October 26, 2005
Flipped Genetic Sequences Illuminate Human Evolution and Disease
By comparing the human genome with that of the chimpanzee, man's
closest living relative, researchers have discovered that chunks of
similar DNA that have been flipped in orientation and reinserted into
chromosomes are hundreds of times more common in primates than
previously thought. These large structural changes in the genome,
called inversions, may account for much of the evolutionary difference
between the two species. They may also shed light on genetic changes
that lead to human diseases.
Although humans and chimpanzees diverged from one another
genetically about six million years ago, the DNA sequences of the two
species are approximately 98 percent identical. Given the 2005
publication of the draft chimpanzee genome sequence, researchers can
now readily identify the differences between the human and chimp
genomes. These differences lend insight into how primates evolved,
including traits specific to humans.
“We are using an evolutionary approach to identify mutations that may predispose people to disease.”
Stephen W. Scherer
The researchers published their findings in the October 28, 2005,
issue of the journal Public Library of Science Genetics (PLoS
Genetics). The paper was published early online. Senior author
Stephen W. Scherer is a HHMI international research scholar, a senior
scientist in the Genetics and Genomic Biology Program at the Hospital
for Sick Children in Toronto, Canada, and an associate professor of
molecular and medical genetics at the University of Toronto.
 | | | | |  |  | | | | |  |  | Chimpanzee and Human Chromosomes
Inversion of DNA segments between chimpanzee and human chromosomes... more
Illustration: Jeffrey R. MacDonald
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This research expands on a Nature paper published on
September 1, 2005, by HHMI investigator Evan E. Eichler at the
University of Washington. Eichler's group determined that novel
duplications of genetic material within humans also significantly
contribute to differences between the species.
Instead of identifying sequence changes between the two genomes at
the base-pair level, Scherer focused his research on large structural
variations in chromosomes between humans and chimps, specifically
genetic inversions. Inversions can disrupt the expression of genes at
the point where the chromosome breaks, as well as genes adjacent to
breakpoints.
“From a medical genetics perspective, there are probably
hundreds of disease genes that have not yet been characterized,”
said Scherer. “The vast majority of disease gene discovery has
been based on gene sequencing, but this is not a comprehensive view of
chromosomes. We are using an evolutionary approach to identify
mutations that may predispose people to disease.”
According to Scherer, prior to this research, only nine inversions
between humans and chimps had been identified. Using a computational
approach, Scherer's group identified 1,576 presumed inversions between
the two species, 33 of which span regions larger than 100,000 base
pairs—a sizeable chunk of DNA. The average human gene is smaller,
only about 60,000 bases in length.
Scherer's team experimentally confirmed 23 out of 27 inversions
tested so far. Moreover, by comparing the chimp genome with its
ancestor, the gorilla genome, they determined that more than half of
the validated inversions flipped sometime during human evolution.
Perhaps even more interesting than the abundance of inversions that
Scherer's group unveiled was their discovery that a subset of the
inversions are polymorphic—taking different forms—within
humans, meaning that the human genome is still evolving. When the 23
experimentally confirmed inversions were tested against a panel of
human samples, the scientists found three inversions with two alleles
or pairs of genes displaying the human inversion in some people,
whereas others had one allele of the human inverted sequence and one
allele of the normal sequence in chimps.
Having one allele with an inversion and one allele without
represents a ticking time bomb in genetic terms, Scherer said, since
these alleles may improperly align and recombine during replication,
ultimately causing DNA deletions or a loss of DNA that subsequent
generations inherit. Scherer's prior research on Williams-Beuren
syndrome, a disease caused by DNA micro-deletions, identified a
significantly higher incidence of inversions among the parents of
afflicted patients.
Interestingly, one of the inversions that Scherer identified as
polymorphic in his current paper includes a gene known to be involved
in colorectal cancer. Whether individuals polymorphic for this
inversion are at increased risk for the development of colorectal
cancer is not yet known.
Scherer said that his group looked at only a very small subset of
the human population when assessing the prevalence of polymorphisms. He
suspects that polymorphisms, and structural variations in general, may
be much more common than his preliminary analyses suggest.
“These findings may cause people to rethink their ideas about
how species evolved,” Scherer said. “They also highlight
how the mechanisms of evolution may be associated with
disease.”
Scherer determined that about 10 percent of the presumed inversions
either contain a complete gene within the flipped region, constitute a
flipped region within a gene, or cause a breakpoint somewhere within a
gene. These inversions represent prime targets for disease gene
discovery, which Scherer's team is exploring further.
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Cindy Fox Aisen
