Genome duplication: The evolution of gene functions in development after genome duplication, focusing on skeletal development.

Two rounds of whole genome duplication (called R1 and R2) occurred at about the time of the radiation of early vertebrates. The human genome bears the mark of these events with four paralogs of a few genes (like Hox clusters, Notch genes, and many more) and thousands of genes with 2 or 3 extant copies derived from these vertebrate genome duplications (VGD). Understanding the rules that govern the evolution of paralogs derived by genome duplication (called ohnologs) is important because ohnologs are often involved in related human diseases and their redundancy may help buffer against disease. To serve as an unduplicated outgroup for the VGD, we initiated a program to understand the developmental genomics of the larvacean urochordate  Oikopleura dioica.

 By preparing the first genetic map of the zebrafish genome (Postlethwait et al., 1994) and comparing zebrafish gene maps to emerging data on the pufferfish genome, we discovered in 1998 that these lineages shared a genome duplication that must have occurred at the base of the teleost radiation, the teleost genome duplication (TGD) ((Amores et al., 1998) (Postlethwait et al., 1998)). Because the TGD is substantially more recent than the VGD, it serves as a model to discover rules that govern the evolution of genes and genomes after genome duplication. Furthermore, it has been proposed that the extra genes provided by the VGD and TGD may have been instrumental in promoting the radiation of vertebrates and teleosts.

Wrestling towards an understanding of how ohnologs evolve resulted in the duplication, degeneration, complementation (DDC) hypothesis ((Force et al., 1999), which suggests that, in addition to gene loss and the origin of new functions, which we called nonfunctionalization and neofunctionalization, duplicated genes could be preserved by partitioning ancestral subfunctions between them, subfunctionalization (Postlethwait et al., 2004).

After identifying the TGD, work in the lab focused on two main issues, the connectivity of the zebrafish and human genomes despite the TGD (Postlethwait et al., 2000; Postlethwait et al., 1998; Woods et al., 2005) and testing predictions from the DDC hypothesis (Amores et al., 2004; Postlethwait et al., 2004; Yan et al., 2002). To connect teleost to mammalian genomes, we developed the Synteny Database (, an online tool for the analysis of conserved syntenies (Catchen et al., 2009).

To connect the duplicated genomes of teleosts to those of humans and other mammals, we need a ray-fin fish species that diverged from the teleost lineage before the TGD. Recent work in the lab has focused on developing such a model, and we found that the spotted gar (Lepisosteus oculatus), an ancient air-breathing North American fish fills this role. We helped to develop a reduced representation methodology for making genetic maps with huge numbers of markers (Miller et al., 2007) and then adapted it to Illumina-based next-generation DNA sequencing (Amores et al., 2011) while writing de novo software to analyze the samples (Catchen et al., 2011). Results showed that the gar lineage indeed diverged before the TGD and, remarkably, that its genome arrangement is substantially more similar to the human genome than it is to teleost genomes, despite the biological similarity of gar to teleosts. We conclude that gar provides the intermediate necessary for the functional connection of teleost and human genomes. Furthermore, the gar genome provides an excellent comparator for identifying teleost conserved non-coding elements (unplublished).

Amores, A., Catchen, J., Ferrara, A., Fontenot, Q. and Postlethwait, J.H. (2011) Genome evolution and meiotic maps by massively parallel DNA sequencing: Spotted gar, an outgroup for the teleost genome duplication. Genetics. 188:1-10.  PMCID:  pending.

Amores, A., Force, A., Yan, Y. L., Joly, L., Amemiya, C., Fritz, A., Ho, R. K., Langeland, J., Prince, V., Wang, Y. L., Westerfield, M., Ekker, M., and Postlethwait, J. H. (1998) Zebrafish hox clusters and vertebrate genome evolution. Science 282, 1711-4.

Amores, A., Suzuki, T., Yan, Y. L., Pomeroy, J., Singer, A., Amemiya, C., and Postlethwait, J. H. (2004) Developmental roles of pufferfish Hox clusters and genome evolution in ray-fin fish. Genome Res. 14:1-10.  PMC314266.

Catchen, J., Amores, A., Hohenlohe, P., Cresko, W., and Postlethwait, J.H. (2011) Stacks: building and genotyping loci de novo from short-read sequences. G3 1:171-182.  doi: 10.1534/g3.111.000240. PMCID:  pending.

Catchen, JM, Conery, JS, Postlethwait, JH (2009) Automated identification of conserved synteny after whole genome duplication, Genome Research19(8):1497-505.  PMC2720179

Force, A., Lynch, M., Pickett, F. B., Amores, A., Yan, Y. L., and Postlethwait, J. (1999) Preservation of duplicate genes by complementary, degenerative mutations. Genetics 151, 1531-45.  PMC1460548.

Miller, M. R., Atwood, T. S., Eames, B. F., Eberhart, J. K., Yan, Y.-L., Postlethwait, J. H. and Johnson, E. A. (2007) RAD marker microarrays enable rapid mapping of zebrafish mutations. Genome Biology 8(6):R105.  PMC2394753.

Postlethwait, J., Amores, A., Cresko, W., Singer, A., and Yan, Y. L. (2004) Subfunction partitioning, the teleost radiation and the annotation of the human genome. Trends Genet. 20:481-90.

Postlethwait, J. H., Johnson, S. L., Midson, C. N., Talbot, W. S., Gates, M., Ballinger, E. W., Africa, D., Andrews, R., Carl, T., Eisen, J. S., and et al. (1994) A genetic linkage map for the zebrafish. Science 264, 699-703.

Postlethwait, J. H., Woods, I. G., Ngo-Hazelett, P., Yan, Y. L., Kelly, P. D., Chu, F., Huang, H., Hill-Force, A., and Talbot, W. S. (2000) Zebrafish comparative genomics and the origins of vertebrate chromosomes. Genome Res. 10:1890-1902.

Postlethwait, J. H., Yan, Y. L., Gates, M. A., Horne, S., Amores, A., Brownlie, A., Donovan, A., Egan, E. S., Force, A., Gong, Z., Goutel, C., Fritz, A., Kelsh, R., Knapik, E., Liao, E., Paw, B., Ransom, D., Singer, A., Thomson, M., Abduljabbar, T. S., Yelick, P., Beier, D., Joly, J. S., Larhammar, D., Rosa, F., Westerfield, M., Zon, L. I., Johnson, S. L., and Talbot, W. S. (1998) Vertebrate genome evolution and the zebrafish gene map. Nat. Genet. 18, 345-9.

Woods, I. G., Wilson, C., Friedlander, B., Chang, P., Reyes, D. K., Nix, R., Kelly, R. D., Chu, F., Postlethwait, J. H., and Talbot, W. S. (2005) The zebrafish gene map defines ancestral vertebrate chromosomes. Genome Research 15, 1307-1314.  PMC1199546.

Yan, Y. L., Yan, Y. L., Miller, C. T., Nissen, R. M., Singer, A., Liu, D., Kirn, A., Draper, B., Willoughby, J., Morcos, P. A., Amsterdam, A., Chung, B. C., Westerfield, M., Haffter, P., Hopkins, N., Kimmel, C., Postlethwait, J. H. (2002) A zebrafish sox9 gene required for cartilage morphogenesis. Development 129(21):5065-79.