What does it mean to say a gene causes something?

When writing about the genetics of sensory processing sensitivity, I’ve tried to be careful to use the phrase “associated with” rather than “causes.”  I do this because genes don’t directly code for anything.  To a first approximation, genes either code for proteins or for regulation of when those protein coding genes are expressed.*  Different alleles of the same gene code for different versions of the gene’s protein**.

Sometimes, the link between a change in the DNA and the phenotypic outcome is obvious.  To return to perennial favorite sickle cell anemia:  there are several different alleles that can cause sickle cell anemia (which appear to have arisen independently, adding even more weight to the hypothesis that the alleles are adaptive), but they all affect the hemoglobin protein.  A change in one nucleotide leads to a single amino acid change in the protein. Under certain conditions, this leads red blood cells to take the characteristic sickle shape, which causes a pile up in the blood vessels, which causes oxygen deprivation.  All of these things are easy to observe (comparatively) and easy to track the chain of causation.  And even with that, it’s not quite fair to call it “the sickle cell allele”, because the same allele also codes for malaria resistance.

The genes associated with high sensitivity don’t do anything nearly so obvious.
DRD4 7R (the mutation associated with high sensory sensitivity, ADHD, greater susceptibility to maternal trauma, and nomadicism) occurs in the DRD4 gene, which produce dopamine receptor D4.  It does not lead to an amino acid substitution: rather, there’s a string of amino acids that may be repeated somewhere between 2 and 11 times: the 7R allele codes for 7 of them.  I am unable to find any evidence we know what this does to the tertiary (three dimensional) shape of the protein or even where the D4 receptor is typically found, much less how these mutations affect metabolism.  There’s a lot of high level correlational studies about various mutations and various phenotypic pathologies, like schizophrenia and parkinsons, but there isn’t a nice neat chain of causation like we see in sickle cell.

The other gene I talked about,  5-HTTLPR, isn’t even a real gene.  It’s a promoter region for SLC6A4which codes for a protein that transports serotonin.  That means that mutations in 5-HTTLPR can affect when, where, and how much serotonin transporter is produced, but not the amino acid sequence of the transporter.

What are the phenotypic consequences of slight variations in the expression of this gene?  That’s a really good question.  It could theoretically affect anything that is affected by serotonin, whose  clients include “the digestive system” and “the central nervous system.” And if it’s affecting your digestive system, it could affect your nutrition. So pretty much anything, ever, could plausibly be affected by mutations in this area.

The DRD4 gene doesn’t code for parkinson’s disease.  It codes for a protein.  Any variation in that protein will have a multitude of consequences, one of which might be parksinson’s.  There is no one gene for high sensitivity: there’s a number of genes that influence a number of traits, one of which may be sensory sensitivity.  So please remember that if someone tells you gene foo codes for happiness, they are not your friend.

*There are exceptions, but they’re very complicated and don’t change what I’m about to say.

**This is a simplification.  It’s possible to have two different DNA sequences code for identical proteins and yet lead to slightly different outcomes, because is slower or more error prone to transcribe.

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