Autism, Genetics, and Evolution

This is a post that I was hoping someone else would write. I'm not an expert in any of the three subjects, but believe that there may be some interesting links between them. If anyone knows more, feel free to comment and/or rebut. This is a learning exercise and I will appreciate any feedback. Most people, including me, believe that autism has a major genetic/epigenetic component. While I suggested in my first post that in some (and maybe even many) cases there may be something more than just genetics or inherited epigenetics required to cause autism, the evidence of - at a minimum - a genetic/epigenetic link is undeniable.

Genes encode the information required to make proteins, which are the basic building blocks in organisms (including us), and the creation of proteins determines the structural, biochemical, physiological, and behavioral characteristics of an organism. An allele is any one of a number of viable DNA codings of a gene occupying a given locus (position) on a chromosome, i.e. one option within the set of potential expressions for that gene. An individual’s genotype for a gene is the set of alleles that the gene possesses. In humans there are normally two copies of each chromosome, thus two alleles make up the individual’s genotype. The phenotype of an individual (i.e. the appearance or specific traits) is the result of the expression of the genotype, as modified by environmental factors and potentially some amount of random variation.

Genetics is the science of genes, heredity (the transfer of characteristics from parent to child), and the variation of organisms. Genetics is linked to evolution through population genetics, which is the study of the distribution and changes in allele frequencies (the measure of the relative frequency of an allele occurring) of genes within a population under the influence of the four factors of evolution: natural selection, genetic drift, mutation, and migration. Thus genes, as well being the blueprint for the ‘construction’ of the individual and of populations, are a link to our ancestors, back to the beginnings of humanity.

Mutations are the drivers of evolution, and are changes to the genetic material. They can be caused by copying errors during cell division, exposure to environmental factors (e.g. radiation, chemicals, viruses), or occur naturally during meiosis (the process of dividing a diploid cell, i.e. with two sets of chromosomes, into four haploid cells – e.g. sperm or ovum – each with one half of the chromosomes of the original cell that have been resorted to mix the original maternal and paternal genetic information). Most mutations have no significant effect, and the changes are reverted via DNA repair before they become permanent. Those that affect the organism become subject to the rules of natural variation (for beneficial and deleterious mutations) or genetic drift (neutral variations).

For genes to get into the next generation, the gene’s owner has to reproduce and pass them on to the next generation. Without reproduction, a genetic expression, no matter how beneficial to the individual, dies with that individual. A flippant example: a person can have a variation that enables them to unfailingly predict the rise and fall of stock prices (which could potentially be a huge advantage in life). But if that person does not reproduce then that allele or genetic variation dies with them. Natural selection is the process by which favorable alleles – those that benefit the individual’s fitness (in genetic terms the ability to survive and reproduce) - tend to accumulate over time. Deleterious genetic variations tend to reduce the chance of the host to reproduce, and therefore these alleles tend to be removed from the gene pool over time.

Genetic drift is the process by which neutral variations – those that do not influence the capability to reproduce of either the individual or the species - become either an increasing or decreasing percentage of the population. Statistical theory suggests that neutral genes will reproduce with a normal distribution, but each generation of genetic distribution is unique, and builds upon the former. So if a genetic variation is present in 50% of the population, statistical theory says that the variation will be passed on through a normal distribution of probabilities. Let’s say that the genes through random variation get passed on to 51% of the population in the next generation. The new starting point is therefore not 50% but 51%. Over time neutral variations will either become ‘fixed’, i.e. universal within a population, or extinct. The smaller and more isolated a population is, the faster that genetic drift will drive an allele up or out.

Migration occurs when organisms move from one location to another, and is one of the ways in which genetic variations move into new locations and new populations. The genetic host begins or joins a new population and successfully reproduces, so that their genes become part of the new population’s genetic base. Again, depending on the number of hosts involved in the migration and the success of the new variation in the new environment, the processes of natural selection and/or genetic drift will apply.

Human migration can be traced genetically via two different streams: mitochondrial DNA and Y chromosomes. Mitochondrial DNA (mtDNA) is passed only from mother to offspring and varies little over time, changing through mutations. Analysis of these mutations enables us to track matrilineage, right back to a common ancestor, dating perhaps 150,000 years ago. Y chromosomes are passed only from fathers to sons, and the same type of analysis yields a common ancestor between 60,000 and 90,000 years ago. By tracking variations in mtDNA and Y chromosomes it is possible to track the movement of humanity over time, out of Africa. Two schools of thought exist on this – the Oxford school, which suggests a migration out of Africa 85,000 years ago populated the rest of the world, and the Cambridge school, which suggests a migration 60,000 years ago, followed by at least one subsequent migration.

Regardless of which school is correct (which should be answered by the Genographic Project), the net result is that while all of current humanity has two common ancestors, the paths of humanity diverged tens of thousands of years ago. While there have been subsequent migrations and intermixing of various populations within some geographies, one can also see where the paths of humanity have diverged. For example, the ancestors of the European and Asian branches of humanity diverged perhaps 40,000 years ago. The Mongol empire, spanning from Eastern Europe to China and Korea, was able to unite many of the eastern and western descendents of this migration during parts of the 13th and 14th centuries, and certain elements within the Mongol empire were very prolific (nearly 8% of men living in the former Mongol empire or 0.5% of the male population of the world appear to be descendents of one man), but even this empire did not include Japan, which successfully fought off Mongol invasions, and there have been no major migrations out of Central Asia or Eastern Europe of a scale to link the Asian and Western European haplogroups in any significant way in the post-Mongol empire period. The net result is that any genetic variation (allele frequency) shared in to any significant degree between people of Japanese, central Asian, and Western European descent has to have existed for tens of thousands of years.

The net effect of all of the four evolutionary forces is that there is no stasis. Mutations introduce new alleles (i.e. genetic variation) into a population. An allele will either increase or decrease in frequency within a population. Natural selection and genetic drift ensure that any variation is either on the way up or out, although over the course of many generations. Migration enables alleles to move from one population or location to another, at which point they become subject to the other forces of evolution. And to be clear, the process is amoral. Genetic variations increase or decrease in frequency depending on their ability to influence the owning organisms’ fitness, i.e. ability to successfully reproduce, regardless of the relative merits of the variation from a moral perspective.

What does this have to do with autism?

Autism clearly has a genetic component, thought to include perhaps four or five, or perhaps ten or more genes. The alleles linked to autism must adhere to the same rules as every other genetic variation. In other words, natural selection, genetic drift, mutations, and migration all apply. So, for the genes that cause autism to continue to exist, they must either confer a benefit to the host’s fitness, be neutral in implication, or must be the result of a regularly occurring set of mutations.

Autism may be in part the result of regularly occurring genetic mutation. But, if this mutation were to occur spontaneously, with no causative genetic variation, then if one person in a family had autism, the odds of a sibling also having autism would be no different than those of the population as a whole, i.e. 1 in 166. Obviously this is not the case. Since autism is more likely to occur within families, then if it is a mutation, the potential for mutation must be part of the family’s genetic heritage, and subject to the normal rules of population genetics and evolution.

As part of natural selection, an allele must reproduce at the same or higher rate than the population as a whole. If it does not then it will become increasingly rare over time. To be controversial, there is evidence that autism in its current manifestation is not a positive or neutral variation from a fitness perspective (Billstedt, Gillberg and Gillberg, “Autism after Adolescence: Population-based 13-to 22-year Follow-up Study of 120 Individuals with Autism Diagnosed in Childhood” in J Autism Dev Discord, 2005 Jun;35(3):351-60) (Howlin, Goode, Hutton, Rutter, “Adult outcome for children with autism”, in J Child Psychol Psychiatry, 2004 Feb;45(2):212-29) (Howlin, “Outcome in high-functioning adults with autism with and without early language delays: implications for the differentiation between autism and Asperger syndrome” in J Autism Dev Discord 2003 Feb;33(1):3-13) and others . Some autistics obviously procreate. The issue is whether this rate of procreation occurs at a level sufficient to maintain the existing prevalence rate of autism over time, and the evidence from above is that it does not. Given that rates of inheritance can range from 2% to 8% or even 10% (Constantino JN et al, 2006), any reduced rate of reproduction for the allele combinations that cause autism would relatively quickly have a sizeable negative impact on the prevalence or frequency of the individual alleles. And reduced reproduction combined with genetic drift would presumably cause frequency to quickly spiral downwards.

On this basis, the alleles that cause autism should have been eliminated long ago. There is no clear evidence of when these alleles first entered the human gene pool, but it is possible to make some assumptions. The theory of a common human ancestor and migration out of Africa suggests that for autism to be a world-wide phenomenon, it would have had to have been the result of either a) similar mutations (in effect, if not type) occurring within geographically separate populations, b) migration between populations on a scale great enough to ensure relatively common prevalence rates, or c) the alleles that cause autism existed prior to humanity diverging on different paths. The first option is a stretch from a probability perspective. There is no known historical migration to support the second option. That leaves option c.

If option c is correct, then in the example of Japan compared to Western Europe, the divergence in populations due to migration occurred probably 40,000 years ago. Assuming 30 to 35 years per generation (which is conservative), there have been 1100 to 1300 generations since the two populations diverged. This presumably should have been enough time to eliminate the various alleles that cause autism from the gene pool, if they are in fact deleterious.

Obviously this has not occurred. This means that the individual alleles that in combination cause autism must individually or in lesser combinations have had a beneficial effect to compensate for the reduced reproductive rates of autistics. There may be some evidence for this in the finding that parents of autistics are more likely to be systemizers (e.g. physicists, engineers, mathematicians), which may confer an advantage in some environments. One can speculate how much of an advantage systemizing might have been in historical agrarian societies, as distinct from today’s much more urban environment, but this advantage may have existed over time, and may be increasing with the adoption of universal public education, the move from agricultural and artisan to more systems oriented employment, and more opportunities for upward social mobility. There may also be other benefits resulting from the individual alleles or combinations of alleles that would also provide a natural advantage. But for autism to be entirely genetic, a separate natural advantage would have to exist for each of the alleles that contribute to the condition (since each allele can exist independently of the others), to compensate for autism’s overall reduction in ‘fitness’.

There is also another possibility. Given the potential for exogenous factors to play a causative role in at least some cases, it is also possible that at least some of the combinations of alleles that currently cause autism may not have always had a negative effect. Since allele combinations can affect more than one trait, it is possible that the autistic genes have both a positive and potentially a negative impact on fitness, but that the negative impact could require additional causative factors to pull the trigger –factors that historically might have been less prevalent. As an example, there is some evidence of autoimmune issues within the families of autistics. Perhaps without the additional stress of an autoimmune ‘hit’, the negative impact of the alleles may not have been triggered, rendering their impact on the host as neutral or mildly advantageous. Other suggested factors could include other immune issues, enhanced vulnerability to viral infections or environmental toxins.

In any of these cases, these alleles that in combination cause autism may not historically have had as significant a negative impact on autistic reproductive fitness – the vulnerability may have existed but not have been triggered - allowing the benefits of the alleles to further their reproduction over time. Hypothetically, perhaps these genes benefited autistic intelligence but without a corresponding negative sensory integration impact. In this case the “hidden hordes” might have existed, but without enough of the negative implications of autism to affect their fitness over time. More recent changes in the environment (not necessarily over the last ten years, but accumulating over decades or the last couple of centuries) may be now having more of an effect on vulnerable individuals. If this is the case then this effect may also be increasing over time.

Just one of a range of possibilities to think about...

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Update - Related posts:

Autism and Minicolumns (Sept 5, 2006)

Autism and the Evolution of the Brain (Oct 13, 2006)