Your Genome Structure, Not Genetic Mutations, Makes
By Brandon Keim
July 29, 2011
A new look at the human genome suggests that
unappreciated variations in its fundamental
architecture, rather than point-by-point mutations, may
be responsible for most genetic difference among people.
Point-by-point mutations, called single nucleotide
polymorphisms, involve simple changes to DNA lettering.
They're the best-studied type of variation, the target
of most genomic disease hunts, and the substance of
commercially available personal genome readouts.
More complex yet less-studied are structural variations,
which involve large-scale changes: wholesale
duplications and reversals, or unexpected additions and
omissions, of long DNA sequences.
Traditional genome sequencing techniques are too fuzzy
and piecemeal to make sense of these, yet "our
observations suggest that structural variations are more
specific to individuals than single nucleotide
polymorphisms are," wrote researchers led by Jun Wang of
the Beijing Genomics Institute in a July 24 Nature
It might seem counterintuitive that big changes have
been harder to detect than small ones, but it's a
consequence of how genomes are read. Every method
involves breaking long DNA sequences - the human genome
contains three billion DNA pairs - into pieces, then
trying to reassemble them. The methods vary according to
fragment size and reassembly technique, but as a rule
it's far less expensive and time-intensive to use small
As a result, most genomic studies, including gold-
standard genome-wide association surveys, involve
sequences reassembled from small pieces. As with a
jigsaw puzzle or a book, however, larger fragments would
work better. If the pieces are too small, or the text
blocks just a few letters long, it's difficult to be
certain what the final product ought to look like. It's
possible to compare two pieces, but not puzzle sections
"One reason you've heard more about single nucleotide
polymorphisms, that they've come to the fore even though
they're a more minor form of variation than these
structural variants, is that they were easier to see,"
said Yale University bioinformaticist Mark Gerstein, who
was not involved in the study.
In the new study, Wang and colleagues used algorithms
that assemble long, relatively intact genome sequences
from small fragments, allowing them to see more
structural variation than is usually possible. In a
high-profile earlier study, they'd used it to sequence a
giant panda genome; this time they compared structural
variations across 106 people from the 1000 Genomes
They found that individuals seem to be distinguished
less by their SNPs than their structural variations.
"Defining structural variations will be of considerable
importance for future analyses of personal genomes,"
The new study didn't attempt to link structural
variation with traits or disease, but it's possible that
as-yet-unstudied structural variations contain a portion
of what geneticsts call the "missing heritability." Of
common disease risk that's clearly hereditary, only a
small fraction can currently be traced to genes.
"Structural variations are a very hot topic," said
Gerstein. "They're probably the major form of variation
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