A groundbreaking study by scientists from Israel and Ghana, published in the current issue of *PNAS*, shows that an evolutionarily significant mutation in the human *APOL1* gene occurs not randomly, but more frequently where it is needed to prevent disease. This fundamentally challenges the notion that evolution is driven by random mutations and links the findings to a new theory that provides a new concept for the origin of mutations for the first time.
The implications for biology, medicine, computer science, and perhaps even our understanding of the origin of life itself are potentially far-reaching.
A random mutation is a genetic change whose probability is independent of its benefit. Only when these supposed random events occur does natural selection examine them, separating the beneficial from the harmful. For over a century, scientists believed that a series of such random events accumulated bit by bit over time to create the diversity and splendor of life around us.
However, it has never been possible to directly investigate whether mutations arise randomly in the DNA. Mutations are rare events relative to the size of the genome, and technical limitations have so far made it impossible for scientists to examine the genome in sufficient detail to track individual mutations as they occur naturally. To solve this problem, Prof. Adi Livnat of the University of Haifa, director of the Sagol Lab for Evolution Research, lead author Dr. Daniel Melamed, and the team developed a new, highly precise detection method and recently applied it to the famous HbS mutation, which protects against malaria but causes sickle cell anemia in homozygotes. The results showed that the HbS mutation did not arise randomly but occurred disproportionately in the gene and population where it was needed. Now, they report the same non-random pattern in a second mutation of evolutionary significance.
The new study investigates the de novo emergence of a mutation in the human APOL1 gene. This mutation protects against a form of trypanosomiasis, a disease that has plagued Central Africa in the past, causing tens of thousands of deaths annually until recently. In people with two copies of the gene, it also increases the risk of chronic kidney disease. If the APOL1 mutation arises randomly, it should occur at a similar rate in all populations and then spread under the pressure of trypanosomes. However, if it does not arise randomly, it might actually be more common where it is beneficial. The findings support the non-random pattern: the mutation was much more common in sub-Saharan Africans, who have battled endemic diseases for generations, than in Europeans, who have not, and precisely at the spot in the genome where it offers protection. “The new findings fundamentally challenge the notion of a random mutation,” said Livnat.
DOI: 10.1073/pnas.2424538122.
