Unstable Protein Variants found in the Domainome Linked to Many Human genetic Diseases

Good news! This research was already published in early January 2025, but it was apparently not covered by popular science articles and newsletters until now.

"Every human is born with 50 to 100 genetic variants that were not present in their parents. ...

Genetic variants that change a protein’s amino acid sequence, producing protein variants, cause a third of all known human genetic diseases. Yet, scientists know very little about how most of these single nucleotide mutations affect protein function. ..."

"... Most genetic changes that swap one amino acid for another cause disease by making the protein less stable, according to the largest study of human protein variants to date. Unstable proteins are more likely to misfold and degrade, causing them to stop working or accumulate in harmful amounts inside cells.

The study  ... helps explain why minimal changes in the human genome, also known as missense variants, can cause disease at the molecular level. ...

discovered that protein instability is one of the main drivers of inherited cataract formation, and also contributes to some neurological, developmental, and muscle conditions.

The team analysed 563,534 variants, including 621 that are known to cause disease, and catalogued their impact on proteins. Three in five, or 61 per cent, of these variants caused a detectable decrease in protein stability, highlighting the possibility of developing therapies aimed at stabilising proteins. Instability was even higher in recessive conditions, where copies of a gene from both parents are necessary to cause disease. ..."

From the abstract:

"Missense variants that change the amino acid sequences of proteins cause one-third of human genetic diseases. Tens of millions of missense variants exist in the current human population, and the vast majority of these have unknown functional consequences.

Here we present a large-scale experimental analysis of human missense variants across many different proteins. Using DNA synthesis and cellular selection experiments we quantify the effect of more than 500,000 variants on the abundance of more than 500 human protein domains.

This dataset reveals that 60% of pathogenic missense variants reduce protein stability. The contribution of stability to protein fitness varies across proteins and diseases and is particularly important in recessive disorders. We combine stability measurements with protein language models to annotate functional sites across proteins.

Mutational effects on stability are largely conserved in homologous domains, enabling accurate stability prediction across entire protein families using energy models. Our data demonstrate the feasibility of assaying human protein variants at scale and provides a large consistent reference dataset for clinical variant interpretation and training and benchmarking of computational methods."

Unstable Protein Variants Linked to Many Human Diseases | The Scientist "The Human Domainome 1—the largest library of human protein variants—reveals the cause of certain genetic disorders, paving the way for personalized medicines."

Human ‘Domainome’ reveals root cause of inherited conditions (original news release) "The largest catalogue of human protein variants to date has revealed that protein destabilisation is the main driver of inherited genetic conditions and paves the way for precision medicine and AI-driven treatments."

Site-saturation mutagenesis of 500 human protein domains (open access)

Fig. 1: Mutating the human Domainome.

Fig. 4: The contribution of protein destabilization to genetic disease.