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 observations suggest that structural variations are more specific to individuals than single nucleotide polymorphisms are, according to researchers. It might seem counter-intuitive 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 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 or paragraphs.