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.

The death of privacy: an anthropological perspective

For most of the world's creatures now and ever, life is a naked phenomenon. Organisms, their phenotypes and their behavior, were lived entirely in the open. Mating, selection, survival and so on all occurred that way. Those were the kinds of groups in which we too evolved as a species. So, how did privacy become so important to us? We can imagine a scenario; human history at warp speed.

For tens of thousands of years, predominantly small ancestral bands of close kin made their living by hunting and gathering, dwelling around a camp (and, eventually, a campfire). Local groups moved around frequently, abandoning sites and finding new ones--for example, to follow food resources. All must have been public, and basically nothing private. That included the shared and basically equal nature of material possessions, as well as the nature of each person's physical and behavioral traits. Everyone was related to everyone else, in known (indeed, prescribed) ways. It was, perhaps, a gossiper's heaven, since everything was known about everyone by everybody.

Over thousands of years, especially after the implementation of agriculture 10,000 years ago, large, permanently settled but no longer kin-based populations became our environment. Individuals increasingly lived in isolated nuclear (or perhaps 3-generation) families in separate dwellings. They acquired and could accumulate personal possessions, largely interacting with people unrelated to themselves in any known way. Close relatives knew a lot about their own affairs, but less about others'. Society became more unequal, and people developed increasingly private lives, as we know them today.

Very large societies require administrative structures (governments) for protections of all sorts, and to avoid the chaos of conflicts of interest and personal conflicts. This includes the protection of individuals' privacy from intrusion by others (which we name 'crime'). Industrial societies, at least in part because of the growing inequities they developed, came increasingly to recognize personal privacy, including ownership, as important or even fundamental.

Disputes, that traditionally were settled by the families involved, or by a local strong-man, became society's business, with standardized codes of acceptable behavior and of sanctions for violations, that is, laws. Probably beginning with property, society protected individual possession as well as individual rights not to disclose possessions.

Humans build their emotions and belief systems around their ways of life. So, associated with these societal privacy traits were senses of outrage or embarrassment if the traits became known. They may make a person vulnerable to social or material risks, by revealing weaknesses, or his deceits, greed, and the like.

Personal traits including health became largely private unless revealed by the individual or family, but physicians necessarily had to know. As a result, even in the Hippocratic oath around 2400 years ago, physicians promise that

"All that may come to my knowledge in the exercise of my profession or in daily commerce with men, which ought not to be spread abroad, I will keep secret and will never reveal."

There are many obvious reasons for this. The healthy could easily take advantage of the sick or even of health risks they know such people may face. Relatives would perforce know a lot, but could be trusted, at least comparatively. In modern times, the obvious reasons for health privacy include the possibility that disease may be used to discriminate against people in various ways (jobs, insurance, etc.), and this would go against the legalized sense of things-that-are-nobody-else's-business.

Medical genetic data on their surface can be viewed simply as another source of diagnostic or therapeutic information, like blood pressure or 'where does it hurt?' But there are several basic differences:

1. Genetic data about a person are also informative about his/her relatives
2. Genetic data can be informative about any of the person's characteristics, not just the currently-presenting disease, and including normal as well as disease traits
3. Genetic data may be of predictive value about a person's future, in a way that vested interests can use to discriminate among people to their detriment and the gain of the discriminator (e.g., HMO, insurer, employer, pension plan). Even police and the military get into the act in many forensic, security, or other ways.

It is for this reason that many are concerned about privacy issues in relation to 'personalized medicine' which, at its core means computerized storage and analysis of DNA sequence data for the purposes of assessing existing or potential phenotypes of the individual (not just a group).

There are many professional bioethicists thinking about this, as well as lawyers, journalists, legislators, and scientists. Indeed, we ourselves are happy to be helping train a graduate student who is both knowledgeable in modern genetics and a practicing lawyer. She should be an unusually qualified individual to help as society negotiates between science, society, and the law.

A lot of worry is being expressed, some of it professional angst (making careers out of the issues), given that it seems wholly inevitable that, barring some gross national trauma, personal DNA sequence data bases are inevitably going to proliferate. Unless we get bored with genetics, our technological age is in love with DNA and is widely embracing it, both to great profit and because of the accepted promise of major health advances.

Much of this debate is moot because the lid certainly cannot be kept on such a bottle. Data bases will increase, become more shared, computerized, coordinated, public, and difficult to contain. Interpretation of all sorts will accompany that growth. More and more people will learn more and more about more and more people--or at least will think they did.

How far this goes nobody can know, but it may be most useful to think ahead and stop knotting one's stomach about the details of regulation. Let's do something that is probably more useful to think about: let's assume that everyone's complete DNA sequence and its interpretation is entirely public, and can be known to anybody who wants to look. Let's further make the au courant assumption that DNA is the deterministic causal blueprint for who and what each of us is.

Such changes are to a great extent likely to occur, and in a way they spell the death of much of the sense of privacy that we have lived with for the roughly 10,000 years since the dawn of settled agricultural societies.

Younger generations will be born into this system, after us grouchy old goats pass the scene. For new generations this will just be how things are. The effects of such data, and how they're handled, will be worked out--fallibly, imperfectly and with abuses, as always in human affairs. But we will work them out! We know that, as humans, we can live publicly naked lives. That doesn't mean we can do it free of trauma, and history does not suggest we'll always do otherwise. In a sense, in regard to this particular issue, in shedding our privacy clothes, we'll be going back to our beginnings.