Cancer and other bad genes

A question I have heard from thoughtful patients for years. If natural selection is supposed to weed out bad genes, why do we still have so many of them? Heart disease, Alzheimer’s, cancer risk genes, autoimmune predispositions. Why are these still in the gene pool?

The honest answer is that the question contains a hidden assumption that does not hold. Natural selection does not care what happens to you after you have reproduced and reared your young. From an evolutionary standpoint, anything that lets you reach reproductive age and successfully raise offspring is neutral or positive. Anything that kills you at 60 is, evolutionarily speaking, irrelevant. We are stone-age genes living a much longer life than the genes were optimized for.

The kinds of bad genes

The genetic problems that produce disease come in a few flavors. The most dramatic is the single-nucleotide polymorphism, or SNP, where one DNA letter is swapped for another in a critical position. SNPs cluster in some families and appear sporadically in others. Some regions of the genome are more vulnerable to oxidative damage and accumulate more of these substitutions over time.

The more common situation is allelic variation. Most genes come in several normal variants, called alleles, each producing a slightly different version of the protein. None of these alleles are mutations in the strict sense. They are variations the species carries because they have been useful in some context.

One specific example. APOE

The APOE gene comes in three main alleles, E2, E3, and E4. The E4 variant is associated with roughly a three to four-fold increase in risk for late-onset Alzheimer’s disease, an elevated risk for cardiovascular disease, and higher LDL cholesterol on average. Carriers of two copies of E4, depending on the study, have lifetime Alzheimer’s risk as high as 60 percent.

Why is this allele still around? Because it is the ancestral version. The E4 variant is what humans started with. It traces back to our ape ancestors and was selected for, in part, because it confers resistance to certain viral infections, including some forms of hepatitis. In a world where most people died of infectious disease before reaching what we now call middle age, E4 was a positive. The E3 and E2 variants emerged later as humans started living longer and eating more cooked meat, and they handle the modern environment better at the cost of giving up some of the infection resistance.

So APOE4 is not a defect. It is an ancestral variant that performed well in the environment it was selected in, and performs poorly in the environment we now live in.

The bigger picture

Statistically, most of the chronic disease you fear will be driven more by epigenetics than by your starting genetics. Most people are dealt a reasonable genetic hand. What spoils the hand is the lifestyle stacked on top of it. Poor diet, sedentary behavior, chronic stress, sleep deprivation, low omega-3 status, low vitamin D, chronic systemic inflammation, accelerated telomere attrition. All of these are leveragable factors that sit on top of the genome and decide which of your genes get expressed loudly and which stay quiet.

That is why I am not particularly impressed when a patient tells me their father had a heart attack at 55, so they are doomed. The genetic loading is real. The epigenetic environment is also real, and it is in your control to a degree that surprises most people.

What to do about it

The recommendations have not changed.

• Get your omega-3 index above 8 percent.
• Hold 25-hydroxy vitamin D between 50 and 75 ng/mL.
• Eat a low-glycemic, low-inflammatory pattern with adequate protein and lots of plants.
• Sleep on a regular schedule.
• Train consistently. Mix resistance and aerobic work.
• Manage stress with whatever practice you will actually do.

If you know your APOE genotype or have a strong family history of a specific disease, get into a clinician’s office who actually understands the genetics and can match interventions to the specific risk. The generic recommendations above still apply. The specific ones get more nuanced.

— Doc