A genetic mutation that caused a person to live longer than expected, and how it was finally explained

Imagine a biology textbook that explains that genetic mutations cause increases in a cell’s lifespan by four days, but this is not a universal rule. While that would be an unfortunate side effect of doing a calculation, in other ways, it would actually be pretty straightforward.

If you put the 1,000 base pairs of DNA in a row, and then added a single nucleotide, a calcium ion, the trick isn’t dissimilar to the elementary algebra of doing a series of x’s and y’s and -ox’s together. The nucleotide goes into the chromosome’s dark side, or whatever part of the genome gets cleaved off because of a mutation. The calcium ion chases it through the DNA, where a system of binding proteins recognizes it. If they get close, and come together briefly, they will click.

This connection between nucleotide and calcium ion, called the “recombination hypothesis,” is well supported by other experiments. Recombination is one possibility on many on a very long list of possibilities, however, and it is not a powerful factor in real organisms. Even when sequencing the entire genome, it usually does not seem to be a huge driver of change. The possibility of a field that it does not explain is the most interesting to us, and led us to publish a paper in the Dec. 28 issue of Nature.

We find that mutations that cause enhanced lifespan are more likely to be combined with mutations that make the desired effect much more likely. Those two types of mutations are distributed unevenly in people; those that cause extra days in a cell are far more likely to come from a single spot of the chromosome and to be nearly 1,000 base pairs long. We found such mutations to be much more common in animal systems and to be spread across the entire genome in the same way.

Many people with the BRCA mutation, for example, have extra bases in chromosomes 3 and 6 (the ones that make reproductive endocrine cells). In the same vein, mutations that increase the expression of proteins on a chromosome — for example, by shrinking — occur at several spots on the chromosome. In case after case, we found both kinds of mutations in some subset of human genomes, but for all of them the events happen more frequently in cells that express those proteins more or less exclusively, and they are spread across the whole genome. That is just not true for most mutations. They seem to spread more evenly, and the events are not as likely to occur when the cells are interacting only with each other.

Leave a Comment