A new study by a team of researchers from Israel and Ghana has brought the
first evidence of nonrandom mutation in human genes, challenging a core
assumption at the heart of evolutionary theory by showing a long-term
directional mutational response to environmental pressure. Using a novel
method, researchers led by Professor Adi Livnat from the University of Haifa
showed that the rate of generation of the HbS mutation, which protects
against malaria, is higher in people from Africa, where malaria is endemic,
than in people from Europe, where it is not.
"For over a century, the leading theory of evolution has been based on
random mutations. The results show that the HbS mutation is not generated at
random but instead originates preferentially in the gene and in the
population where it is of adaptive significance," said Prof. Livnat. Unlike
other findings on mutation origination, this mutation-specific response to a
specific environmental pressure cannot be explained by traditional theories.
"We hypothesize that evolution is influenced by two sources of information:
External information that is natural selection, and internal information
that is accumulated in the genome through the generations and impacts the
origination of mutations," said Livnat.
Ever since Darwin we have known that life arose by evolution. But how,
exactly, does evolution—in all its grandeur, mystery and complexity—happen?
For the past century scientists have assumed that mutations occur by
accident to the genome and that natural selection, or the survival of the
fittest, favors beneficial accidents. The accumulation of these presumed
genetic accidents under natural selection over the millennia leads in turn
to adaptations, from the hawk's sharp eye to the human cardiovascular
system.
While widely held in the scientific community, this view has always left
open fundamental questions, such as the problem of complexity. Can the
sequential accumulation of small random changes, each beneficial on its own,
lead within the timespan available to the evolution of such astonishingly
complex and impressive adaptations as we see around us in nature, such as
eyes, brains or wings, where complementary parts interweave into a complex
whole? However, the only alternative at the fundamental level conceived of
up until now consisted of variants of Lamarckism—the idea that organisms can
somehow respond directly to their immediate environments with beneficial
genetic change. Since Lamarckism has not worked in general, the notion of
random mutation remained the prevailing view.
In order to distinguish between the random mutation and natural selection
explanation and the possibility that nonrandom mutation is important, Prof.
Livnat and his lab manager, Dr. Daniel Melamed, developed a new method for
detecting de novo mutations—mutations that arise "out of the blue" in
offspring without being inherited from either parent. In breaking a new
accuracy record, their method allowed something not previously
possible—counting of de novo mutations for particular points of interest in
the genome.
They then applied their method to examine the de novo emergence of the human
hemoglobin S (HbS) mutation, perhaps the most well known point mutation in
biology and evolution. HbS provides protection against malaria for people
with one copy but causes sickle-cell anemia in those with two. Malaria
itself, a vector-borne blood disease, has arguably been the strongest
selection pressure acting on humans in the last 10,000 years, often causing
more than a million deaths per year in Africa in the recent past. HbS is
also used as a central example of random mutation and natural selection in
evolution: It has been long assumed to have arisen accidentally in an
individual in sub-Saharan Africa and then spread inside Africa via natural
selection until its malaria-protective benefits were balanced out by its
sickle-cell anemia costs.
By examining the de novo origination of HbS, Livnat was able to disentangle
for the first time whether the malaria-protective mutation arises randomly
and spread in Africa only because of selection pressure or instead whether
it could actually be originating de novo more frequently in sub-Saharan
Africans—a group that has been subject to intense malarial selection
pressure for many generations. If the mutation is random, then it should be
equally likely to emerge in both geographical groups. However, if mutation
is nonrandom, then perhaps it would actually emerge more frequently in
Africans.
"There are at least two possible reasons why such a question had not been
asked before," explains Prof. Livnat. "First, it had been assumed that
mutation is random. Second, even if one had wanted to ask such a question,
it would not have been possible with previous methods."
Contrary to the widely accepted expectations, the results supported the
nonrandom pattern. The HbS mutation originated de novo not only much faster
than expected from random mutation, but also much faster in the population
(in sub-Saharan Africans as opposed to Europeans) and in the gene (in the
beta-globin as opposed to the control delta-globin gene) where it is of
adaptive significance. These results upend the traditional example of random
mutation and natural selection, turning it into an example of a nonrandom
yet non-Lamarckian mutation.
"Mutations defy traditional thinking. The results suggest that complex
information that is accumulated in the genome through the generations
impacts mutation, and therefore mutation-specific origination rates can
respond in the long-term to specific environmental pressures," said Prof.
Livnat. Previous studies, motivated by Lamarckism, only tested for an
immediate mutational response to environmental pressures. "Mutations may be
generated nonrandomly in evolution after all, but not in the way previously
conceived. We must study the internal information and how it affects
mutation, as it opens the door to evolution being a far bigger process than
previously conceived," Livnat concluded.
Until now, investigators have been limited by technology to measuring
mutation rates as averages across many positions in the genome. Overcoming
this barrier, the new method developed by Livnat and Melamed allowed the HbS
mutation to be the first to have its mutation-specific origination rate
measured, opening up new vistas for studies on mutation origination. These
studies have the potential to affect not only our fundamental understanding
of evolution, but also our understanding of diseases that are caused by
mutations, namely genetic disease and cancer.
The article was accepted in the scientific journal Genome Research and
appears in an advance online form.
Reference:
Daniel Melamed et al, De novo mutation rates at the single-mutation
resolution in a human HBB gene-region associated with adaptation and genetic
disease, Genome Research (2022).
DOI: 10.1101/gr.276103.121