseases may be a source of shame, whether you find it justifiable or not. There is a reasonable ground for privacy, because communicable diseases are reflective often of life choices one has made. When it comes to genes if you have a major loss of function mutation or a disease which is likely to develop at some point before your death (e.g., early onset Alzheimer’s disease), then there are clear grounds for keeping that information close to the vest. But you don’t bear any responsibility for your genotype, nor do you gain any merit or demerit from your genotype. It is a contingent accident of history, and the information is not who you are, it is just the loading of the die you were given by dint of your birth.

This not just about genetics. It is about life. We already have many private firms, from credit rating agencies to Facebook, to marketers, to the government, monitoring our movement, and attempting to anticipate our choices. One can opt out from this information ecology, but unless one goes off the grid and lives in a subsistence lifestyle it can be a part-time job to do this. Mind you, there are gains to this information ecology, as you are solicited for products and services which previous choices suggest you would be predisposed toward. Similarly, there are upsides and downsides toward an open health and genetic information ecology. If you have a risk allele for a disease with a diet interaction effect, then there is a clear course of action. My own hunch is that this world is coming, no matter our wish, and we need to act in its early phases to grasp the shape of the future and set the parameters of the game. We can’t be passive. The information cloud is going to be there, and someone will parcel and claim it.

It may be trite, but when I push for open genomics on my friends and family I’m not telling them what they may gain. Rather, I’m arguing that the world may gain, and therefore downstream we may gain.

(Republished from Discover/GNXP by permission of author or representative)
• Category: Science • Tags: Genomics, Personal Genomics 
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Larry Moran has a post up, Who Owns Your Genome?, where he mentions me apropos of the HeLa genome disclosure:

In my opinion, there is no excuse for publishing this genome sequence without consent.

Razib Khan disagrees. He thinks that he can publish his genome sequence without obtaining consent from anyone else and I assume he feels the same way about the sequence of the HeLa genome [Henrietta Lacks’ genome, and familial consent].

In response to Larry, I don’t have a definitive opinion about the HeLa genome disclosure in terms of whether it was ethical to release it or not. “Both sides” have positions which I see the validity of. I think ultimately the root issues really date to the 1950s, not today, and they don’t have to do with personal genomics as such. Also, I’d recommend Joe Pickrell’s post, Henrietta Lacks’s genome sequence has been publicly available for years.

Larry also has a question in the comments:

Let’s try a thought experiment. Everyone is free to answer. I’d prefer a simple “yes” or “no” followed by an explanation.

Imagine that you have paid to have your entire genome sequenced. You announce that you intend to upload it to a public site so that anyone can see it. Your parents, your siblings, and your children, all object, saying that this would violate their privacy.

Do you upload it anyway? (“Yes” or “no.” Please respect the rules of a thought experiment and don’t try to quibble about the scenario.)

Yes, I’d upload it, and I will (since I’ve committed to uploading it when I have it done). Also note that my daughter is too young right now to give consent, and she probably will be too young when I upload the genome, so I’m going to do something which might impact her as a child.

One nuance I would like to add though is that decisions may vary given circumstance. For example, if you have one of the high penetrance BRCA mutations, you may not want to expose your family’s information for pragmatic reasons. But my question would be: why do people talk about their highly heritable illnesses in public forums already? I’ve seen media profiles of women with a BRCA mutation, with female relatives. By talking about this they’re exposing their family’s genetic information implicitly. Therefore, I suspect many of the pragmatic concerns are moot, because though there is privacy in regards to health information, there isn’t a taboo about discussing one’s health status in public. Most of the time people who have these diseases want their story put out there to aid in medical advancement and consciousness raising (though obviously there are exceptions).

And that is a subset of the primary issue I have with many worries about privacy and policy and the genome. Just transpose the structure of worries into other fields, and you wonder where the analogous concern is elsewhere. For example, in regards to health I’d argue diet is a much larger issue than genomics, at least for non-aged morbidity. But there is a huge industry of diet books, and very few people see licensed nutritionists. The point here isn’t to argue for paternalism or anti-paternalism, it’s to suggest that genetics isn’t special. It is important, it is cool, and it is fascinating. But so are many other things.

(Republished from Discover/GNXP by permission of author or representative)
• Category: Science • Tags: Health, Personal Genomics 
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Rebecca Skloot has an op-ed in The New York Times, The Immortal Life of Henrietta Lacks, the Sequel. I’ve read it a few times now and I’ll be honest and say I’m not totally clear on some of the points she’s trying to make, so I didn’t have a strong reaction to it. This is in contrast to Michael Eisen, who has a post up, The Immortal Consenting of Henrietta Lacks. He told me on Twitter that he had some exchanges with Skloot (on Twitter) which informed his response, so he probably has more context than I do. Eisen says:

I find the way Skloot’s NYT piece moves back and forth between the historical transgressions against Henrietta Lacks and the contemporary threat to her relatives’ privacy incredibly misleading. I doubt this was intentional – rather I think it reflects muddled thinking on her part about these issues. But either way, by juxtaposing the entirely justifiable empowering of the Lacks family to grant individual consent on Henrietta’s behalf with the desire of the same family to protect its genetic privacy, Skloot is implying that these are one and the same – that we should give ANY family the right to veto the publication of a relative’s genome.

I don’t know if Skloot is actually implying this.* If so, then I disagree with her on this, as I’ve stated in the past. But I do want to emphasize I feel that the op-ed overemphasizes the power of genes. For example: “Imagine if someone secretly sent samples of your DNA to one of many companies that promise to tell you what your genes say about you. That report would list the good news (you’ll probably live to be 100) and the not-so-good news (you’ll most likely develop Alzheimer’s, bipolar disorder and maybe alcoholism.” It’s a op-ed in The New York Times, so I don’t hold this against the author.

But much of the controversy about this stuff would be diffused if people were more straightforward about the comparative advantage of genetic information over any other sort of information. If, for example, you tell people that you have a health condition which is known to run in families (e.g., breast cancer), then you’re also telling people about your family. To my knowledge there isn’t a tacit social contract that you need to check with your family before you ever discuss you health status, though I could be out of the loop on this.

* Skloot disputes Eisen’s characterization of what she meant to imply. See her response in Eisen’s comments.

(Republished from Discover/GNXP by permission of author or representative)
• Category: Science • Tags: Personal Genomics 
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I’ve gotten several emails about the Vice interview of Geoffrey Miller on BGI’s Cognitive Genetics Project. It’s a sexy piece, and no surprise given Miller’s fascination with the future of China and science (something I share to a moderate extent). But for the love of God please watch this Steve Hsu video first before reading that.

The problem that seems to crop up with this project, which has been in the works for years, is that any public mention blows up into extreme hyperbole. And yet when I’ve talked to Steve about it he’s often much more modest about the possibilities, even if the ambitions of the people involved in the endeavor are rather grand. I’m also moderately worried that the likely low probability of implementation of the sort of embryo screening for a quantitative trait like intelligence is going to confuse people as to the more probable and ubiquitous application: focusing on large effect deleterious mutations. As a new father the frequency of congenital defects is just staggering,* and I am highly motivated by this issue. In a China where family size is likely to stay small for the medium term future there will surely be a powerful demand side pressure for children without life altering diseases or abnormalities. Whether that is right or wrong, I am willing to bet that it will be routine reality for the affluent Chinese before the decade is out.

Also, I think Miller overdoes it on how China is overtaking the West in genetics (genomics). There is some caution in some cutting edge domains which might have unpalatable ideological implications, but American universities, and places like the Sanger or Max Plank Institute have a huge store of human capital. In fact I would hazard to predict that for the short to medium term future most of the “blue sky” biological research will still be done outside of China, while the Far East will focus on squeezing as much efficiency and insight as possible out of the basic science pioneered in the West.

* Yes, I know that it’s a 1 out of 30 probability. That’s really, really, high for most expectant parents. Think of a congenital defect as tail risk. Unlikely, but totally devastating when it does occur.

(Republished from Discover/GNXP by permission of author or representative)
• Category: Science • Tags: Personal Genomics 
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After my previous post my wife started doing research online. The autosomal dominant condition that I have is almost certainly localized to one particular chromosome (there is a large effect QTL there that is strongly associated with my condition). Additionally, I inherit this condition from my mother. My daughter has her whole pedigree genotyped, thanks to 23andMe. My wife went into the Family Inheritance feature, and compared the identity by descent blocks shared between my mother and my daughter. And, it turns out that on that chromosome the only segments inherited from me, her father, come from my father. Ergo, she can not have inherited the autosomal dominant condition from my mother, since she did not inherit those alleles from her!

We are very happy right now. This is one reason I don’t really care about what the F.D.A. thinks about direct-to-consumer personal genomics. We’re talking about commodity technology. And no one is going to stand between you and your health, if you are motivated.

Addendum: With hindsight I could have figured this out myself a year ago. It just hadn’t crossed my mind.

(Republished from Discover/GNXP by permission of author or representative)
• Category: Science • Tags: D.T.C. Personal Genomics, Personal Genomics 
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Razib Khan
About Razib Khan

"I have degrees in biology and biochemistry, a passion for genetics, history, and philosophy, and shrimp is my favorite food. If you want to know more, see the links at"