My dogs' evolutionary history. Part 3: Inside scoop and why

Recall that we ordered DNA testing kits for our mutts. First we made predictions, then we revealed the results. Today I want to tell a bit more of the story...

yawn

Remember that time a doctor used a vibrator on my hips because I had a cyst on my knee? I was all into it "for science." It was an opportunistic science sting operation. There was totally gum on my shoe. There was all kinds of pseudoscience that day.

Anyway, I was all psyched up for that sort of Dateline-style, hidden camera intrigue when I called up Mars Veterinary, the people who do the analysis for Wisdom Panel doggie DNA kits, last Friday afternoon. I was all psyched up because, as Kevin said, I needed, "to make sure they're not defrauding people."

Me? I do? Little old me?

That sounds about right. I mean, just because I can see all the educational potential here doesn't mean I should be endorsing it without understanding it better. And while I'm understanding it better shouldn't I make sure they're not entirely full of s--t?

But I already know they're not full of s--t because they gave us results for both Elroy and Murphy that made sense. They didn't report crazy results and there are lots of ways they could have... there are 200 breeds on that list, most of which do not look like our dogs or like they've wafted their DNA anywhere near our dogs.

So, they can't be completely fraudulent. Whew. Okay then, less of a burden on me for this interview. But wait. Could it be maybe a little more nuanced, this hypothetical fleecing? After all, they're the ones who saw my blog and reached out to me to have an interview--isn't that a little big brothery? And, after all, their website doesn't tell us what their methods are, not really, not for those of us who have ever operated a PCR machine or run a gel. And they don't tell us what these markers are in our dogs' reports that led them to make the reports. I'm used to having too much information, even, because of 23andMe.

Anyway, there were all kinds of reasons to be professional when I called up the veterinary geneticist. But after she answered my first question so well, I pretty much lost all professionalism and drooled all over her, albeit through the phone.

Here's what I learned. Please bear with me... I didn't take direct quotes because (a) that's hard to do without a hands-free headset (or fancy recording software I don't have because I never needed), and (b) I got a wee bit excited and flailed my arms most of the conversation. 

All questions and answers are my paraphrasing.

Question: Are you using a chip or what? How are you genotyping?

Answer: A chip like 23andMe's isn't cost effective. Yes, there's a chip but it's not specific to the test. They use a sequenom platform. It's PCR markers combined into panels.  They run those PCRs for 321 markers, broken up into several panels, optimized so that they don't interfere with each other clearly and don't have to change primers. They use nested PCR for segmenting around the mutation and then to get the exact SNP they throw the DNA in a mass spec to find the particular A, T, C or G mutation. Each has a different weight, so each can be identified. 

Question: Do you get both alleles from that?

Answer: Yes. They don’t sequence in both directions but they sequence both chromosomes.

Question:  Are those 321 markers for visible or perceptible phenotypes? 

Answer: No. None are visible phenotype. They're ancestry markers/SNPs.

Question:  Have you found any dogs that have none, not one, of those breed markers?

Answer: No. And we don't expect to. But it's not completely out of the question given the spectral nature of variation over space and time. 

Question: How did you validate your mixed breeds family tree methods? Do you have mixed dogs with known parents and grandparents and type them all in the family?

Answer: The pure breed tests validate so well already. And also, yes, they do validate with mixed dogs with known heritage but not many. The methods are built out of Ostrander's research with 85 breeds, 5 dogs from each and 96 microsatellites. She licensed the patent exclusively to WisdomPanel. 

Question: How do your mixed breed reports compare to how people guess based on external cues? Aren't people already good at guessing their mutts ancestries?
Answer: Actually they're not. Ancestry DNA testing is much better. People aren't that good at guessing mutt ancestry based on phenotype, as far as the few studies suggest. (There's one by Victoria Voith that I want to check out and there's one by Levy on pitbulls specifically.)

***

We chatted for much longer than that and she shared all kinds of interesting information about genetics for dogs' visible traits and also lots about their reproduction which I'm keen to learn about. But that right there's all the relevant information regarding our doggie DNA testing experience that I got during the 30 minute phone call. She was completely open with me about everything which is why I'm kicking myself that I forgot to ask why they require the dog's weight when you submit its cheek swabs. I have a hunch, however, that it's got something to do with validating their mixed breed body size estimates given how many people use WisdomPanel on shelter puppies that will be better adopted if their projected size is known. 

So the question remains... If you don't have a puppy or don't care what it will grow up to look like or be like, why do Wisdom Panel? 

The promotional video on the homepage sums up why many people might do it: 

I wasn’t sure what my dog was made up of...Pretty sure she wasn’t just a [breed name]...I wanted to know so I could tell people when they ask me 'what kind is she?'

This is fascinating.

Why do we care where our dogs come from or what kind they are? Same reason we care the same things about humans and ourselves. And it all boils down to the fundamentals of the field of anthropology... and it's complicated.

And finally, why have I titled all three of these posts "my dogs' evolutionary history"? Because evolutionary history is a synonym for family history and for ancestry. And vice versa, all around. And, clearly, I'm trying to make a point about that.

When you type "evolution" into the Wisdom Panel website search, this is what you get:

But that's not going to stop me from using this to teach evolution. I've decided that Wisdom Panel will be a good alternative for students who aren't interested in doing 23andMe in my anthropology courses, so I'm going for it.

Dogs, humans, what's the difference?  A lot and not.

http://evolutionpsa.tumblr.com/

23andLess

A new report out of 23andMe suggests that one can learn more about risk for common traits from relatives than from individual DNA sequences.  The fact is about as surprising as a sunrise, and has been known for a long time (as has the reason for it).  Acknowledging this sounds more than typically forthcoming from this company, but they do put their own spin on it, saying the combination of family history and the kind of genetic risk estimation they sell is best.  Family history predicts common diseases and risk estimates the rare ones. 

The reason that family history is so predictive is quite simple: family history integrates all your relatives' genetic variation to reveal, at least within their respective environmental contexts, the net effect of that variation.  You inherit half your variation from each parent (given some reasonable assumptions), so the net risk experienced by your parents is much greater than that likely to be predicted from a single variant in a single gene in your DNA sequence.

Several papers have shown this in various ways.  A clever one a few years ago noted that Francis Galton's family correlations from Darwin's time (he was a cousin of Darwin's) provides a better prediction than modern genotype sequencing.

We might be expected to revel in this confession by 23andLess, since we have criticized this whole endeavor of personalized genomic medicine as a bit of snake-oil selling.  Of course, there are countless variants that for some generally rare, mostly pediatric traits are highly predictive.  Companies can provide this information if you have these variants, but even then unless they are recessive in their effects, if you have the gene you'd already have the disease or trait.  For decades there have been honorable practitioners, called genetic counselors, who worked within medical schools generally and were carefully licensed to do this.  They identify known genetic risks and advise about recurrence risks and the like.  But they were professionals, working with physicians, not hustling to the public for corporate profit.

At the same time, let's step back and ask about the idea of family risk.  If that's based on genetic variation (that is, if you filter out environmental effects), then certainly your DNA sequence would contain the variants involved!  That means that, properly done, sequencing should be able to identify the variants that account for your resemblance to your parents. But studies to date have shown that variants identified by GWAS and other approaches only account for a small fraction of the parent-offspring correlation. That is the gist of the current report, stated in another way.   The issue, then, is how to identify what's causal and what isn't, among the huge amount of DNA sequence you share with any individual relative.

Various authors have made suggestions. Some say the problem is that each of us is affected by one or more very rare variants and even if you carry the same from your parent, finding it in a sea of sequence data is nigh impossible.  Authors favoring the rare-variant idea are trying their best to devise such methods.  One is to look at multiple close, affected relatives and winnow down the shared amount to the part that's actually causal.  Another prominent group is trying to argue that it is not the sum of individual genetic variants that determines risk but that interactions among variants is what contributes to risk.  This is a statistical nightmare to work out, but if it were true it would mean that we really have already identified the variants in question, but not the way they interact.

The most likely truth at this stage is that such common traits like heart disease or how tall or heavy you are, are determined by a very large number of genes, mostly with individually very small effects.  Each person with the 'same' trait--each diabetic, say--has that trait for a different genetic reason.  Individual genetic variants may be causal contributors, but they are not very important.

If this is so, and we could find a way to document the individual effects, we could use each person's genome sequence to tally up all their particular set of risk variants and compute their risk, even if specific approaches usually couldn't be tailored to his/her specific risk set.  In essence, we would gain nothing but a usually false sense of precision by doing so.  We'd be just as well off, in practice, to look at family history (or even more so, directly relevant risk traits like glucose levels, obesity, etc.).  And this is under the assumption that we know of or don't have to worry about, environmental effects.  That is a huge can of worms that everyone is just conveniently ignoring.

The same, by the way, applies to attempts to identify or characterize traits in terms of genes responsible for their adaptive evolution--and for essentially the same reasons.