August 10, 2000
Mutation Rate of Male Sex Chromosome Lower than Expected
Genetic sequencing and analysis of regions of the X and Y
chromosomes of humans, chimpanzees and gorillas, reveals a much smaller
difference in mutation rates of the two sex-determining chromosomes,
say researchers from the Howard Hughes Medical Institute at the
Massachusetts Institute of Technology.
The results cast doubt on the idea that sperm production is
inherently more prone to error than egg production. The finding also
means that genetic-disease-producing mutations that had been attributed
to what was thought to be a fundamentally higher mutation rate in males
must now be explored in terms of their individual underlying causes,
says HHMI investigator David C. Page, who is at
the Whitehead Institute for Biomedical Research at MIT. Page and
Whitehead colleagues Hacho B. Bohossian and Helen Skaletsky report
their conclusions in the August 10, 2000, issue of Nature.
“When we began this project, I anticipated that we would simply come up with a more precise estimate of this ratio, adding a few more decimal places. Instead we got a very different answer.”
David C. Page
"We were led to pursue this question because an understanding of how
mutations arise is part of the fundamental underpinnings of human
genetics," said Page. "Without mutations, there would be no genetic
variation and, thus, no genetics. And this particular question of the
balance of mutations that arise in mothers as compared to fathers has
been a fundamental question in genetics for more than half a
century."
Page and his colleagues set out to examine differences in mutation
rate because they believed that previous measurements may have been
skewed because the earlier studies were based on comparisons of
corresponding genes on the X and Y chromosomes that may have been under
different evolutionary constraints. Page's team chose to compare DNA
sequences within large regions of the human X and Y chromosomes that
showed no evidence of harboring genes, and thus, would be far more
likely to represent accurately the base mutation rate of those
chromosomes.
The regions of X and Y studied by Page's team showed nearly 99
percent identity because these regions had undergone massive DNA
sequence swapping between the two sex chromosomes only three to four
million years ago, during the evolution of humans. To ascertain the
original, primitive sequences of those regions, the scientists used
homologous segments of the X chromosomes of chimpanzees and gorillas,
which are more closely related to humans than species used in previous
studies.
"Those earlier studies had looked at much older duplication events
in primates, using sequences that were much more diverged from each
other," said Page. "With regions containing 99 percent similarity, it
was very easy for us to find those single nucleotide substitutions and
to be sure that they represented isolated one-time events.
"It’s like going out on a perfectly smooth beach early in the
morning after the tide has gone out and counting raindrops on the
unmarked surface. We were dealing with a very clean experiment of
nature, in which every individual mutation was captured."
The scientists selected as a target for their study a portion of the
highly homologous regions—composed of about 38,600
nucleotides—that was found in the human X and Y chromosomes and
in the chimpanzee and gorilla X chromosomes. Their sequencing and
comparison revealed that this segment of the human X and Y chromosomes
differed in only 441 nucleotides.
The scientists then pinpointed the mutations in human sex chromosome
by comparing each nucleotide variation with sequence data from the
chimpanzee and gorilla X chromosome sequences. For example, if a
particular nucleotide alteration was found on the human Y chromosome,
but not on the human, chimpanzee or gorilla X chromosome, the mutation
was presumed to have taken place on the human Y chromosome.
Using this technique, the scientists were able to infer which human
sex chromosome originally harbored a given nucleotide substitution.
From these data, they calculated a male-female mutation rate ratio of
about 1.7—much lower than the previously suggested ratio of
5.
"When we began this project, I anticipated that we would simply come
up with a more precise estimate of this ratio, adding a few more
decimal places," said Page. "And instead we got a very different
answer."
The finding of such a modest difference in X and Y mutation rates
could have important consequences for genetic studies of inherited
diseases, said Page.
"Until now, the far greater number of cell divisions involved in
making a sperm than in making an egg has provided a very attractive
rationalization for what appeared to be the much higher mutation rate
in the male versus female germline," he said. "However, our results
suggest that there is something closer to sexual parity in mutation
rates." This parity implies that the cell divisions involved in making
sperm are of much higher fidelity than was previously appreciated, said
Page. Also, he said, the finding challenges scientists to explore
differences among cell divisions in terms of mutation risk.
"Our findings have implications, not just for disorders that are
sex-linked, but for all genetic disorders where mutations are a major
contributor, regardless of chromosomal sites, and regardless of whether
they affect boys or girls," Page emphasized.
The higher incidence of Y chromosome mutations that produce some
inherited diseases could be due to specific, highly mutable nucleotide
positions—mutational "hotspots"—that represent departures
from the normal rate of mutational. Thus, understanding these anomalous
mutation sites might require a better understanding of how the
particular sequences might be prone to mutation said Page.
"We have now moved the baseline considerably, so that these hotspots
now appear as very special cases, that really have to be studied and
understood as special cases," he said.
|
