Human Chromosome 19 Sequence Revealed

The finished sequence of human chromosome 19, the most gene dense of all human chromosomes, has been released by JGI and its collaborators. With an accuracy calculated at better than 99.99%, the finished code reveals 55.8 million base pairs and 1461 protein-coding genes, including genes related to such recalcitrant diseases as familial hypercholesterolemia and insulin-resistant diabetes. Calculating that they successfully sequenced 99.9% of the euchromatin of chromosome 19, the researchers estimated the total size of the chromosome to be 63.8 Mb. The complete whole-genome shotgun sequence shows excellent agreement with earlier physical and genetic maps.

Gene densities of human chromosomes.

The density of genetic information on chromosome 19 is impressive. It boasts 6.4% of its sequence identified as exons, more than four times the average for the human genome. Locuses known to contain protein-coding genes cover 50% of the finished sequence (including introns and exons). Each single megabase of sequence on average holds 26 protein-coding loci. Much of the topography (more than 25%) consists of tandemly arranged gene families, and there is a high density of repeat sequences (nearly 55% of the chromosome).

Besides confirming 1,320 known gene loci, annotation efforts revealed 141 novel loci and 321 pseudogenes. Comparisons to existing expressed sequence tag (EST) sequences gave evidence of multiple splicing patterns for a high percentage of annotated gene loci (70%). Considering the uneven overall depth of EST coverage, the 98% alternative splicing rate for genes overlapping 500 or more ESTs suggested that nearly all loci on chromosome 19 have alternative transcripts.

The relationship between physical and meiotic distance was atypically nonlinear for the male meiotic map (red) but not the female (blue) or sex-averaged (yellow) maps.

Comparison of physical distances (based on the sequence data) and recombination distances (based on the deCODE meieotic maps) revealed an unusually nonlinear relationship for the male map but not for the female or sex-averaged maps. In the male map, the section near the centromere, especially the proximal q arm, showed an unusually low meiotic distance. However, the male map was similar to those for other human chromosomes in having increased recombination near the telomeres.

Large blocks of synteny with mouse were found in the new sequence, but internal rearrangements were discovered within the synteny segments, particularly in the p arm. (The q arm aligns almost completely with mouse chromosome 7 and rat chromosome 1.) Smaller segments with only rare areas of 1:1 orthology (because of duplication and rearrangement) correspond with tandem gene families. Both coding and noncoding conservation between mouse, rat, and human are extensive. Notably less noncoding conservation occurs with Takifugu, though coding sequence is conserved extensively. The clustering of noncoding conservation with Takifugu in the proximal q arm suggests these sequences play a role in basic vertebrate function.

Interchromosomal (red lines) and intrachromosomal (blue lines) segmental duplications on chromosome 19 (>20kb, >95% similar). A-G, gene clusters detected in duplicated sequences.

Thus far, 97 single-gene traits have been mapped to chromosome 19, and three-quarters of those have been assigned to specific genes. However, at least 20 inherited diseases have not yet been assigned to a specific gene. Chromosome 19 also harbors at least one gene that participates in a multiple-gene disease trait (neurturin, which encodes the ligand of a tyrosine kinase receptor; a mutation in this gene causes Hirschsprung's disease only if the receptor gene is also affected). Future work with the finished sequence of chromosome 19 will enhance human understanding of both single-gene and multi-gene disease susceptibilities as well as the role of noncoding sequences.

Authors

J. Grimwood, J. Schmutz, E. Bajorek, S. Black, C. Caoile, Y.M. Chan, M. Denys, J. Escobar, D. Flowers, D. Fotopulos, C. Garcia, M. Gomez, E. Gonzales, L. Haydu, F. Lopez, C. Medina, L. Ramizrez, J. retterer, A. Rodriguez, S. Rogers, A. Salazar, M. Tasi, N. Vo, J. Wheeler, K. Wu, J. Yang, M. Dickson, R.M. Myers (Standord Human Genome Center); A. Terry, U. Hellsten, D. Goodstein, O. Couronne, A. Aerts, S. Caenepeel, A. Copeland, E. Dalin, P. Dehal, J.C. Detter, T. Glavina, N. Hammon, T. Hawkins, I. Ho, W. Huang, S. Israni, J. Jett, K. Kadner, H. Kimball, Y. Lou, S. Lowry, D. Martinez, J. Moran, M. Nolan, S. Pitluck, M. Pollard, P. Predki, S. Rash, A. Salamov, D. Smith, V. Solovyev, H. Tice, A. Ustaszewska, I. Dubchak, L.A. Pennacchio, P. Richardson, D.S. Rokhsar, E.M. Rubin, and S.M. Lucas (JGI); L.A. Gordon, A. Olsen, J. Lamerdin, M. Tran-Gyamfi, L. Ashworth, E. Branscomb, A. Carrano, M. Christensen, A.M. Georgescu, M. Groza, A. Kobayashi, S. Malfatti, P. McCready, I. Ovcharenko, G. Quan, T. Slezak, M. Wagner, and L. Stubbs (JGI and Lawrence Livermore National Laboratory); M. Altherr, C.A. Cleland, K. Nelson, N. Thayer, and G. Xie (JGI and Los Alamos National Laboratory); V. Larionov, S.-H. Leem (National Cancer Institute); A.P. Popkie, X. She, and E.E. Eichler (Case Western Reserve University); T.S. Furey (University of California, Santa Cruz); P. DeJong (Children's Hospital Oakland); and D. Gordon (University of Washington).

Publication

"The DNA sequence and biology of human chromosome 19," Nature 428, 529-535 (2004), doi:10.1038/nature02399.

Funding

This research was funded by the U.S. Department of Energy Office of Biological and Environmental Research.