13 September 2011

"The stamp of one defect": an endless series on harmful mutations

Not surprisingly, Hamlet weighed in on the nature vs. nurture question, at least once.

So, oft it chances in particular men,
That for some vicious mole of nature in them,
As, in their birth,―wherein they are not guilty,
Since nature cannot choose his origin,―
By the o’ergrowth of some complexion,
Oft breaking down the pales and forts of reason,
Or by some habit that too much o’er-leavens
The form of plausive manners; that these men,
Carrying, I say, the stamp of one defect,
Being nature’s livery, or fortune’s star,
Their virtues else, be they as pure as grace,
As infinite as man may undergo,
Shall in the general censure take corruption
From that particular fault: the dram of eale
Doth all the noble substance of a doubt,
To his own scandal.

Hamlet, Act I, Scene IV, The Oxford Shakespeare

It is certainly true that "the stamp of one defect" can wreak havoc on the scale that Hamlet describes, and whether the result is a debilitating physical limitation or damage to "the pales and forts of reason," the outcome is tragic by any measure.

Reflecting on the reality of inherited dysfunction, we might be tempted to assume that a "vicious mole of nature" is something seen only "in particular men," and that those who are not so characterized (let's call them "normal people") have been dealt a genetic hand that lacks such devilish cards. Normal people don't have bad genes.

Okay, so in the real world I suspect that most people are not so naïve; if you're reading this blog, then you probably know that bad genes can be carried by normal, healthy people. Nevertheless, when we think about bad genes – or more technically, deleterious mutations – we are likely to think that they are not very common.

There is at least one good reason to assume that deleterious mutations are uncommon in the human gene pool: good old-fashioned natural selection. Deleterious mutations are eliminated from every gene pool by natural selection, and everyone knows that. Given that this fact is both obvious and widely known, it is likely to be a surprise to many people to discover deleterious mutations in any significant frequency in any population anywhere.

But in fact, deleterious mutations are ubiquitous in populations of all sorts, and they don't necessarily go away just because they're harmful. To assert or imply (as many regularly do) that a deleterious mutation cannot be maintained in a population is to oversimplify a basic principle to the point that it becomes badly misleading.

But how? How can a harmful mutation remain in a population? Consider this list of possible explanations, which are not mutually exclusive.
  1. The mutation is only harmful in certain circumstances (e.g., certain environmental conditions or certain combinations of other genes) and is invisible or even beneficial in others.
  2. The mutation is only harmful when present in two copies, and is invisible or even beneficial when present in one copy.
  3. The mutation exerts its harmful effects after the organism has reproduced.
Now, that list doesn't seem to take the problem seriously enough. It's a list of reasons why the mutation isn't really harmful; instead, the gene is conditionally harmful or its harmful effect is irrelevant from an evolutionary perspective.

Here are some more interesting possibilities.
  1. The mutation is truly harmful, but the population is (or recently was) quite small and so natural selection acts less intensely. Put metaphorically, the population "tolerates" the deleterious mutation because it doesn't have a "choice."
  2. The mutation is truly harmful, but in previous generations it was beneficial.
  3. The mutation is truly harmful, but it comes as a package deal with something else that is beneficial. The net effect is positive.
I think that list covers just about everything. Explanation number 3 isn't very interesting, so we probably won't come back to it very often. Explanation number 5 is a special case of number 1, in which the environment has changed permanently.

That's the overview. This post serves as the introduction to an open-ended series on deleterious mutations, and the debut for two new tags: "deleterious mutations" and "bad genes." The next post in the endless series will discuss a new paper in PLoS Genetics, which presents evidence for "hitchhiking" of deleterious mutations in humans. That sounds like a risky business, now doesn't it?

Image: Kemble in the role of Hamlet, standing on a grassy bank wearing a long cape edged with fur and a large feathered hat on his head; he is holding a skull in his hand. Engraving after Sir Thomas Lawrence. Courtesy of Wellcome Images.

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