It's Raining Genomes: Two Human Chromosomes and a Whole Rat

This past week saw big news in genomic sequencing. In separate papers in Nature, human chromosomes 13 and 19 and a draft genome of the storied Rattus norvegicus were unveiled.

Chromosome 19 is well-known in AD circles, as it hosts the ApoE gene, as well as loci for atherosclerosis susceptibility. In addition, several years ago there were hints from several labs of a possible AD risk locus on chromosome 19 distinct from ApoE (see, e.g., Poduslo and Yin, 2001).

Andrew Dunham of Wellcome Trust Sanger Institute in Hinxton, in the U.K., and his numerous collaborators now present the complete sequence of chromosome 19. They find that it is the most crowded chromosome described to date, with more than double the genome-wide concentration of genes. This includes 1,461 verified gene loci (along with 321 pseudogenes), accounting for 2,341 full-length mRNA transcripts, with evidence for many additional splice variants.

The chromosome is also dense in repeat sequences, which account for 55 percent of the chromosome, whereas none of the other sequenced chromosomes (to date, 6, 7, 14, 20-22, and Y) exceed 46 percent. Some 25 percent of the chromosome 19 genome consists of clustered gene families arranged in tandem, including many zinc finger transcription factors, members of the cytochrome P450 family, and several immunoglobulin-like receptors.

The researchers uncovered 141 novel gene loci, with the remaining 1,320 already known. It should be heartening for those who have previously produced physical or genetic maps of chromosome 19 that all the sequence-tagged sites from these maps were also found in this sequencing. Among these are a number of already mapped and described genes for rare, single-gene disorders, for example, the genes for hypercholesterolaemia and insulin-resistant diabetes. However, there are also many loci that show evidence for contributing to complex traits, write the authors.

Chromosome 13, by contrast, is sparsely populated. Jane Grimwood of Stanford University in Palo Alto, California, and her colleagues found 633 genes versus 296 pseudogenes, but only 6.5 genes per Mb, compared to the genome-wide average of 10 per Mb. Comparison to previous maps finds that this one contains all the markers from the deCODE genetic map, and 98 percent of genes from the Marshfield map as well as Genemap '99.

Of the 633 genes found, 231 are known genes, 97 are novel genes, and 145 are novel transcripts. A number of cancer-related loci are found on this chromosome, and it is hoped that these results will help researchers zero in these genes. In addition, chromosome 13 contains some immunoglobulin E-related genes.

The rare "chromosome 13 dementias"—familial British dementia and familial Danish dementia—provide the main link to AD (reviewed in Rostagno et al., 2002), although researchers have also suggested a link to late-onset AD in a Finnish study (Hiltunen et al., 1999).

And then there is the much-maligned, and misnamed Norway rat (Norwegians are quick to point out that it actually came from central Asia), loved only by the scientists who have found it immensely useful. In recent years, it has lost some "market-share" as a biomedical experimental model to the mouse. But with the publication of a high-quality draft (90 percent complete) of the Norway rat genome in Nature, the rat may regain some of its prominence, and recent studies on transgenic rat development suggest it may again become a more wisely used model species.

The Rat Genome Sequencing Project Consortium found that the rat genome (2.75 Gb) is about intermediate in size between the mouse (2.5-2.6 Gb) and human (2.9 Gb). They note that almost all human disease-associated genes have orthologues in the rat genome. Indeed, almost 90 percent of rat genes have orthologues in humans.

The sequencing has created a stir in comparative genomics, because researchers are now able to compare the mouse, rat, and human genomes to shed light on questions such as which traits are shared by primates, rodents, and other mammals, versus those shared only by rodents.

Another 30 papers with more detailed analyses are published in the April issue of Genome Research. Among the conclusions of some of these is that the rat genome is much more "dynamic" than the human genome, with a much higher rate of change in individual bases, as well as more shuffling of blocks of genes.

In a News and Views article accompanying the rat genome paper, Kerstin Lindblad-Toh of the Broad Institute in Cambridge, Massachusetts, notes that with each new species sequenced, the ability to predict the identity and functions of unknown genes and regulatory elements increases. Currently underway are the sequencing of the chimpanzee, macaque, dog, cow, and opossum genomes. "The high quality of the rat genome sequence, and the speed with which it was produced leads us to expect great things in the near future," writes Lindblad-Toh.—Hakon Heimer

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References

Paper Citations

  1. Poduslo SE, Yin X. A new locus on chromosome 19 linked with late-onset Alzheimer's disease. Neuroreport. 2001 Dec 4;12(17):3759-61. PubMed.
  2. Rostagno A, Revesz T, Lashley T, Tomidokoro Y, Magnotti L, Braendgaard H, Plant G, Bojsen-Møller M, Holton J, Frangione B, Ghiso J. Complement activation in chromosome 13 dementias. Similarities with Alzheimer's disease. J Biol Chem. 2002 Dec 20;277(51):49782-90. PubMed.
  3. Hiltunen M, Mannermaa A, Koivisto AM, Lehtovirta M, Helisalmi S, Ryynänen M, Riekkinen P, Soininen H. Linkage disequilibrium in the 13q12 region in Finnish late onset Alzheimer's disease patients. Eur J Hum Genet. 1999 Sep;7(6):652-8. PubMed.

Further Reading

Primary Papers

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  2. Dunham A, Matthews LH, Burton J, Ashurst JL, Howe KL, Ashcroft KJ, Beare DM, Burford DC, Hunt SE, Griffiths-Jones S, Jones MC, Keenan SJ, Oliver K, Scott CE, Ainscough R, Almeida JP, Ambrose KD, Andrews DT, Ashwell RI, Babbage AK, Bagguley CL, Bailey J, Bannerjee R, Barlow KF, Bates K, Beasley H, Bird CP, Bray-Allen S, Brown AJ, Brown JY, Burrill W, Carder C, Carter NP, Chapman JC, Clamp ME, Clark SY, Clarke G, Clee CM, Clegg SC, Cobley V, Collins JE, Corby N, Coville GJ, Deloukas P, Dhami P, Dunham I, Dunn M, Earthrowl ME, Ellington AG, Faulkner L, Frankish AG, Frankland J, French L, Garner P, Garnett J, Gilbert JG, Gilson CJ, Ghori J, Grafham DV, Gribble SM, Griffiths C, Hall RE, Hammond S, Harley JL, Hart EA, Heath PD, Howden PJ, Huckle EJ, Hunt PJ, Hunt AR, Johnson C, Johnson D, Kay M, Kimberley AM, King A, Laird GK, Langford CJ, Lawlor S, Leongamornlert DA, Lloyd DM, Lloyd C, Loveland JE, Lovell J, Martin S, Mashreghi-Mohammadi M, McLaren SJ, McMurray A, Milne S, Moore MJ, Nickerson T, Palmer SA, Pearce AV, Peck AI, Pelan S, Phillimore B, Porter KM, Rice CM, Searle S, Sehra HK, Shownkeen R, Skuce CD, Smith M, Steward CA, Sycamore N, Tester J, Thomas DW, Tracey A, Tromans A, Tubby B, Wall M, Wallis JM, West AP, Whitehead SL, Willey DL, Wilming L, Wray PW, Wright MW, Young L, Coulson A, Durbin R, Hubbard T, Sulston JE, Beck S, Bentley DR, Rogers J, Ross MT. The DNA sequence and analysis of human chromosome 13. Nature. 2004 Apr 1;428(6982):522-8. PubMed.
  3. Lindblad-Toh K. Genome sequencing: three's company. Nature. 2004 Apr 1;428(6982):475-6. PubMed.
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