Personal genomics lives!

Reflecting back to it I think I started “exploring personal genomics” in the late 2000s. That’s when direct-to-consumer testing started to become popular, albeit very niche. The book Exploring Personal Genomics is now 5 years old, and a lot has changed since then. In the same year, 2013, David Mittelman and I cowrote Rumors of the death of consumer genomics are greatly exaggerated in Genome Biology.

Now Science has a commentary out, Crowdsourced genealogies and genomes, which reviews how large amounts of public data, genetic and classical genealogical, are being used to change the field before our very eyes. I would recommend though that you read the less edited (longer, more detailed) version on the website of the authors, Crowdsourcing big data research on human history and health: from genealogies to genomes and back again.

This fact from that piece is really illustrative of what’s happening today:

As the number of customers of whole-genome DTC genetic testing just crossed 16 million, it is worth noting that almost two-thirds of them joined since the beginning of 2017 [19]. Based on current rates, this number of customers is predicted to be close to 100 million by end of 2020.

Notes from the personal genomic inflection point

There’s a debate that periodically crops up online about the utility, viability, and morality of returning results from genetic tests to consumers. Consumers here means people like you or me. Pretty much everyone.

If you want to caricature two stylized camps, there are information maximalists who proclaim a utopia now, where people can find out so much about themselves through their genome. And then there are information elitists, who emphasize that the public can’t handle the truth. Or, more accurately, that throwing information without context and interpretation from someone who knows better is not just useless, it’s dangerous.

Of course, most people will stake out more nuanced complex positions. That’s not the point. Here is my bottom-line, which I’ve probably held since about ~2010:

  1. The value for most people in actionable information in direct-to-consumer genetics is probably not there yet when set against the cost.
  2. With the reduction in the cost of genotyping and sequencing, there’s no way that we have enough trained professionals to handle the surfeit of information. And there will really be no way in 10 years when a large proportion of the American population will be sequenced.

At some point, the cost will come down enough, and the science probably is strong enough, that direct-to-consumer genetics moves away from novelty and early adopters to the mass market. At that point, we need to be able to make the best use of that data. Genetic counselors, geneticists, and doctors all cost a fair amount of money and have a finite amount of labor supply to provide to the public. They need to focus on serious, complex, and consequential cases.

To some extent, we need to reduce much of interpretation in the personal genomics space to an information technology problem. For example, if someone’s genotype pulls out a bunch of statistically significant hits of interest the tool should automatically condition significance on that individual’s genetic background.

Yes, there are primitive forms of these sorts of tools out there already. But they’re not good enough. And that’s because there isn’t the market need. But there will be.

Our family’s pedigree in 23andMe

With 23andMe’s new update to its ancestry, the results for my family have changed. Not for me, since I’m not of European descent, and this looks Euro-focused (no surprise). But my wife and kids are different.

My wife has two great-grandparents who were born in Norway. 23andMe is picking that up immediately. It also picks it up in my children, from left to right, my daughter, my younger son, and my older son. With more than 3 million in their database 23andMe has knowledge of which haplotypes are unique to Norway, and which are not. When you click “Norway,” it says “We predict you had ancestors that lived in Norway within the last 200 years.” That’s telling me that they detect IBD segments uniquely found in Norwegian populations of a particular length threshold.

My youngest is on a new chip, so the Western Asian & North African I dismiss. But I’m not sure I believe some of the European admixture estimates. The two boys exhibit very little drop off in Scandinavian. But my daughter is way lower. This is not unreasonable, but they also exhibit differences in East Asian ancestry. And I’ve looked but I can’t detect this on PCA plots. My daughter is, in fact, more distant from Han Chinese than my sons.

In the future, I think perhaps genealogy-focused results, which show matches within particular nations, should be partitioned from admixture analysis. That’s how it used to be.

(it is a curious coincidence that both my more Scandinavian children are heterozygotes on the KITLG locus for the derived variant, though I know they get it from their mostly German grandfather)

The 23andMe BRCA test

In case you were sleeping under a rock, 23andMe got FDA approval for DTC testing of markers related to BRCA risk. Obviously, this is a pretty big step, in principle.

But the short-term implications are not that earth-shaking.

From the FDA release:

The three BRCA1/BRCA2 hereditary mutations detected by the test are present in about 2 percent of Ashkenazi Jewish women, according to a National Cancer Institute study, but rarely occur (0 percent to 0.1 percent) in other ethnic populations. All individuals, whether they are of Ashkenazi Jewish descent or not, may have other mutations in BRCA1 or BRCA2 genes, or other cancer-related gene mutations that are not detected by this test. For this reason, a negative test result could still mean that a person has an increased risk of cancer due to gene mutations….

Apparently, women with one of these variants have a 45-85% chance of developing breast cancer by age 70. So the penetrance is high.

It seems that you’ll know if this sort of test is going to have utility for you based on family history.

The big thing is the transition to DTC. This will increase availability and drive the price down. That’s probably going to mean more work for those engaged in interpretation and education. False positives are going to start being a major thing….

Helix kit price waived until December 26 at 2:59am EST

Happy Hanukkah! My main qualm with wishing you a happy holiday is that I’m a thorough assimilator and I don’t want to be disemboweled.

For the context, listen to the Stuff You Missed in History Class episode on the Maccabean Revolt. As a Jewish friend of mine once observed, the Maccabees were kind of the Al-Qaeda of their day (today she would have said ISIS).

With that out of the way, I want to give you a heads up that Helix has a sale going until December 26 at 2:59am EST where the $80 kit cost for purchase of any app is waived if you haven’t purchased at app before. Just enter the promotion code HOLIDAY at checkout.

That means presales of Insitome’s Regional Ancestry is no more than $19.99, while Neanderthal is $29.99 and Metabolism is $39.99 (this applies to all of Helix’s products except embodyDNA by Lose It! and Geno 2.0 by National Geographic).

Why does it matter? Again, Helix banks a high quality exome+ (the + is for non-exonic positions) when you purchase any of their apps. If you want subsequent apps you don’t have to sent another kit in, you just buy the app and get the results. Also, I do have to say that from what I’ve seen and heard Helix’s laboratory facilities are top-notch in terms of getting results turned around rapidly.

Genomic ancestry tests are not cons, part 2: the problem of ethnicity

The results to the left are from 23andMe for someone whose paternal grandparents were immigrants from southern Germany. Their mother had a father who was of English American background (his father was a Yankee American with an English surname and his mother was an immigrant from England), and grandparents who were German (Rhinelander) and French Canadian respectively on their maternal side.

Looking at the results from 23andMe one has to wonder, why is this individual only a bit under 25% French & German, when genealogical records show places of birth that indicates they should be 75% French & German (more precisely, 62.5% German and 12.5% French). Though their ancestry is 25% English, only 13% of their ancestry is listed as such.

First, notice that nearly half of their ancestry is “Broadly Northwestern European.” Last I  checked  23andMe uses phased haplotypes to detect segments of ancestry. This is a very powerful method and is often quite good at zeroing in on people of European ancestry. But with Americans of predominant, but mixed, Northern European background rather than giving back precise proportions often you obtain results of the form of “Broadly…” because presumably, recombination has generated novel haplotypes in white Americans.

But this isn’t the whole story. Why, for example, are many of the Finnish people I know on 23andMe assigned as >90% Finnish, while a Danish friend is 40% Scandinavian?

The issue here is that to be “Finnish” and “Scandinavian” are not equivalent units in terms of population genetics. Finns are a relatively homogeneous ethnic group who seem to have undergone a recent population bottleneck. In contrast, Scandinavia encompasses several different, albeit related, ethnicities which are geographically widely distributed.

Ethnic identities are socially and historically constructed. Additionally, they are often clear and distinct. This is not always the case for population genetic classifications. On a continental scale, racial classification is trivial, and feasible with only a modest number of genetic markers. Why? Because the demographic and evolutionary history of Melanesians and West Africans, to give two concrete examples, are distinct over tens of thousands of years. Population genetic analyses which attempt to identify or differentiate these groups have a lot of raw material to work with.

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South Asian Genotype Project

It’s been a few years since I’ve done any serious “Genome Blogging.” Mostly I’ve been very busy and there isn’t much low-hanging fruit left as it is. But today I want to announce that I’ll be running the generically titled “South Asian Genotype Project.”

The way it works is simple: send me a 23andMe, Ancestry, or Family Tree DNA raw genotype file to contactgnxp -at- (though 23andMe’s new chip has far less overlap with other platforms earlier, so probably best if you were typed before August 2017).

In the subject please put:

  1. “South Asian Genotype Project”
  2. The state/province your family is from
  3. Ethnolinguistic group
  4. If applicable, caste

In the body of the email you can put Y and mtDNA and any other information you want. Obviously your data is confidential and I won’t identify you by name, just ethnolinguistic group and such.

Since the last time I did this I have some scripts that make this a lot of easier, so hopefully I’ll be adding individuals to this spreadsheet every few days. I’ll give project members an ID and try to email them when the results are up.

The main motivator for this project on my part is that people still ask me questions about Sinhalese, Nasrani Christians, and other assorted groups which we don’t have answers to because current research projects haven’t focused on them.

Since Zack worked on the Harappa Ancestry Project we know a lot more about South Asian ancestry. Basically, there is an ANI-ASI cline, and some South Asians have exogenous ancestry off this cline. Indian Jews have Middle Eastern ancestry, while Bengalis have East Asian ancestry, and some groups in Pakistan have African ancestry. With that in mind I’ll be testing a smaller number of populations. The marker set is 240,000 SNPs by the way.

Below are some representative results. You can see that my results from three DTC services are basically the same. Also, some South Indian groups (see Pulliyar) show “Dai” ancestry, when I’m pretty sure it’s just that I didn’t sample as much on the extreme portion of the ASI-cline.

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Razib Khan’s raw genotype data on 23andMe, Family Tree DNA, Geno 2.0 and Ancestry

It has been a while since I posted an update on my genotype. Since then I’ve been tested on most of the major platforms. I don’t see any harm in releasing this to the public or researchers who want to look at it (though I don’t know why anyone would).

You can download all the files here.

Having my genotypes public is pretty useful for me. If I inquire about someone’s genetics oftentimes people get weirdly defense and ask “what about you?” I Just invite them to look at my raw data and analyze it for themselves! I’m not a hypocrite about this.

Over the years I’ve had researchers inquire about my ethnicity when they stumble upon my genotype on platforms such as openSNP. So in full disclosure, most of my ancestry is pretty standard eastern Bengali. I’m more East Asian shifted than most Bangladeshi samples in the 1000 Genomes project, but then my family is from Comilla, in the far east of eastern Bengal (anyone who cares, my Y is of course R1a1a-Z93 and my mtDNA U2b).

As before I’ll put the genotype under a Creative Commons license:Creative Commons License

Bank your exome with Helix for free ($0.00) [update, SALE ENDED!]

Update: Sale over!

I wasn’t going to do this again, but I’ve decided to promote Helix’s special discount. It ends at 2:59 AM EDT November 10th. Eight hours from when I push this post.

Obviously, there is a conflict of interest as I work for one of Helix’s partners. What does that mean?

  • Helix does an exome+ sequence and stores your data.
  • Then, you buy applications which use that data.
  • The company I work for is one of the application providers.
  • “Exome” means that Helix does a very accurate medical grade sequence of all your genes. The “+” points to the fact that they include a substantial number of positions which are not within genes (in the “junk DNA”). That totals up to 30,000,000+ markers (the exome is 1% of your whole genome). This is not trivial. Current direct-to-consumer genomics companies are looking at 500,000 to 1,000,000 markers with SNP arrays.
  • Helix keeps this data. Within a few months, you can buy the data at cost (it won’t be cheap!). But the model is that you buy a la cart apps, which will be affordable (our products are affordable).

I’m laying this all out very plainly because many people are asking me about these details right now as the sale winds down, and this includes people who are pretty savvy about personal genomics. Here is why I think you should get the kits now:

  1. It gets my company more customers. That’s the self-interested part, and less important for the target audience.
  2. For you, it gets you an exome that you can buy later without any upfront cost. For the next eight hours, Helix is basically waiving the kit costs by dropping the price $100.

Our Neanderthal product is now $9.99. Our Metabolism product is $19.99. These products are great, as they give you functional information in a very user-friendly manner. But a lot of my readers can analyze their own data, so what’s the incentive then? Again, the incentive is that you get an exome for free, and can later buy it if you want, or, perhaps even a savvy personal genomics consumer will find an app they’ll want to purchase. Normally the kit is $80, so buying it now means you’ll never have to pay this cost. If you are the type of person who has qualms about a private company keeping your data, this may not be for you.

Of course, there are other app developers in the Helix store, so just buy whatever you want. This is a way to get your exome sequenced for free nowI will tell you that the Insitome apps are among the cheapest.

Finally, a lot of people are buying “family-pack” quantities. I got four kits for example for my immediate family. Unfortunately, there are some issues with the Helix site and the extra purchases. You can buy more than one easily at Amazon right now. Our Neanderthal product is not in low stock. The Metabolism product has only a few left, though I don’t know what that means.

Note: The discount is client-side, so you may need to switch browsers if you are going to the Helix site to buy (or turn off ad-block). From what I can see Amazon does not have these issues.