AlphaMissense: Google DeepMind's New Tool to Uncover Disease-Causing Mutations

Wednesday - September 27 2023, 20:38 UTC - 1 year ago

Google DeepMind's AlphaMissense is a new tool that helps uncover disease-causing mutations. It analyzes DNA sequences and works out which DNA letter swaps likely lead to disease. In tests, it categorized 89 percent of the tens of millions of possible genetic typos as either benign or pathogenic. However, this tool is only meant to be viewed as a tip-line for disease-causing mutations, and is not to be used for diagnoses.

Proteins are like Spider-Man in the multiverse. The underlying story is the same: each building block of a protein is based on a three-letter DNA code. However, change one letter, and the same protein becomes a different version of itself. If we’re lucky, some of these mutants can still perform their normal functions. When we’re unlucky, a single DNA letter change triggers a myriad of inherited disorders, such as cystic fibrosis and sickle cell disease. For decades, geneticists have hunted down these disease-causing mutations by examining shared genes in family trees. Once found, gene-editing tools such as CRISPR are beginning to help correct genetic typos and bring life-changing cures. The problem? There are more than 70 million possible DNA letter swaps in the human genome. Even with the advent of high-throughput DNA sequencing, scientists have painstakingly uncovered only a sliver of potential mutations linked to diseases.

This week, Google DeepMind brought a new tool to the table: AlphaMissense. Based on AlphaFold, their blockbuster algorithm for predicting protein structures, the new algorithm analyzes DNA sequences and works out which DNA letter swaps likely lead to disease. The tool only focuses on single DNA letter changes called "missense mutations." In several tests, it categorized 89 percent of the tens of millions of possible genetic typos as either benign or pathogenic, said DeepMind.

AlphaMissense expands DeepMind’s work in biology. Rather than focusing only on protein structure, the new tool goes straight to the source code—DNA. Just a tenth of a percent of missense mutations in human DNA have been mapped using classic lab tactics. AlphaMissense opens a new genetic universe in which scientists can explore targets for inherited diseases.

"This knowledge is crucial to faster diagnosis" wrote the authors in a blog post, and to get to the "root cause of disease." For now, the company is only releasing the catalog of AlphaMissense predictions, rather than the code itself. They also warn the algorithm isn’t meant for diagnoses. Rather, it should be viewed more like a tip-line for disease-causing mutations. Scientists will have to examine and validate each tip using biological samples.

"Ultimately, we hope that AlphaMissense, together with other tools, will allow researchers to better understand diseases and develop new life-saving treatments," said study authors Žiga Avsec and Jun Cheng at DeepMind.

Let’s Talk Proteins .

A quick intro to proteins. These molecules are made from genetic instructions in our DNA represented by four letters: A, T, C, and G. Combining three of these letters codes for a protein’s basic building block—an amino acid. Proteins are made up of 20 different types of amino acids. Evolution programmed redundancy into the DNA-to-protein translation process. Multiple three-digit DNA codes create the same amino acid. Even if some DNA letters mutate, the body can still build the same proteins and ship them off to their normal workstations without issue.

The problem is when a single letter change bulldozes the entire operation. Scientists have long known these missense mistake sequences are liable for inherited diseases. The trick was to track them down.