September 01, 2005
A New View of Human-Chimpanzee Genome Differences
Comparisons of the human genome and the newly completed draft of the
chimpanzee genome have unearthed major differences between the patterns
of large duplicated segments of DNA in the two species. These segmental
duplications — which straddle large stretches of DNA — appear to have
had a significant impact in altering the genomic landscape of apes and
humans.
The popular understanding of the genetic differences between
chimpanzees and humans should be recast in light of the findings of
major differences in segmental duplications, said the senior author of
the study, Evan Eichler of the Howard Hughes Medical Institute at the
University of Washington School of Medicine.
“So when we talk about how similar chimps and humans are, we really need to be careful that we are referring to variation in the whole genome as opposed to just those single-base-pair changes.”
Evan E. Eichler
The traditional comparison cited in textbooks is that the difference
is 1.2 percent, based on variations in single base-pairs in gene
sequences. “But our data on these duplications shows a 2.7
percent difference, base per base, between chimps and humans,”
said Eichler. “So when we talk about how similar chimps and
humans are, we really need to be careful that we are referring to
variation in the whole genome as opposed to just those single-base-pair
changes.”
Eichler led the research team which published the comparative genome
analysis in the September 1, 2005, issue of the journal Nature.
Their research article was one of several analyses that accompanied a
report on the draft sequence of the chimpanzee genome. Eichler also
participated in the chimpanzee genome project.
Eichler and his colleagues in Seattle collaborated with researchers
from the University of Bari in Italy, the Max Planck Institute for
Evolutionary Anthropology, the Washington University School of Medicine
in St. Louis, Children's Hospital of Oakland Research Institute and the
National Library of Medicine.
Duplications of extensive segments of DNA occur during the
production of sperm or eggs because of a predisposition of certain
sites along the chromosomes to undergo breakage and rearrangements,
Eichler explained. The resulting segmental duplications are
evolutionarily important because they give rise to extra copies of
genes that allow evolution to more freely “experiment” with
mutations that could give rise to new traits, said Eichler. However,
they can also lead to some two dozen genetic diseases.
Comparative analysis of segmental duplications in humans and
chimpanzees could give important insights into why such specific
abnormalities tend to occur and when these events arose. “The
chimp can provide us historical information about ancestral states of
disease,” said Eichler. “We know that there are some
disease `architectures' that are shared between chimp and human, so we
know that is the ancestral state. But other predisposing structures
have arisen only in the human lineage, so such comparisons can provide
important information on the genetic histories of disorders and disease
susceptibilities of the human species.”
In their analysis, the researchers mapped the draft chimpanzee
sequence data onto the human genome sequence as a reference. With their
comparative map, they used sophisticated computational analysis to
distinguish three categories of segmental duplications — those found
in humans but not in chimpanzees; those found in chimpanzees but not in
humans; and those shared between humans and chimpanzees. The
researchers looked for duplications greater than about 20,000 base
pairs in length.
Their analysis revealed that about a third of the duplications were
found in humans but not in chimpanzees. “This was surprising,
because it tells us that there is a high frequency of de novo
duplications that arose over the time of human and great ape
evolution,” said Eichler. “In contrast there are a lot of
theories out there that duplications emerge and are maintained through
selection or other processes such as gene conversion.”
In analyzing the chimpanzee-only duplications, the researchers found
that chimpanzees showed fewer sites of duplication than humans, but
they did have a great number of copies of the duplicated segments. Of
particular interest to the scientists, was that a few of the shared
duplications were often “hyperexpanded” in the
chimpanzee.
In one of the more extreme cases, while the human genome showed four
copies of one segment, the chimpanzee genome showed some 400 copies.
“Such hyperexpansions are interesting because they occur on the
ends of chromosomes,” said Eichler. “In the case of the
segment that showed such massive duplication, it occurred near a region
that in the great apes is broken into two chromosomes, but in humans is
the fused chromosome two.” Such a difference hints at some
chromosomal instability in both species that resolved itself
differently in humans than in chimpanzees, he said.
Eichler was also intrigued by the data indicating that
chimpanzee-only or human-only duplications tended to occur near regions
of shared human-chimpanzee duplications — a phenomenon the researchers
dubbed “duplication shadowing.” Discovery of this
phenomenon, he said, could lead to greater understanding of the
properties of chromosomal regions that tend to experience
instabilities. “Such regions are pretty important from an
evolutionary perspective, because a lot of people operate under the
assumption that these types of mutational processes are randomly
distributed,” said Eichler. “But in essence, they are not.
There is probably something about these regions that has made them
particularly hot in terms of change over the course of evolutionary
time.”
The next major project the researchers will tackle is trying to
understand what the differences in segmental duplication mean for the
species in terms of the evolution of genes embedded in those segments.
“At the top of our list is to work out which of the genes in the
duplications show signatures of natural selection,” said Eichler.
“This is a big question, because our hypothesis is that the big
differences in structure between humans and chimps arose or might be
tolerated because of important adaptations in the genes
themselves.” There are a few examples of such rapidly evolving
duplicated genes, but these genes have not been systematically analyzed
due to the difficulties in characterizing genes in these regions of the
genome.
When the genome of another great ape, the orangutan, is completely
sequenced, the data should provide researchers with the opportunity to
gain even more insight into evolutionarily important genetic
differences between humans and other primates, he said.
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Howard Hughes
