Human Chromosome 16 Sequence Details Extensive Duplication

JGI researchers, in collaboration with scientists from six other institutions, have completed the sequencing and analysis of human chromosome 16. The last of the three chromosomes making up the U.S. Department of Energy's share of the Human Genome Project, chromosome 16 includes genes for metallothionein (a protein involved in regulating and detoxifying heavy metals), cadherin and iroquois gene families (which take part in DNA repair), and sites for diseases such as polycystic kidney disease and acute myelomonocytic leukemia. The work revealed 30 novel genes and 79 putative novel genes, 341 pseudogenes or pseudogene fragments, and some of the most extensive segmental duplication seen in any human chromosome.

Correspondence between alignment length and interchromosomal (red) and intrachromosomal (blue) duplication.

Several large structural polymorphisms were found on chromosome 16. These tended to be associated with the many segmental duplications that make up 9.89% of the chromosome's sequence. (The average across the entire genome is 5.3%.) The large structural polymorphisms appear to lead to variations among humans that affect phenotype or disease susceptibility. For example, a 450-kb inversion was found to exist between two haplotypes of one of the most extensively duplicated regions, containing genes for a subunit of eukaryotic translation initiation factor 3 (EIF3S8), sulphotransferase 1A, and Batten disease. Another large polymorphism (360 kb), the human homolog of the hydrocephalus-inducing gene, is a recently duplicated gene sometimes found on chromosome 1. Over all, 91 genes were found in regions of segmental duplication. There appears to have been a recent expansion of duplication on the chromosome. By comparing substitution rates in great apes, the researchers estimated that up to 7% of the chromosome's mass is accounted for by segmental duplications that have arisen in the last 10 million years.

The analysis included comparisons between human chromosome 16 and homologous chimpanzee, dog, mouse, rat, chicken, and fish (Fugu) sequences. Segmental maps were used to analyze homologous relationships across the vertebrates, and fine-scale DNA comparisons were used to identify slowly evolving regions. In comparisons of the density of conserved noncoding regions across vertebrates, the densities for human/mouse/rat and human/mouse/dog/chicken were only slightly higher than the genome-wide average. Surprisingly, the density for human/mouse/fish was about 2.4 times the genome-wide average. Thus, while chromosome 16 has maintained expected levels of noncoding sequence conservation since the split between mammals and birds, it has retained a surprising amount of the more ancient noncoding sequence shared with fish.

In agreement with previous studies showing the association of human/fish conservation with developmental genes, the longest human/mouse/dog/chicken synteny segment contains a 5-Mb subregion on which 59% of the human/mouse/fish noncoding elements are clustered—along with at least six developmental transcription factors. In contrast, the second longest human/mouse/dog/chicken synteny block, nearly equal in length, showed no noncoding conservation between human/mouse/fish. This result suggests that the functions of the shorter sequence are more diverged in distant species than they are in mammals.

The sequence and initial analysis of chromosome 16 should provide a useful foundation for future analytical efforts. Indeed, one such effort, the Encyclopedia of DNA Elements (ENCODE) project, has already selected three sites on chromosome 16 for further study and deep annotation. One of the chosen sites (one of two selected randomly) lies within the gene desert in the second longest human/mouse/dog/chicken synteny segment and contains no genes. Its inclusion bodes well for further understanding of the role of noncoding sequence in human biology.

Authors

J. Martin, L.A. Gordon, A. Terry, U. Hellsten, A. Aerts, J.C. Detter, T. Glavina, D. Goodstein, I. Grigoriev, N. Hammon, T. Hawkins, W. Huang, S. Israni, J. Jett, K. Kadner, H. Kimball, Y. Lou, S. Lowry, J. Morgan, S. Pitluck, M. Pollard, P. Predki, S. Rash, A. Salamov, D. Scott, H. Tice, M. Tran-Gyamfi, A. Ustaszewska, P. Richardson, D.S. Rokhsar, and S.M. Lucas (JGI); C. Han, H. Blumer, N.C. Brown, W.J. Bruno, J.M. Buckingham, D.F. Callen, C.S. Campbell, M.L. Campbell, E.W. Campbell, J.F. Challacombe, L.A. Chasteen, O. Chertkov, H.C. Chi, L.M. Clark, J.D. Cohn, M. Dimitrijevic-Bussod, J.J. Fawcett, L.A. Goodwin, D.L. Grady, C.E. Hildebrand, P.B. Jewett, M.-C. Krawczyk, T. Leyba, J.L. Longmire, T. Ludeman, G.A. Mark, K.L. McMurray, L.J. Meincke, R.K.Moyzis, M.O. Mundt, A.C. Munk, B. Parson-Quintana, D.O. Ricke, D.L. Robinson, E.H. Saunders, T Shough, R.L. Stallings, M. Stalvey, R.D. Sutherland, R. Tapia, J.G. Tesmer, L.S. Thompson, D.C. Torney, L.E. Ulanovsky, P.S. White, A.L. Williams, P.L. Wills, J.-R. Wu, D. Bruce, N.A. Doggett, L. Deaven, and P. Gilna (Los Alamos National Laboratory); M. Christensen, M. Groza, C.F. Manohar, and R.D. Nandkeshwar (Lawrence Livermore National Laboratory); S. Prabhakar and O. Couronne (Lawrence Berkeley National Laboratory); X. She and E.E. Eichler (University of Washington); Y.M. Chan, E. Bajorek, S. Black, C. Caoile, M. Denys, M. Dickson, J. Escobar, D. Flowers, D. Fotopulos, M. Gomez, E. Gonzales, L. Haydu, F. Lopez, L. Ramirez, J. Retterer, A. Rodriguez, M. Tsai, N. Vo, K. Wu, J. Yang, J. Schmutz, J. Grimwood, and R.M. Myers (Stanford Human Genome Center); P. DeJong (Children's Hospital Oakland); G. Xie, M. Altherr, and N. Thayer (JGI and Los Alamos National Laboratory); E. Branscomb and A. Kobayashi (JGI and Lawrence Livermore National Laboratory); and E. Rubin and L.A. Pennacchio (JGI and Lawrence Berkeley National Laboratory) .

Visualization with the program Parasight shows the pattern of interchromosomal duplication (red) for chromosome 16 (central horizontal line) and intrachromosomal duplication (blue) (>20kb, >95%). Purple bars indicate centromeres.

Segmental homology maps show continuous segments between human chromosome 16 and homologous portions of chimp, mouse, rat, dog, and chicken genomes.

 

Publication

"The Sequence and Analysis of Duplication-Rich Human Chromosome 16," Nature 432, 988-994 (2005), doi: 10.1038/nature03187.

Funding

This research was funded by the U.S. Department of Energy.