Mutations driving evolution are informed by the genome, not random, study suggests
edited
by Gaby Clark,
reviewed by Robert
Egan
https://phys.org/news/2025-09-mutations-evolution-genome-random.html
MEMDS
experimental setup. Credit: Proceedings of the National Academy of
Sciences (2025). DOI: 10.1073/pnas.2424538122
A
study published in the Proceedings of the National
Academy of Sciences by scientists from Israel and Ghana shows that an
evolutionarily significant mutation in the human APOL1 gene arises not randomly
but more frequently where it is needed to prevent disease, fundamentally
challenging the notion that evolution is driven by random mutations and tying
the results to a new theory that, for the first time, offers a new concept for
how mutations arise.
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 chance of arising is unrelated to its
usefulness. Only once these supposed accidents arise does natural selection vet
them, sorting the beneficial from the harmful. For over a century, scientists
have believed that a series of such accidents has built up over time, one by
one, to create the diversity and splendor of life around us.
However, it
has never been possible to examine directly whether mutations in the DNA
originate at random or not. Mutations are rare events relative to the genome's
size, and technical limitations have prevented scientists from seeing the
genome in enough detail to track individual mutations as they arise naturally.
To overcome
this, 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 ultra-accurate detection method and recently applied it to the famous HbS
mutation, which protects from malaria but causes sickle-cell anemia in
homozygotes.
Results
showed that the HbS mutation did not arise at random, but emerged more
frequently exactly in the gene and population where it was needed. Now, they
report the same nonrandom pattern in a second mutation of evolutionary
significance.
The new
study examines the de novo origination of a mutation in the human APOL1 gene
that protects against a form of trypanosomiasis, a disease that devastated
central Africa in historical times and until recently has caused tens of
thousands of deaths there per year, while increasing the risk of chronic kidney
disease in people with two copies.
If the APOL1
mutation arises by chance, it should arise at a similar rate in all
populations, and only then spread under Trypanosoma pressure. However, if it is
generated nonrandomly, it may actually arise more frequently where it is
useful.
Results
supported the nonrandom pattern: the mutation arose much more frequently in
sub-Saharan Africans, who have faced generations of endemic disease, compared
to Europeans, who have not, and in the precise genomic location where it
confers protection.
"The
new findings challenge the notion of random mutation fundamentally," said
Livnat.
From
random mutation to natural simplification
Historically,
there have been two basic theories for how evolution happens— random mutation
and natural selection, and Lamarckism—the idea that an individual directly
senses its environment and somehow changes its genes to fit it. Lamarckism has
been unable to explain evolution in general, so biologists have concluded that
mutations must be random.
Livnat's new
theory moves away from both of these concepts, proposing instead that two
inextricable forces underlie evolution. While the well-known external force of
natural selection ensures fitness, a previously unrecognized internal force
operates inside the organism, putting together genetic information that
has accumulated over generations in useful ways.
To
illustrate, take fusion mutations, a type of mutation where two previously
separate genes fuse to form a new gene. As for all mutations, it has been
thought that fusions arise by accident: one day, a gene moves by error to
another location and by chance fuses to another gene, once in a great while,
leading to a useful adaptation. But Livnat's team has recently shown that genes
do not fuse at random.
Instead,
genes that have evolved to be used together repeatedly over generations are the
ones that are more likely to get fused. Because the genome folds in 3D space,
bringing genes that work together to the same place at the same time in the
nucleus with their chromatin open, molecular mechanisms fuse these genes rather
than others. An interaction involving complex regulatory information that has
gradually evolved over generations leads to a mutation that simplifies and
"hardwires" it into the genome.
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In the
paper, they argue that fusions are a specific example of a more general and
extensive internal force that applies across mutation types. Rather than local
accidents arising at random locations in the genome disconnected from other
genetic information, mutational processes put together multiple meaningful
pieces of heritable information in many ways.
Genes that
evolved to interact tightly are more likely to be fused; single-letter RNA
changes that evolved to occur repeatedly across generations via regulatory
phenomena are more likely to be "hardwired" as point mutations into the
DNA; genes that evolved to interact in incipient networks, each under its own
regulation, are more likely to be invaded by the same transposable element that
later becomes a master-switch of the network, streamlining regulation, and so
on. Earlier mutations influence the origination of later ones, forming a vast
network of influences over evolutionary time.
"Previous
studies examined mutation rates as averages across genomic positions, masking
the probabilities of individual mutations. But our studies suggest that, at the
scale of individual mutations, each mutation has its own probability, and the
causes and consequences of mutation are related," says Livnat.
"At
each generation, mutations arise based on the information that has accumulated
in the genome up to that time point, and those that survive become a part of
that internal information."
This vast
array of interconnected mutational activity gradually hones in over the
generations on mutations relevant to the long-term pressures experienced,
leading to long-term directed mutational responses to specific environmental
pressures, such as the malaria and Trypanosoma–protective HbS and APOL1
mutations.
New genetic
information arises in the first place, they argue, as a consequence of the fact
that mutations simplify genetic regulation, hardwiring evolved biological
interactions into ready-made units in the genome. This internal force of
natural simplification, together with the external force of natural selection, act over
evolutionary time like combined forces of parsimony and fit, generating
co-optable elements that themselves have an inherent tendency to come together
into new, emergent interactions.
"Co-optable
elements are generated by simplification under performance pressure, and then
engage in emergent interactions—the source of innovation is at the system
level," said Livnat. "Understood in the proper timescale, an
individual mutation does not arise at random nor does it invent anything in and
of itself."
Redefining
how evolution works
The
potential depth of evolution from this new perspective can be seen by examining
other networks. For example, the gene fusion mechanism—where genes repeatedly
used together across evolutionary time are more likely to be fused together by
mutation—echoes chunking, one of the most basic principles of cognition and
learning in the brain, where pieces of information that repeatedly co-occur are
eventually chunked into a single unit.
Yet fusions
are only one instance of a broader principle: diverse mutational processes
respond to accumulated information in the genome, combining it over generations
into streamlined instructions. This view recasts mutations not as isolated
accidents, but as meaningful events in a larger, long-term process.
More
information: Daniel
Melamed et al, De novo rates of a Trypanosoma -resistant mutation in two human
populations, Proceedings of the National Academy of Sciences (2025). DOI:
10.1073/pnas.2424538122
Journal
information: Proceedings
of the National Academy of Sciences
Provided
by University of
Haifa
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