A note on my piece in Slate

By Razib Khan | October 18, 2013 9:00 pm


Credit: 50% to Razib

Most of you are probably aware that I have a piece that was just published in Slate today, Which Grandparent Are You Most Related to? I’m not used to writing articles for the general interest audience, so I really appreciate Laura Helmuth’s feedback. All errors and confusions in the piece are mine, and there remains one major issue which I did not correct or refine to my satisfaction in the final draft. Michael Eisen pointed out on Twitter that my use of the law of segregation to compute the probability of inheritance from a single grandparent (50% of the autosome vs. 25% as expected) is misleading. I did include a section on recombination in earlier drafts, but couldn’t find a way to elegantly write about crossing over at length without become turgid. In the end I thought my reference to recombination was clear enough to allow one to infer that the true probability was much lower (close to zero as Michael notes), all the while maintaining the illustrative power in relation to the segregation in meiosis of homologous chromosomes. I was wrong, and hopefully this is will serve as a lesson in terms of how to hone my skill at balancing between opaque oversimplification and excessive technical detail. The empirical result of variation across grandparents was probably sufficient in this case.

  • Dmitry Pruss

    I think you handled the recombination question quite well – and BTW I noticed it because it appeared in Google news feed among editor’s choices, that’s impressive, man!

    Now it gives me a good place to ask a couple questions which lingered on my tongue after you pinned FC’s piece
    (http://www.fastcompany.com/3018598/for-99-this-ceo-can-tell-you-what-might-kill-you-inside-23andme-founder-anne-wojcickis-dna-r). Both are about testing infant daughters, and both children have minority ancestries with too few genetic studies done in them (South Asian, East African).

    Both authors dismiss ethical concerns about testing minor children for grave adult-onset conditions, just out of hand. Alzheimer’s? Breast cancer? Let’s take a look! Could you expound on it, please? Are you going to let your child know of a positive result (yours was negative, I know, but you were prepared for any eventuality, right?) At what age and in what settings? Have you considered a possibility that the progress of medicine will result in prevention of these genetic problems before your child is old enough to suffer from them? And lastly, I know that you and me and most our readers are all for sharing the genetic info, but don’t you think that some people will be adamantly against such sharing, even with their relatives, even decades from now – perhaps including your child? (My feeling is that the FC author was just ignorant, but that you must have weighed all these problems and planned for contingencies, and I would love to hear more from you).

    And very briefly, the minority ancestry issue. If a SNP is an indirect risk marker in population X, how often is it the case that the association still holds in a very unrelated population Y? And if a SNP is the direct cause of a clinical condition, then how often would it be a common cause in both X and Y? The FC author just unlocked BRCA results and concluded that her daughter isn’t at risk for breast cancer – although neither of the 3 tested alleles plays any role in hereditary cancer in East Africa,

    • razibkhan

      re: recombination. but you already know the answer (as do i). so you saw it. i do think it’s going to confuse a lot of ppl who don’t think in this manner.

      re: consent. it’s case by case. i think different people have different values and dispositions. i think we should leave it up the individual parents, like we do a lot of things. get rid of protections for christian scientist parents re: medical treatment in case law, and then let’s talk about personal genomics.

      If a SNP is an indirect risk marker in population X, how often is it the case that the association still holds in a very unrelated population Y?

      depends on how minor the allele is, right? for the stuff that’s large enough effect and frequency to get picked up in GWAS it looks a lot more portable than i would have thought 5 years ago (i would not have thought anything, because there wasn’t enough data).

      • Dmitry Pruss

        Of course the ethics depends on the viewpoint, on cultural background, on education. And formally speaking, 23andMe is intended for education / entertainment rather than for clinical use, which muddles the consent issue. And the consent for childhood-onset disease testing isn’t controversial. But I wanted to know how _you_ were going to handle the issue of unconsented disclosure _specifically_ for grave adult-onset genetic conditions for which the test has a strong predictive value.

        >for the stuff that’s large enough effect and frequency to get picked up in GWAS it looks a lot more portable than i would have thought

        Could you give some good examples? I first thought about a SNP in angiotensin gene which predicted hypertension in both white and African Americans, but then I bit my tongue because the derived risk allele turned out to be nonexistent in Africa, and a European admixture in African Americas.

        • razibkhan

          my wife and myself are both into maximal information. we can’t predict how our offspring is going to be, but values and genetic dispositions toward values are both heritable. so we’ll sequence and divulge as soon as she is capable of grasping things if there’s an issue.

          re: GWAS:


          this is not an isolated paper, but 2013 so it is up to date. my prior is assume it is predictive in other populations, weighted by inverse of genetic distance.

          • Dmitry Pruss

            Interesting GWAS comparison, thanks. If taken by face value, it would mean that about half of the SNPs predictive in Europeans are still predictive in East Asia, but very few work in African Americans. That despite the fact of substantial European admixture in the latter, implying that the overall effect of the ancestral African causative variation is much stronger. The paper discusses LD islands as a possible explanation of partial sharing of predictive marker in Europe and E Asia … but to have half of the markers in, sort of, ROLLOFF-defiant segments is unexpected. The paper also briefly touches on biases of publicability as a possible cause of replicating East Asian studies. They dismiss this concern, but I think that they are too quick in their dismissal. IMVHO much of lower-quality publications from East Asia are not just biased, but fudging the data. I personally saw studies where AFs and phenotypes in the cohorts changed from paper to paper. I also personally knew a DNA purveyor who changed recorded phenotypes of the subjects with each collaboration (and since her samples were drawn from genetically dissimilar ethnic minorities, it was a guaranty of association (pos or neg) every time)

          • Dmitry Pruss

            PS one of my fav examples of China Association Factory has _not_ been replicated in Europe, but only because its authors didn’t seek to replicate a European study. The gene is BRCA2 btw. But it is still highly cited – not too long ago, I had to placate a very unhappy investigative journalist, who sent blood samples to 23andMe, two more similar outfits, and a clinical testing lab. One of his reports highlighted a BRCA2 SNP which has been “shown to associate with cancer” in an obscure Chinese study; but “strangely”, the clinical lab didn’t have it on the report. The variant in question has almost perfectly 50% AF in Europeans, and isn’t far behind in the Chinese too, in case if that tells you something :)

          • razibkhan

            yes re: chinese papers. sad.

            re: SNP generalizability, some of it might be LD. but let’s keep in mind that out-of-africa share 90+% of their genomes from ~1000 ppl who left in a punctuated event (de facto punctuated event). the genetic distance to africans is higher, so it makes sense that you’d have a lot less bang for the buck in these populations with SNPs ascertained in one of the non-african groups (usually europeans).

            but the idea of portability is important for me, since i’m about 50% ‘europeanish’ (west eurasian). so i weight the GWAS appropriately.


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About Razib Khan

I have degrees in biology and biochemistry, a passion for genetics, history, and philosophy, and shrimp is my favorite food. In relation to nationality I'm a American Northwesterner, in politics I'm a reactionary, and as for religion I have none (I'm an atheist). If you want to know more, see the links at http://www.razib.com


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