On a crowded train, some passengers ride in silence while others push toward the exit. The same happens in blood: as we age, cells with mutations appear, and most of these mutations are neutral. They just 'ride along' with the cell every time it divides. Such neutral mutations are called passenger mutations. Some people accumulate more of them than others, and this raises the risk of blood cancer and heart disease. Scientists set out to find out why.
They took blood from 791,067 people across two large biobanks and counted each person's burden of passenger mutations: how many neutral changes had built up in their blood cells. Then they compared this burden with millions of inherited DNA variants. It turned out that 81 regions of the genome influence how fast mutations accumulate. 39 of them were already known, and 42 were discovered for the first time. Among the new ones is the MBD2 gene, which works like a reader: it reads chemical marks on DNA that control gene activity. If another gene, DNMT3A, writes these marks and TET2 erases them, MBD2 interprets them. Harmful variants in MBD2 speed up the accumulation of mutations.
Now it's clear: why some people accumulate mutant cells faster depends on the genes we inherited from our parents. This knowledge can already be used to assess blood cancer risk from a routine blood test. Scientists also noticed that the mutation burden differs across regions, and this isn't explained by income or air quality. That means there are unknown environmental factors that also affect how blood ages.
The MBD2 gene identified in this work encodes a protein that reads methylation marks on DNA. If DNMT3A is a writer and TET2 an eraser, then MBD2 is a reader that interprets what is written. Deleterious variants in this 'reader' increase mutation burden just as somatic mutations in the 'writer' or 'eraser' do.
The idea that neutral 'passenger' mutations can serve as clocks ticking out the age of a clone echoes the concept of molecular clocks from Greg Egan's novel Permutation City, where cell age is determined by the accumulation of random changes.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.