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
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 24 July Nature Biotechnology study.
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 fragments.
As a result, most genomic studies, including
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 or paragraphs.
"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
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," they wrote.
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 geneticists call
the "missing heritability." Of common disease risk that's clearly
hereditary, only a small fraction can currently be traced to
"Structural variations are a very hot topic," said Gerstein.
"They're probably the major form of variation in humans."