What mapping approach did the Human Genome Project use?

The Human Genome Project used clone-by-clone sequencing as its mapping approach. Scientists first built a physical map of the genome, then selected overlapping DNA clones in an ordered path before sequencing them.

The large DNA fragments were usually carried in bacterial artificial chromosomes, or BACs. Researchers identified how the BACs overlapped, arranged them along chromosomes, and then fragmented each selected clone into smaller pieces for Sanger sequencing. Computers assembled those smaller reads, while the physical map supplied the larger-scale order.

This strategy is also called hierarchical shotgun sequencing, map-based sequencing, or BAC-by-BAC sequencing. Those terms describe closely related aspects of the same approach, which is why they can be confusing in quiz questions. The public HGP favored this mapped strategy because whole-genome shotgun sequencing was considered difficult to assemble reliably for a genome as large and repetitive as ours.

The private Celera project used a more direct whole-genome shotgun strategy in parallel. Improvements in computing and sequencing later made whole-genome shotgun methods much more practical.