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On The Evolution of the Serotonin Transporter Gene

A gene that can modulate stress response may have big behavioral consequences.

Flickr creative commons
Source: Flickr creative commons

In the last couple blog posts, I introduced the serotonin transporter promoter gene, or 5-HTTLPR. It’s a gene that controls how many serotonin re-uptake transporters you have, and differences in this gene you inherit likely affects how strong an acute stress response you can muster. There are two basic alleles, short and long (the long gene has 14 repeats of the same sequence while the short gene is 12), so three genotypes (as we get one from mom and one from dad) are: short short, long long, and short long. Just to make things complicated, there is a relatively rare mutation on the long allele that diminishes its function so it acts more like the short allele, so it may be best to think of these alleles as low expression and high expression rather than short or long, for accuracy.

The interesting thing about 5-HTTLPR is that its frequency in populations is very different based on ethnicity. The low expression allele is found most often in Asians, less often in Caucasians, and lowest in those of African descent. However all populations have the low expression allele in at least 10% of people, which likely means it has been selected for over the years, that something about the low expression allele gives an evolutionary advantage in certain situations, while the high expression allele has advantages in other situations. Given the low expression allele seems to lead to a more intense stress response, it would make sense the low expression allele wins out when people are facing an acute stress, but chronic stress may cause problems for these folks, but that’s a bit of a reach making a lot of assumptions.

When you study genes and behavior, you have to be careful not to get all Gattaca about it, because what we don’t know about genes and behavior dwarfs what we do know. Behavior is modulated by a whole bunch of genes, after all. I’ve seen reports talking about assigning soldiers duties based on a separate COMT warrior vs worrier genotype predicated on the assumption that so-called “warriors” are less likely to get PTSD…5-HTTLPR would also be a candidate for this sort of thinking. Maybe you send the low expression folks in for a short more intense tour of duty with lots of rest and recovery after…but if you combine the two genes (COMT and 5-HTTLPR) you will have worried low expressers, warrior low expressers, worried high and low expressers, plus middle of the road carriers of both alleles…and that’s just two of thousands of genes that influence behavior. It gets very complicated, very quickly, not to mention ethically dicey when you add in future technological advances such as CRISPR that can edit genomes and snip out undesirable genes or add supposedly desirable ones*.

In addition, behavior is usually a continuum, not just “worried” or “warrior” or “more stressed out” vs “less stressed.” Between human experience and the multiple genes that control temperament, it’s truly impossible to predict individual behavior from the kind of data we have now about these genes. They are just clues and perhaps tendencies, not a Rosetta stone unlocking all the secrets of genes and behavior.

Flickr creative commons
Source: Flickr creative commons

In order to make more sense of what is going on with the 5-HTTLPR genotypes before anyone gets carried away assigning jobs to people based on genotype, we can look at our primate cousins. You see similar differences in high and low expression alleles of the 5-HTTLPR in some monkeys and all apes. We might get some more ideas as to what behaviors these alleles influence and how it evolved in human populations by studying primates.

In these primates, the low expression and high expression alleles are somewhat different than the human ones…some have 23 repeats, some 24 or 14…this means this same functional genetic difference has evolved multiple times in separate primate lineages. That usually means there’s an evolutionary advantage to having one allele, the other, or sometimes what is called a “heterozygote advantage” where having a mix of alleles is preferred (maybe short long is the best of both worlds over time in humans…who knows?), thus leading to both alleles perpetuated in offspring of the population. Since most of these primates live in social structures, and serotonin systems in part regulate how we deal with social interactions, it seems most likely there is something about these genes that give an evolutionary advantage in some social situations. Perhaps short term high competition favors low expressers who have more cortisol and a stronger stress response, whereas in low competition times, the high expression carriers win out…that’s just a theory that may be a bit easier to test in controlled social situations in primates than in humans.

Eventually, we will have a full understanding of the genes that influence behaviors and all the subgroups within. This information will be useful in mental health to help us treat people based on likely pathology based on genotype, and also useful in preventing pathology. Thinking ahead about what we want to do with that information in other situations, such as planning careers or subdividing groups of soldiers will be an ethical challenge for the future.

*If you haven’t listened to the Radiolab podcast on CRISPR, listen to it on your next commute, walk with the dog, or visit to the gym. It’s a doozy, and very informative.

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Copyright Emily Deans MD