Genetic predictability steadily erodes during evolution, new study shows
Rendering of the X-ray crystal structure of the 700-million-year-old ancestral steroid receptor (blue), bound to DNA, gray. Starting from this protein (and eight of its descendants), the Thornton Lab engineered libraries of mutants containing every possible amino acid state at all 76 sites in the protein (spheres). Credit: Joe Thornton, UChicago

Predicting the effects of future changes in genetics and evolution is a critical goal. Scientists generally assume that the effects of a particular genetic change applied to past and future versions of the same gene.

A new study by University of Chicago scientists shows that this assumption is wrong. By combining cutting-edge techniques in experimental biochemistry and evolutionary reconstruction of ancient proteins, the study directly measured how the effects of every possiblemutation in a biologically essential gene changed across 700 million years of evolution. The effects of most genes changed as the genes evolved, with some effects being detrimental and others being inconsequential.

It is not possible to reliably predict the effects of most changes into the future or back into the past. The findings show that the potential fate of amutations is determined by the particular set of chance events that happened during the gene's history. The events determine the effect eachmutation has at each time point and the probability that it will be incorporated into the gene during evolution.

Many people think that natural selection has maximized our genes to do the best job possible, according to the senior author of the study.

The study was published in Science on May 20.

700 million years of evolution have been scanned.

The first author and graduate student Yeonwoo Park and the research scientist Brian P. H. Metzger collaborated to perform the first comprehensive study of changes in the effects of mutations over time. They looked at a family of genes that code for steroid hormones. The effects of estrogen, testosterone, and cortisol on reproduction, immunity, and a wide range of diseases are regulated by these intracellular proteins. About 700 million years ago, a single common ancestor gave rise to the receptors found in almost all animals today.

The team used a technique pioneered in Thornton's lab to reconstruct the genes for the ancestors of the entire family. A series of eight other genes in the family were reconstructed. They were able to study the ancient genes in their lab.

Genetic predictability steadily erodes during evolution, new study shows
Graduate student Yeonwoo Park holding a tube containing a library of thousands of mutants of a 700-million-year-old gene. Credit: Joe Thornton, UChicago

They used a new biochemical technique called deep mutational scanning to measure the effects of huge collections of genes. A graduate student, Park, used a strategy developed by his professors to engineer every possible change at every site in the genes of the nine reconstructed receptors. They used a laser-based technology calledSort-seq to measure the ability of every Mutant to carry out its biological function after they incorporated them into yeast.

The researchers traced the effect of everymutation on deep evolutionary time. Epistasis is a phenomenon in which the impact of a change at one site in a gene can vary from state to state. The effects of the changes in the genes at other sites will change as well.

Although the existence of epistatic interactions is well known, the extent to which they affect the course of evolution has never been studied. Major evolutionary theories assume that the effects of most mutations stay constant over time. Genetics are used in the present to predict evolution into the future or into the past.

Park, a PhD student in Genetics, Genomics, and Systems Biology, said that they were surprised by how pervasive epistatic drift is. The effects of the ancestors will be forgotten in the future, but some mutations drift fast, some more slowly, and each one forgets the effects it once had.

Figuring out unpredictability.

A practical benefit of the team's work is that it gives scientists a way to quantify future unpredictability using experiments. Thornton pointed to an example.

Thornton said that they wanted to predict whether the new versions were likely to be dangerous or not. If we do a series of experiments in the virus over time, we will know how much the effect of every single change is going to be. We can express how confident we are when we predict the effect of a particular bug.

Thornton and Park are expanding the study to include every possible pair of mutations that could have occurred in the receptors. The team will be able to see all the genetic interactions that caused drift during the long-term evolution of the family.

The causes of the drift will be revealed in the new project.

More information: Yeonwoo Park et al, Epistatic drift causes gradual decay of predictability in protein evolution, Science (2022). DOI: 10.1126/science.abn6895. Journal information: Science Citation: Genetic predictability steadily erodes during evolution, new study shows (2022, May 19) retrieved 19 May 2022 from This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.