Saturday, August 18, 2012

Humans are a mess

We are full of significant mutations... maybe the GOP has an answer.

Two recent papers describe the partial sequencing of thousands of human genomes. What did they find? We are a mess, full of genetic variations (i.e. mutations). Far more variations than a typical population of our size. Their conclusion is that the explosive population growth we have experienced over the last ~ 5,000 years has allowed the accumulation of a large excess of deleterious mutations, compared to the more stringent selection that would have happened if our numbers had stayed more constant.

The population history of humanity is that Africans have the most diversity, Africa being the origin and home of our species. Various migrations out of Africa, to Europe, Asia, and Australia, happened in small groups; small sub-sets of the genetic pool available in Africa, thus constituting bottleneck events that reset genetic diversity in those new regions to low levels.

These papers continue a story that has been developing since the first human genome was sequenced in 2000: the hunt for human genetic variation, which accounts for much of the diversity of the human body and mind, in sickness and in health. At first, researchers set up huge projects to find common variants and link them to common diseases. The idea was that perhaps there was a "gene for" heart disease, and "gene for" cancer, and the like, and that a few common variants in those key genes would explain most disease susceptibility. We could make up a few diagnostic kits, predict everyone's future, and voila- molecular medicine would arrive.

Well, needless to say it was a bit more complicated and they were making a false virtue of the limitation of primitive sequencing technology. As mentioned previously, elementary evolutionary theory would have told them that common variants are common because they don't have strongly deleterious effects- they can not be responsible for a significant disease burden, because if so they would be selected out of the population.

Now we are to the point that thousands of genomes can be substantially sequenced without too much trouble, and these papers discuss the rates and nature of the rarer variants that come out of that analysis. Variants that can have much stronger effects on disease. In the limit case, an embryo gets a fatal mutation that prevents it from being born at all. Next up would be a less-than-fatal birth defect that may not prevent life, but does prevent reproduction. These kinds of variants never propagate in the population at all. They arise and die immediately, and are thus vanishingly rare.

So there is a sliding scale of mutations, from harmless ones that propagate by random drift in the population, not being subject to any selection pressure, to deleterious ones that get selected out (by "purifying" selection) at a rate directly related to how bad they are (their effect on "fitness").

The current projects tried to estimate the harmfulness of their observed variants in two ways. One was by comparing synonymous and non-synonymous mutations in protein-coding genes. The universal genetic code has 64 three-letter codes for 20 amino acids, so some of the codes are interchangeable, i.e. synonymous. Thus some mutations in a protein-encoding gene have no effect, and comparing those to the ones that do change the resulting protein gives a measure of the strength of selection in that area of the genome, and on those variants.

The first paper is titled: "An Abundance of Rare Functional Variants in 202 Drug Target Genes Sequenced in 14,002 People". They find a direct relation between the frequency of a variant in the population and its likelihood of being synonymous, which is to say that it would have very low or no effect on the organism.

The frequency of variants in the samples genomes (x-axis; singleton means it happens once in the whole data set, doubleton twice, etc., MAF = mutant allele frequency) relates inversely to their likelihood of encoding a change in a protein (non-synonymous; NS), vs a synonymous change (S) (y-axis).

But.. both groups mention that that the rate of rare and damaging mutations is unexpectedly high in the human populations they sample, traceable to the recent phase of exponential growth with relatively weak purifying selection.
"On average, individuals possess between 318 and 580 predicted functional protein-coding SNVs [single nucleotide variants] depending on how functional variants are defined."
"In particular, the vast majority of protein-coding variation is evolutionarily recent, rare, and enriched for deleterious alleles."
- quotes from the second paper, entitled "Evolution and functional impact of rare coding variation from deep sequencing of human exomes." Here, "deep" means they sequenced a lot of samples, and "exome" means they only sequenced coding part of genes, not promoters, introns, other control regions, or other junk of the larger genome.
The second paper performs a more complicated estimate of which variants might have real effects on the organism, affecting coding areas with known function, conserved domains, etc. They provide their counts in an elegant "fiddle" plot:
Plot of the frequency of mutations in putatively functional positions. European-American genomes (EA) and African-American genomes (AA), under more (dark) or less (light color) conservative models of what constitutes a functional mutation, using definitions that extend beyond simple synonymous/non-synonymous coding to take into account the known function and centrality of the affected protein and site, and other factors.

This in a genome of only ~25,000 genes. So we are perpetually skating on thin ice, accumulating deleterious mutations across the population that maybe don't get discarded so rapidly under the less-than-stringent conditions that we have experienced over the last few thousand years.

What to do? Our heroic desire to save every premature infant and fix every birth defect shouldn't blind us to the virtues of the selective process over the long haul. On the other hand, diversity is the seed bed not only of cultural vibrance, but also of evolutionary success. That is why scientists have adopted the more neutral term "variation" vs the pejorative "mutation". Just because a variant is in the majority doesn't always make it better.

In times past, there were often very severe selective conditions on human populations (however deficient in the view of these studies!). The battle against nature was far more dire. Disease killed most children, and eventually most adults. Injury or accident didn't mean a trip to the friendly orthopedic surgeon, it meant privation and often starvation. On the positive side, social success in group politics tended to lead to reproductive success, most flagrantly shown by the vast harems kept by the kings of yore. Genghis Khan is thought to have spread his Y chromosome to 8% of the men of Asia.

More recently on the political scene, we have switched from royal hereditary leadership, with its seat-of-the-pants theory of genetics and hereditary merit, to a more or less wide-open functional meritocracy. But critically, it is one where converting one's social success into reproductive success is frowned upon, to say the least. Our fixation on the peccadillos of politicians goes very much against (their) nature.

However, the fact is that a great deal of purifying natural selection in humans still takes place, and most of it happens before birth, in failed conceptions, failed embryos, and stillbirths. This is where unfortunate combinations of all those mutations that these researchers have uncovered are discarded, like bad hands dealt in a card game. This is where sexual reproduction shows its power, as a way to re-deal out genetic hands every generation, allowing some to win, and others to fold, discarding deleterious genetic variants where they become fortuitously concentrated.

So the idea that some eugenic program of Spartan inspection and destruction of newborns is going to do much for our genomes or posterity is fundamentally flawed. But the question of mental capabilities- that is a much more delicate and significant one. Intelligence and other characteristics like temperament, emotional warmth, social skill, artistic ability, even religiosity, are heritable to some degree (though hardly enough to make hereditary nobility a reliable proposition!). These characteristics only become apparent later in life, and have through human history been under much stronger positive selection than they seem to be today.

The main force is probably mate selection- who wants to marry a dolt? Reproduction has generally been the reward of good behavior, and other forms of maturity and success. Now such selection is substantially weaker, as we have outlawed polygamy and frown on other linkages of personal and reproductive success, in an effort to become a more equitable and fair society (fair among men, at any rate). Success is less genetically rewarding. Perhaps that is why the monetary rewards of success have come to be fought over with such unthinking abandon- as a faded remnant of what real success would look like.

That is where I would guess the GOP is going with its Ayn Rand, class warfare campaign. The morality of rewarding the rich and throwing the poor and unsuccessful overboard is that fundamentally, money equates with moral goodness and just deserts. It is a Darwinian proposition where success should be rewarded and lack of success punished. Even if that success was fed by a silver spoon or based on a century of attachment to the government teat, as in the case of the Ryan family. Even if the culture of the moment links the most psychopathic behavior and values to financial success. Wealth is what we worship and should worship, as the premier metric of human value.

The idea that the US might fail to reward the rich enough to run the country in every political, economic, and social sense seems deeply disturbing to the Republican party. But there is more to it. There is a racist element in addition to the classist one; a feeling of entitlement, despite all the lip-service to "equal opportunity". A strong dedication to keeping opportunity firmly in its traditional bounds. The refrain of the country "being lost" and needing to be "regained" is clearly of this sort. Romney's recent bizarre attacks on Obama for inappropriate kindness to welfare recipients fall into this category as well- substantively groundless, but strident dog-whistles with racial meaning. In short, the Darwinian proposition extends to reproduction, that America should remain white, pure, Christian (in the white sense, which now tolerates Catholics, even Mormons, with some grumbling!). It is a population genetic proposition, as well as a political one.

While it is obvious that some degree of meritocracy and reward for success is essential to run a society that is collectively successful in its pursuits, the question is whether we need to go back to a nature-red-in-tooth-and-claw sort of world either to run a working society, or to insure the flourishing of human genes into the future. And there is always the question of what constitutes human merit, in the most ultimate sense.

A recent radiolab podcast marveled at how radiation-resistant humans are, focusing on one Japanese man who survived close calls with both nuclear bomb blasts in world war II, yet went on to have more or less normal children. Wider studies of Japanese survivors and others exposed to radiation have reached similar conclusions. As I mentioned above, most selection takes place before we can even see what is going on- in utero. So the radiation dose is just added to the pile of the many mutations we have anyhow, the bad combinations are discarded, and the better combinations go on to live and reproduce.

So I think we will be OK. The exponential population growth of humanity is over in any case, though whether we enter an apocalyptic population crash due to resource and biosphere constraints remains to be seen. We don't need a politics/economics of fake success and unjust rewards to forge a better future. We need to nurture human diversity and cultural richness where many forms of success are valued- are employed, paid, and supported by our collective prosperity. The leading symbol of Mormonism is, after all, the beehive, not the private equity fund.

  • Christian Kansas, becoming "Brownbackistan". But do the Kochs care about abortion? Probably not. They care about crazy.
  • Books about natural selection and cooperation.
  • What has happened to common purpose?
  • Robots on Mars have message for humanity: government works.
  • Romney- pot calling the kettle black department.
  • Paul Ryan's selective concern about federal power.
  • The real record at Bain.
  • Unemployed continue to get the shaft.
  • The worthiness of Obama, and the unworthiness of Republicans, continued..
  • Sarah Vaughan, misting up.
  • Economic quote of the week, from Simon Jenkins via Bill Mitchell:
"British economic policy is like the Olympic Park without the athletes. It is barren of activity and incident. More than £325bn has been “injected into the economy” by the Bank of England, money that has gone nowhere near the economy. It is sitting in a bank vault. My Olympics legacy would be to get it out and inject it properly. With the economy deep in a liquidity trap, it needs an inventive genius like Boyle, who can blow £60m in just three hours of happiness. As Bob Geldof would have said, had he been invited, “just spend the effing money”."
  • Bonus political image of the week:


  1. "...And there is always the question of what constitutes human merit, in the most ultimate sense."

    And what would "ultimate" mean in a materialistic-reductionist world?

    Interesting that you certainly don't want a society to live and function as if they actually believed that "fairness" or "justice" or "merit" were not "ultimate" in some sense and more that just concepts that can be twisted into meaning the exact opposite.

  2. Hi, Darrell-

    I guess I am saying that these concepts are much more difficult to pin down than using, say, net financial worth. Indeed, I would deny that there is any singular "ultimate" sense by which we can be valued at all. Rather, we contain multitudes and that includes many ways of valuing ourselves and our activities.

    Even worth as measured in Darwinian terms is hardly the last word. We are busy killing off every other species on earth to slake our many appetites. Does that make us better and more successful? I don't think so.

    Really, I am not sure where you are going with the "materialistic-reductionist" argument. Reductionism is a tool, like computers are tools, for analyzing and understanding complex phenomena (and is generally to other modes such as supernaturalism). It is not an overarching philosophy that bars, say, artistic activities or appreciation. Analysis is not everything under the sun. See Sarah Vaughan above.

  3. Good post -- and an interesting take on the GOP perspective.

    What's your take on the evolutionary pressure from birth control? It seems to alter the effects of mate selection. Specifically, "sexual attractiveness" traits are still important, but less important (because birth control allows us to mate without procreating). On the other hand, there may be more pressure in favor of "good parent" traits.

    1. From what I can see, the effect of birth control is that most intelligent members of the human race have fewer children. Medical advances mean a higher percentage of the children of the less intelligent survive, thus perpetuating that genetic strain. This does not bode well for the future of the human race.


  4. Thanks, JD-

    If I were to speculate, I would guess that the effect of birth control is firstly to allow us on the whole to moderate world-wide population growth, surely a critical issue in ecological terms, even as it reduces the numbers to be weeded out by other forms of selection, (as well as the conflicts that might constitute that selection).

    Evolution-wise, it reduces the weight of pure lust on reproductive fitness, replacing it with other motivations more specifically directed to wanting and having children. As you say, the "good parent" traits, though those who want children do not always make the best parents. As mentioned, the cultural and legal norms of monogamy (vs polygamy) have similar effects, broadening and diversifying the genetic base, instead of sharpening selection in a winner-take-all contest that probably leaves the good parent traits (and much else) in the dust.

    Going even more speculative, before birth control, some of these same traits were promoted by social institutions, like marriage, lack of divorce, ostracism, religion, etc. So birth control has led to greater personal autonomy and social atomization, along with many other cultural developments. In selective terms, this may result in a reduction of broader social skills required as the price of entry to reproduction, and thus less selection for the relevant traits, whatever they might be.

    Mr. Kaku's remarks are indeed pretty off the mark. He is right that the Sci-Fi movie model of human evolution has no basis, but it is clear that appearance still matters to people a great deal. And thus results in ongoing selection, though to what end is not clear (to me, at least). As you indicate, evolution is far from over. It never ends for living populations, though by the punctuated equilibrium model, superfical structures may remain static for long periods, reflecting ecological optimization.