Better off dead

A recent paper on the origin of sickle-cell was being discussed, and an interesting question was posed [ by Razib Khan]: why haven’t modifier genes emerged that reduce the bad effects in homozygotes?

Let me say something about those bad effects. The most important one is that someone with sickle-cell disease usually has a ruined spleen before the end of childhood – infarcts. This enormously increases the risk from encapsulated organisms like pneumococcus: in a place or time without effective medical care, this kills you. There are all kinds of other problems that eventually show up if effective medical care gets you over that first hump, but in the past, and in many places today, kids with sickle-cell diseases usually didn’t make it past two.

What about a mutation that led to a milder form, one with the same positive effects in heterozygotes but that that killed homozygotes at age five, instead of two? It would not be favored by selection: five year olds don’t produce any offspring, and they use up more parental resources. Killing homozygotes rapidly (as opposed to slowly) increases the fitness of the sickle-cell allele – it lets the parents start over and produce another kid, who might be a carrier.

There’s a malaria defense in Southeast Asia, Melanesian ovalocyosis, that goes all the way – homozygotes die before birth.

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10 Responses to Better off dead

  1. Ursiform says:

    So the best endpoint is never seeing a homozygote nor knowing what would go wrong.

  2. RCB says:

    More generally, isn’t it also true that evolving resistance to mosquito-borne pathogens is just inherently hard, because the pathogen is also evolving? Particularly, a mosquito-borne pathogen doesn’t need a healthy person walking around to spread the disease – the mosquito takes care of that. So high severity isn’t much selected against. (I’m plagiarizing Ewald.)

    • JP says:

      If the population density is low, the mosquito may have difficulty finding a person.
      I understood that although malaria is an ancient disease, it got a lot worse with agriculture, because the population density increased so much.
      If you reduce the effective population by using mosquito nets the diseases would attenuate, or the mosquitos would evolve to bite you during the day.

  3. Ilya says:

    Wouldn’t it be even more advantageous though to kill the baby even earlier, say, at few months old? Or, better, while a fetus?
    It looks like selection still had some ground the cover, to optimize the process.

  4. Jack says:

    Is there likely much miscarriage “with intent”?

  5. Philip Neal says:

    Retinoblastoma. Why are there survivable, dysgenic, childhood cancers at all?

  6. GAGCAT says:

    Reminds me of this story:

    https://en.m.wikipedia.org/wiki/Abraham_Wald

    One of the problems that the [WW2 statistics group] worked on was to examine the distribution of damage to aircraft to provide advice on how to minimize bomber losses to enemy fire. There was an inclination within the military to consider providing greater protection to parts that received more damage but Wald made the assumption that damage must be more uniformly distributed and that the aircraft that did return or show up in the samples were hit in the less vulnerable parts. Wald noted that the study only considered the aircraft that had survived their missions—the bombers that had been shot down were not present for the damage assessment. The holes in the returning aircraft, then, represented areas where a bomber could take damage and still return home safely. Wald proposed that the Navy instead reinforce the areas where the returning aircraft were unscathed, since those were the areas that, if hit, would cause the plane to be lost.

    The genetic equivalent of missing bullet holes are high frequency heterozygous variants that have never been seen as homozygous in anyone alive.

    Following up on any results requires $$ of course (long read confirmation to make sure het calls are not a mapping artifacts, mouse models, etc etc)

  7. Martin L. says:

    Greg, this is a slight bit of tangent but I want your thoughts. You’re politically incorrect and a true clinical thinker–what do you think of my theory that fibromyalgia is a selected trait for childhood survival? A mother with fibro is going to be much less able to leave the nest on a whim and put her children at risk of who-knows-what. She is forced to stay at home with them.

    This is also why I believe asexuality in women is relatively common. An ace woman is going to be fully devoted to raising her family and not distracted by chasing after strange men–who either could do her and her children grave bodily harm outright, or which could lead to severe retaliation (most traditional cultures don’t look too fondly on female adultery).

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