Most Inherited Diseases Are Not Caused By Errors In The Genes

Cro protein complex with DNA. Picture created by Abalone program. Multi-color image of whole brain created using a computer image processing program (called SUMA), which is used to make sense of data generated by functional Magnetic Resonance Imaging (fMRI) — P99am, CC BY-SA 3.0, and NIH Image Gallery
Public domain, via Wikimedia Commons

I keep on seeing statements in the genetics literature like this [1]:

“In recent decades, genomic studies have delivered hundreds of robust findings that implicate nearly 300 common genetic variants (via genome-wide association studies) and more than 20 rare variants (via whole-exome sequencing and copy number variant studies) as risk factors for schizophrenia.”

These types of statements are based on the assumption that genetic variants cause diseases.

In most cases, they do not.

Here is the way you can tell the difference: if a disease can be traced to a handful of genes, such as Cystic Fibrosis, then genetic errors are likely the cause. But if a disease such as schizophrenia is associated with hundreds of genes, genetic variants are irrelevant.

Diseases such as schizophrenia are structural errors. Less than 5% of the DNA encodes for genes: the instructions to make proteins. The other 95% of the DNA encodes the way these proteins are put together. Twenty-five years ago, this was referred to as “junk DNA”. But almost all of it has meaning.

In 2019, in my paper “Structure Encoding in DNA” in the Journal of Theoretical Biology [2] I hypothesized how DNA encodes the structure of individual body parts. This includes long noncoding DNA sequences and even the retroviruses and transposons currently presumed to be parasitical.

Epigenetic mechanisms — National Institutes of Health via Wikimedia Commons

The bulk of the DNA is blueprints for the fine structure of body parts. They determine the shape of the different valves in the heart, the unique muscles and bones, the fine structure of organs and the composition and function of the hundreds of different parts of the brain.

If a GWAS study finds a disease is associated with hundreds of genetic variants, then the disease is likely caused by epigenetic errors in these noncoding sequences. The genetic variants are not the cause; they are just associated with it.

Let’s use an analogy of a piece of furniture with a problem, like a chest of drawers prone to tipping over.

Dall-E’s idea of an unstable chest of drawers.

If someone were to say that they did a study and found that the quarter-inch screws in the chest came from the Acme corporation, but a good chest had a different supplier and listed all the differences in the bill of materials, you would be nowhere in determining the cause of the chest tipping. You would actually be worse off — you are looking in the wrong place for the error. The error is in how the chest is put together.

A telltale sign that a disease has epigenetic causes is that errors in individual genes typically have a Mendelian inheritance pattern, but problems in structure come from one parent of the other — not both. This is why you might have your mother’s nose and your father’s eyes. Schizophrenia is a disease that has been known for years that does not fit a Mendelian model.

Until we get away from focusing on individual genes and start looking at the parts of the DNA that encode for structure, we will not make progress in understanding the causes of diseases that are epigenetic in nature.

_____

[1] Sullivan, Patrick F., Shuyang Yao, and Jens Hjerling-Leffler. “Schizophrenia genomics: genetic complexity and functional insights” Nature Reviews Neuroscience 25.9 (2024): 611–624.

PMID: 39030273 DOI: 10.1038/s41583–024–00837–7

[2] Van der Mude, Antony. “Structure Encoding in DNA”
Journal of Theoretical Biology, Vol. 492, 7 May 2020, 110205 .

PMID: 32070719 DOI: 10.1016/j.jtbi.2020.110205