Less Is More: Compact Genomes Pay Dividends

Sydney and the Blowfish

In 1993, Sydney Brenner, like many others, recognized that vertebrates are distinct in their morphology and development and that access to the complete sequence of a vertebrate genome would yield valuable insights into the biology of higher species not obtainable from genome studies of yeast, fly, or even the nematode. Moreover, at that time it was not possible, through sequencing technology, to rapidly generate the huge volumes of accurate, inexpensive sequence data necessary for sequencing the human genome to succeed in a cost-effective manner. The good news was that evolution likely dictated that vertebrates would be distinguished from each other at the genomic level more by the ways in which their genes were regulatedrather than by profound differences in gene repertoire (Elgar 1996a). Thus, the goal was to find a vertebrate genome of intermediate size that would be both (1) representative of higher organisms and (2) small enough and gene-dense enough for large-scale genomic studies. Brenner’s organism of choice was the pufferfish (a.k.a. blowfish)Fugu rubripes (Brenner et al. 1993). The era of compact vertebrate genomics was born.

But why Fugu, an exotic Japanese delicacy, known more for its bloated appearance and potent neurotoxin (potentially lethal to diners if not prepared by a knowledgeable chef) than for its utility as a model organism? In a survey of the haploid DNA content of nearly 300 teleostean fishes, Ralph Hinegardner (1968) observed that members of the Tetraodontidae family in particular tend to have very small genomes—on the order of 400 Mb, some 7.5-fold smaller than the 3000-Mb human genome (0.4–0.5 pg/cell vs. 3 pg in the human). Whereas its size suggested that it would be more manageable than a mammalian genome, what was more telling was the discovery that <8% of FuguDNA is repetitive, as compared to ∼60% of human …