Scientists from the Human Genome Project and Celera Genomics left their long-standing rivalry behind last week to participate in the Joint Genome Sequencing Workshop, a meeting designed to seek consensus on the best approach to genome sequencing.
“The goal is to try to look forward and understand what common ground we have, and how to best move forward into the future,” said Gene Myers, Celera’s vice president for informatics research.
The meeting was marked by an atmosphere that was collegial, yet cautious. Most of the 70 or so researchers at the workshop came out in support of a combination of approaches, noting that some of the thorniest problems in finishing the human genome are best handled using a combination of the two projects’ techniques.
While each approach may still have its staunch advocates, they seem to be moving closer together, with most current sequencing projects employing some combination of BAC clones and the whole genome shotgun approach.
Evan Eichler of Case Western Reserve University discussed using random reads from Celera’s whole genome shotgun method as well as the public ordered data for studying large duplicated sequences in the human genome. In addition, different organisms’ genomes might be most effectively sequenced using one method or the other, depending on the number and type of sequence duplications, GC-rich regions, and other factors, Eichler said.
Jim Kent of the University of California Santa Cruz cited the advantages of the HGP’s hierarchical approach, including minimizing the confounding effects of repeating sequences, having a single haplotype within a BAC, and being able to easily distribute work across a number of centers. However, one way to optimize the hierarchical approach, he acknowledged, was to use the shallow initial whole genome shotgun concurrently with mapping.
Celera’s Granger Sutton described the company’s effort to eliminate its dependence on contigs from the public database. Although the sequence Celera published in February did use the public data, a more recent Celera-only human assembly at 5x coverage yielded dependable and significantly larger scaffolds, Sutton said. He attributed the improved results to enhanced algorithms and elimination of some errors found in the public data. “But nobody’s arguing that 5x is a finished sequence,” Sutton said.
Jim Weber, a human geneticist at Marshfield Medical Institute, emphasized the additional depth required in the human genome sequence. He stressed the need to develop an efficient way to find and characterize all the common polymorphisms in the human genome — not only SNPs but also longer-range polymorphisms and insertion/deletions.
Medical research depends on understanding these polymorphisms, he said, and therefore it is important to do raw reads for more individuals than is necessary for other organisms.
“The finished sequence is not going to be the end. It’s just the beginning,” Weber said.