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….

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

My son in the genetics history books

Just saw today that my son’s prenatal sequencing was mentioned in DNA: The Story of the Genetic Revolution:

The ethics of sequencing a presumably health fetus will be debated for years to come. But the day of doing is already here. Razib Khan, a thirty-something graduate student and blogger, decided to sequence his first child’s genome while his wife was still pregnant. Although one instance of whole-genome sequencing in utero was reported in the New England Journal of Medicine in 2012, that had been done to supplement a positive cytogenetic result….

I want to correct the record for future printings: my first son was my second child. And, it was not my decision, it was our decision. My wife was an equal partner, and did as much behind the scenes in making the sequencing happen.

23andMe ancestry only is $49.99 for Prime Day

23andMe has gone below $50 for “Prime Day”! For those of us who bought kits (albeit more fully featured) at $399 or even more this is pretty incredible. But from what I’m to understand these sorts of SNP-chips are now possible to purchase from Illumina for well less than $50 so this isn’t charitable.

At minimum a way to get a raw genotype you can bank later.