variations weren’t found in a healthy
control group. The authors say many
different variants might lead to autism,
including variants that affect genes
important for brain development and
function, as well as variants that affect
multiple other genes.
At least 14 diseases have been associated with copy number variants in the
past few years, Lee says. “We’re going to
find a lot more out there,” he predicts.
But variety is not all bad. “The vast
majority of those differences will have
no impact at all on the person,” Shelling
says. And some may even be good.
A human variety
Indeed, some variations may be tied to
qualities that distinguish humans from
other primates. Certainly, structural variation is part of what makes each person
different from another. Varying copies of
certain regions of the genome may be evolution’s answer to making sure humans
don’t grow genetically stagnant.
“Perhaps it is a deliberate mechanism
to ensure that our genome is always
changing,” Shelling says. “It was a bit of
a shock that we could have a mechanism
that would change the numbers and mess
with our genomes that way.”
Although humans vary at millions of
bases, says Sarah Tishkoff, a geneticist
at the University of Maryland in College
Park, people are overall very alike.
“We still think that as a species we’re
still really quite similar,” she says. “Any
two of us are more similar than any two
Copy number variations also occur
in humans’ ape cousins and may be a
legacy from an ancient ancestor. About
8 million to 12 million years ago, a common ancestor of humans and African
great apes experienced an explosion of
duplications in its genome, Eichler’s
group reported in the Feb. 11 Nature (SN:
3/14/09, p. 14). The large increase in the
gene duplication rate continued into the
common ancestor of humans and chimpanzees. Later the rate slowed again.
Those duplications may have established a genome architecture that predisposes humans to changes in copy
number even today, Eichler suggests. common. Only 8 percent of the variants
In the Feb. 13 American Journal of identified in the study were rare, found
Human Genetics , Eich le r’s grou p in a single family or individual. And only
describes hot spots for copy number 10 rare variants of the 1,320 analyzed
variation, sites located in or next to were found in a child but not the parents,
duplicated regions of the genome. The indicating a new change.
locations hint that such variations arise New mutations are more common in
when chromosomes line up to swap sporadic cases of disease than in cases
geneticinformationduring where the patient has a
recombination. Recombi- family history of the dis-
“It was a bit
nation occurs when chro- ease, McCarroll says. But
of a shock that
mosomes are paired before researchers still don’t know
we could have
separation during the pro- whether rare or common
duction of egg or sperm variants are more likely to
cells. But sometimes exist- be associated with disease.
that would ...
ing gene duplications can About 1 to 2 percent of
cause the chromosomes to our genomes autism and schizophrenia
misalign, and that misalign- cases have been associated
ment leads to further dupli- with rare structural vari-cations or deletions. Last ants, but no common vari-
UNIVERSITY OF AUCKLAND
year in Nature, Eichler and ations have been found to
his colleagues reported comparisons of explain inheritance of those disorders,
individual human genomes suggesting McCarroll says.
that misalignment and unequal swap- In contrast, some cases of Crohn’s
ping during recombination create nearly disease — an inflammatory bowel disor-half of copy number variants. der — have been linked to a common vari-
Damage to DNA may lead to structural ant that deletes defensins, genes involved
changes too. Toxins and other stressors in protecting against invading bacte-sometimes break chromosomes. The ria. And an international consortium
process that repairs broken chromo- reported January 4 in Nature Genetics
somes may add or subtract DNA or mis- that body mass index is linked to a com-takenly relocate a bit of one chromosome mon structural variant: a deletion cover-on to another. ing a stretch of DNA more than 45,000
Still other copy number variants may bases long and containing an important
arise when DNA replication is stalled. gene called NEGR1, which is associated
And mobile bits of DNA — commonly with obesity. No rare structural variants
called jumping genes — do their share of have been linked to either Crohn’s disease
shaping the genome, too. or body mass, McCarroll says.
Most methods of detecting structural Despite what specific genetic additions
variation have not identified the precise and subtractions may contribute to such
location of the end points of the variants, diseases, environmental factors may be
information that is needed to determine just as important in determining who gets
the mechanism that created the variant, sick, says Shelling.
says Steven McCarroll, a geneticist at the “ You ar e not predestined by your
Broad Institutein Cambridge, Mass., and genes,” Shelling says. “If you’ve got a
the Harvard Medical School in Boston. gene that protects you from having can-
Scientists do know that most of the cer, it doesn’t mean you should smoke.
copy number variants in the general If you’ve got a gene that makes you slim,
population are old. In a study pub- you still shouldn’t eat a McDonald’s
lished last October in Nature Genetics, every night.” s
McCarroll and his colleagues found that
over 90 percent of the copy number differences among people in the study are due to
the usual suspects, variants that are quite
s Charles Lee lab: www.chromosome.