Penetrating the fog of 'penetrance'

In genetics there is a hoary old concept called 'penetrance'. It's not a definition of sexual success, so those of you who come to this post (no pun intended) with prurient interest should seek satisfaction elsewhere.

Penetrance is the probability that an individual has a specified trait given that s/he has a specified genotype. Usually, we think of the latter in terms of an allele, like the proverbial dominant A or recessive a in classical Mendelian terms in which genetics is taught.

Penetrance can range from zero -- the trait is never found in a person with genotype G -- to 1.0 (100% of the time the trait is present in persons with genotype G). If 'G' refers to an allele, that allele is called dominant if its presence is always associated with the trait, or recessive if the trait is present only in the absence of the other allele (in gg genotypes).

The key concept, that links simple Mendelian inheritance with general aspects of penetrance is that penetrance is almost always a relative term. The effect of an allele is always dependent on the other alleles in the individual's genome, as well as to aspects of the environment, and also to chance.

Sometimes things seem simple enough that we need not worry too much about these details. Very strong effects that are (almost) always manifest are examples. But when things are relativistic in this way, genetic inherency usually must take a back seat to a more comprehensive understanding.

The first step, and usually a difficult one, is to specify just what genotype you are referring to and, often even more challenging, just what phenotype (trait or aspects of a trait) you are referring to. To use the Einstein phrase that applies to relativity in physics, you have to be clear about your frame of reference.

This is much, much more easily said than done. Is 'heart disease' a useful frame of reference relative to alleles at some gene like, say, ApoE (associated with lipid transport in the blood)? We work with a colleagues, including Joan Richtsmeier here in our own department, who are concerned with craniofacial malformations. There are many such traits, including abnormal closure of cranial sutures (where bones meet in the skull). And, cancer is a single word that covers a multitude of syns (syndromes).

These are examples in which no two cases are identical. When that's so, how can we tell what the penetrance is of a mutation in a particular gene? Probabilistic statements require multiple observations, but also that each observation be properly classified (since probabilities refer to distinct classes of outcomes).

Since a given mutation affects only a single part of a single gene, it can be identified specifically (if, for the moment, we discount the mutations that take place within the person's body each time any of his/her cells divide). But traits can be variable and hard to define precisely, and the rest of the genome will vary in each person, even in inbred mice (because they undergo mutations). The amount of variation depends on the situation, but is very difficult to quantify precisely (recent work on genetic mutations in cancer begins to show this in detail, though we've known it in principle for a long time).

Most of the additional variation, not to mention purely chance aspects of development, homeostasis, and every cell's behavior, is unknown and much of it perhaps not even documentable in principle. Thus, in trying to characterize complex traits, we face real challenges just of definition, and much more so of understanding.

The same is true of evolution. An allele that has zero penetrance cannot be seen by natural selection. An allele with 100% penetrance is always 'visible' to selection in principle. But even there it has no necessary evolutionary implications unless it also affects fitness, that is, reproductive success. And that is another layer of causation with complex definitional issues, that we have written much about.

One bottom line is that just knowing a complete DNA sequence from some representative cell of an individual does not explain phenotypes, phenotypic effects, or evolution.

Aw, G! G-whiz! No G?

Well, according to the world authority on such matters, Salon.com, the crushing news has just been announced: there is no G-spot!

Given her history of dealing with the more sensitive subjects of sex, diarrhea, and halitosis (among others), I thought that our own special collaborator Holly would be the one to comment on this bit of hot research. But Anne thought it might be presumptuous of me to ask her such a thing. And Anne demurred, perhaps thinking that such a subject touched, so to speak, too close to home. So the task fell to me.

The G-spot for those who are uninitiated in the arts of female pleasuring, is a point in the vaginal wall that, when proberly (no misspelling here!) stimulated can lead to exquisite orgasms (for her, too!). But for some of the unfortunate of our better halves, this pleasure oasis doesn't seem to exist.

Cold fish? Just not interested in their partners? Can't really get into it?

Not so, say the experts! Yet another thing that turns out not to be her fault, despite our sexist accusatory society! What was thought perhaps to be a revelation for the new G-eneration of women turns out not to exist at all! It was a sex-toy vendor's scam. All those weird shaped twisting, vibrating, variously sized dildos: they're bunk (from this point of view, at least)!

It turns out that our more socially responsible citizens (university professors), who have to think of something important to research so they can get grants and promotions, did a twin study of the G-spot. Like searches for the Loch Ness monster, they delved deeply but came up empty handed.

More precisely, identical twins who are genetically the same, were no more concordant (didn't agree more) on whether they had the G-experience or not, compared to fraternal (well, sororal) twins who share only half their genes. Or, at least, whether they reported such G-ratification.

Assuming no confounding issues such as monozygous twins picking less knowledgeable partners than sororal twins, nor a strange kind of sibling ribaldry, there simply is no evidence -- at least no genetic evidence -- for the existence of Playboy's favorite playground. Conclusion: it's a myth.

G, that is sooo too bad!

Hey, wait a minute! What kind of conclusion is that? After all, a substantial fraction of women in the study did say they had one (G spot). And so said both kinds of twins! What the heck more do you want for evidence? So maybe this is consistent with a G-enetic reality, and has to do with the well-known variable expressivity of the G-ene, as with any other gene. Maybe the spot's bigger in some than others, or more trigger-happy. Maybe other women, wishing to uphold a demure image, deny what they experience to be true. Maybe they want their husband (or their mates) to feel put down as performance failures.

This relates to the genetic concept of 'penetrance' (no pun intended) that we will discuss in tomorrow's post. Having the G-ene doesn’t imply having the same amount of fun, except probabilistically (i.e., what's the probability that he'll get to the bottom of this phenomenon and figure IT out?).

What I think is the obvious answer to this question is: we need more research! Lot's more research! Maybe, like SETI (where everyone is asked to volunteer their computer to search for ET's in outer space), we can engage the whole population to search for ITs in inner space.

I think I've said enough.... Again, I think this is a ball for Holly or Anne to pick up.

Ken