Wednesday, September 8, 2010

Wild-type humans

Wild-type is the term geneticists use to refer to non-mutants. It literally means organisms that are the same, genetically, as those in the wild, compared to ones that have been grown under coddled conditions in the lab for generations, going soft in the absence of natural selection, or that are specifically mutant at some gene or other. There are no wild-type humans.

Well, maybe there are a few, somewhere, but even they are not really non-mutants. We all carry millions of mutations in our genome – positions where the sequence in our genome differs from the typical sequence. Where everyone else has a “T”, you might have an “A”, for example. Most of these mutations have no consequence – they are simply neutral variation in DNA that has no discernible function. It turns out that most of the genome is not made of genes – the bits of DNA that code for proteins actually comprise only about 2-3% of the total sequence. Mutations that change the code for proteins are by far the most likely to cause disease or to result in an obvious phenotypic difference.

New DNA sequencing technologies have revealed how many mutations of that type each of us carries, on average. Lots: around 10,000 mutations that change the amino acid code of a protein. Those can be broken down based on frequency in the population. Some mutations are seen in many individuals in the population – this implies that they occurred long ago in some individual and have subsequently spread in the descendants of that individual. The inference is that such a mutation does not have a deleterious effect as it would have been selected against if it did. About 90% of protein-changing mutations fall into this common, ancient class. In fact, in many such cases it can be difficult to say which allele (which version of the sequence at a specific position) is “wild-type”.

Some of these common mutations are actually adaptive and may be much more common in some populations than others. These include mutations that affect skin colour, for example, reflecting adaptation to either high sunlight (requiring protective melanin) or lower sunlight (requiring less melanin to allow vitamin D production), as well as variants affecting diet, such as lactose tolerance, adaptation to environmental conditions, such as high altitude, or resistance to specific pathogens or parasites. So, what is wild-type in one population may be mutant in another.

The remaining 10% of mutations are either very rare or “private”, having only ever been observed in one individual. When searching for mutations responsible for genetic diseases, these are the variants that researchers go after. Of course, not all of these will have phenotypic effects. Many changes to the code of amino acids in a protein can be tolerated without compromising function. It is possible to estimate how many rare mutations each of us carries that are likely to affect protein function – this is between 100 and 200, quite a small number, really. As well as mutations that change one DNA base to another, these also include a different class – mutations which result in the deletion or duplication of a whole chunk of a chromosome (copy number variants).

This got me to idly musing about what would happen if you took someone’s DNA sequence and “corrected” all those mutations to the wild-type version. What would the result be? Those 200 or so rare mutations may generally be tolerated (they are clearly not lethal at least) but could still result in suboptimal performance of any number of biochemical, cellular or physiological processes in each one of us. They may also contribute to differences in morphology by subtly affecting processes of growth and development. As these mutations tend to reduce the function of the encoded protein, presumably it should be “better” to have the wild-type version. (For good measure, let’s imagine we can “correct” all the mutations predicted to affect protein function, even if they are slightly more common – say up to 5-10% frequency in the population, but not so common that we can’t say what the wild-type version is).

This was the premise of the excellent movie GATTACA. Apparently the book that inspired it was also good, but I haven’t read it because it didn’t have Uma Thurman in it. The movie did, Uma being somebody’s vision of what a wild-type human female would look like (and who would argue?). Her male counterpart, Jude Law, reinforces the impression that they would be, most importantly, ridiculously good-looking. Poor Ethan Hawke was cast as the guy born by traditional procreative methods, mutations and all.

Beauty is only skin deep, of course, and what really interests me is what would their brains look like? It takes a lot of genes to assemble a human brain and all of us carry mutations in many of those genes. Those differences affect how our brains are wired and influence many aspects of our personality, perception, cognition and behaviour (as pretty much all the posts on this blog describe). What would the brain of someone with each of those deleterious mutations corrected be like? Would they be a genius? Especially empathetic? A naturally coordinated athlete? Would they be left or right-handed? What would their personality be like? Is there a wild-type level of extroversion or neuroticism or open-mindedness?

For some of those traits the optimal level may be different from the maximal level. For brain size, for example, which is correlated with intelligence, there is a trade-off in, first, being able to make it out the birth canal and also in metabolic demand – big brains use a lot of energy. And for may personality traits it is difficult to define a single optimal point along the spectrum – there are many different strategies that may succeed better in different contexts. Being fearless and aggressive may attract the ladies, but could also get you killed young. So, our wild-type humans may have perfect vision and perfect teeth, but it’s much harder to define a perfect personality.

Another consideration is that natural selection has only ever acted on individuals with a genetic burden of mutations – we may thus in some way be adapted to that situation. Some mutations that decrease the function of one protein may be beneficial in the context of another mutation in a different protein. Perhaps putting all the perfect proteins together in one person would not actually generate an optimal system.

In the movie, the generation of these “genetically perfect” beings was accomplished by gradually selecting out all such mutations by screening embryos created by in vitro fertilization. The fatal flaw in this idea is that it considers the spectrum of mutations as static in the population, suggesting that once all the bad ones are weeded out, that will be that. This ignores the fact that the rate of new mutations is actually quite high. Each of us carries about 70 new mutations that are not inherited from our parents. Most of these arise during generation of sperm. The reason that mutations in sperm are more common than in eggs is that women are born with all their eggs already generated. The cells that generate sperm, in contrast, are constantly dividing throughout life. Each division increases the chance of incorporating an error. That is the reason why the rate of dominant Mendelian diseases – which are those caused by single mutations and which include many cases of common diseases such as schizophrenia and autism – increases with paternal age.

Of course, all of the discussion above is based on the premise that genetic effects on physical and psychological traits are predominant. This extreme form of genetic determinism was also espoused in GATTACA, to the point of predicting the cause and date of a person’s death! In reality, genetic factors have a large influence on many of these traits but by no means an exclusive one – intrinsic developmental variation, environmental effects and experience will all also contribute to varying extents. On the other hand, introducing mutations tends not only to change a phenotype but to increase the variance in the phenotype – as the system becomes more compromised, its output becomes more variable.

It would be interesting to ask, therefore, exactly how much variation in these traits would be left across our wild-type humans.

Ng, S., Turner, E., Robertson, P., Flygare, S., Bigham, A., Lee, C., Shaffer, T., Wong, M., Bhattacharjee, A., Eichler, E., Bamshad, M., Nickerson, D., & Shendure, J. (2009). Targeted capture and massively parallel sequencing of 12 human exomes Nature, 461 (7261), 272-276 DOI: 10.1038/nature08250

Roach, J., Glusman, G., Smit, A., Huff, C., Hubley, R., Shannon, P., Rowen, L., Pant, K., Goodman, N., Bamshad, M., Shendure, J., Drmanac, R., Jorde, L., Hood, L., & Galas, D. (2010). Analysis of Genetic Inheritance in a Family Quartet by Whole-Genome Sequencing Science, 328 (5978), 636-639 DOI: 10.1126/science.1186802


  1. Does it stand to reason that a 40 year-old father that had a lifetime of more ejaculations would have a higher incidence of mental disorders in his kids than one who had less? I suppose there's some kind of natural turnover in sperm anyway but forced production would seem to create more cell divisions. Or is that just ridiculous?

  2. John, that's an interesting question that I have never thought of before. I have no idea what the answer is though!

  3. While it would be largely correlative, a survey of fathers with children that have mental disorders could probably elucidate something. Then again, it might be hard to correct for other factors, like the subsequent age of the mothers (who would probably be older too, thereby raising the odds of genetic problems).

  4. you must include punks in this list. most wild people I ever met. absolute crazy, unprinciple people....

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  5. This reading about mutants made think in the experiments xlpharmacy are carrying out with humans and other species, it's something I'd like to know because consequences could be terrible.

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