Wednesday, May 4, 2011

The Earwax Trait Story

My first post related to 23andMe is going to be about something near and dear to my heart: the earwax type SNP rs17822931! Before I start, let me say that I do have wet earwax. Yes, I'm carrying the CC genotype at rs17822931. Not a big shocker considering I'm of 100% European descent.

You may wonder why this particular variant and trait is important at all to me. The real reason is because when I taught human genetics at UCLA, we used the original Nature article as an example of a "modern" genetic study. The students read it and (hopefully) found it interesting to learn that a single SNP (rs17822931) was dictating whether they had wet or dry earwax.

In fact, most of the students were basically unaware that there were two types of earwax! At UCLA, we had students of all different ethnic backgrounds, and it turned out about half of my class had dry and half had wet earwax. That should give you a hint at the ethnic mix there.

Anyway, the point of this post is to explain why, before jumping the gun and shouting that you have dry earwax when you have a CC at rs17822931, you should consider whether or not you're accurately self-diagnosing it, and then why you might have dry earwax when your genotype says you should have wet.

I remember clearly that one student of European descent claimed to have "dry" earwax. She may have (it's not impossible), but another student wisely pointed out something in the paper that may explain why she thought she had "dry" earwax.

In the original study that identified this variant as the one causing the Mendelian earwax type trait (Yoshiura et al., 2006), they explain that they actually had to use two different groups of patients to identify the variant.

The first group consisted of 64 "dry" and 54 "wet" control individuals. This group was "self-declared", meaning they basically checked off a box stating whether they had wet or dry earwax. This first pass group resulted in inconclusive results. Basically, they narrowed down the region with this group, but found some "phenotype-genotype inconsistency" in some of the samples and could not therefore narrow down exactly which was the causative SNP.

So they followed up with an association study on a second group of 126 individuals (88 dry and 38 wet) whose earwax types were identified by a medical practitioner.  In this set, 87/88 individuals with dry earwax were AA. All 38 with wet earwax were GA or GG.

That one GA individual with dry earwax turned out to have a deletion in exon 29 of the ABCC11 gene (downstream of rs17822931 and his G allele).

So this really teaches us two things:
1) Self-diagnosis is not accurate. You may have wet earwax and not know it! Just because it's flaky and seems dry to you does not mean it is dry earwax. And vice-versa.
2) Other mutations do exist! In this case, particularly if you are CT but truly have dry earwax, it's possible you're carrying around a secondary mutation not unlike the unique case in the original paper. It's exceedingly unlikely a CC individual would have such a secondary mutation damaging both alleles without some sort of inbreeding, though, so... keep that in mind if you're going to claim #2 with a CC genotype.

Much of this could be said for nearly any trait determined by SNPs, but the earwax trait makes a convenient real-world example of a simple trait where ascertainment problems (basically, the inability for the layman to know what his true trait is) and the rare secondary mutation can cause perceived discrepancies.

More in-depth stuff on my own 23andMe experiences as I go through them. So far I'm having a blast.