FEATURE ARTICLE
Genetics and the Shape of Dogs
Studying the new sequence of the canine genome shows how tiny genetic changes can create enormous variation within a single species
Elaine A. Ostrander
Sequencing the Dog Genome
The first published sequence of the dog genome was completed in 2003 in an effort lead by Ewen Kirkness at The Institute for Genome Research. Genomes are typically sequenced in many thousands of overlapping segments, and to ensure that the whole genome is recorded at least once, it is estimated that there have to be seven or eight iterations, or "reads," across the entire genome. The 2003 genome, from a standard poodle, was a so-called survey sequence. The genome was sequenced just 1.5 times, so about 80 percent of the genome was present in the final data set. This work was followed shortly thereafter by the release of the draft assembly of the boxer genome, led by Kerstin Lindblad-Toh and colleagues at the Broad Institute, which was done at 7.5x density. With millions of reads successfully completed, nearly 99 percent of the genome is present in the final data set.
Both resources have proved to be extremely useful. The 1.5x sequence provided the first glimpse into the organization of the dog genome, number of genes and organization of repeat elements. One surprise was the discovery of a large number of short interspersed nuclear elements (SINEs) littered throughout the dog genome that were occasionally located at positions with the potential to affect gene expression. For example, the insertion of a SINE element into the gene encoding the hypocretin receptor, a neuropeptide hormone found in the hypothalamus of the brain, results in the disease narcolepsy in the Doberman pinscher. Similarly, a SINE element inserted into the SILV gene (known to be related to pigmentation) is responsible for merle, the mottled patterning of a dog's coat.
The 7.5x female boxer sequence spans most of the dog's 2.4 billion bases in a sum total of 31.5 million sequence reads. The sequence is estimated to cover over 99 percent of the eukaryotic genome and provides data for the existence of about 19,000 genes. For about 75 percent of the genes, the homology (amount of similarity arising from shared ancestry) between the dog, human and mouse genome is very high. The majority of genes contain no sequence gaps, which is a great aid to scientists seeking to test particular genes as candidates for diseases.
Over the course of its evolution, the canine genome acquired more than two million SNPs, which are proving invaluable for understanding the role of genetic variation both within and between breeds. Such SNPs, analyzed using DNA chips or bead arrays, will be important for scientists conducting whole-genome association studies aimed at identifying genes that underlie complex traits in the dog. A dog chip with about 127,000 SNPs is currently available, allowing scientists to interrogate the dog genome at several thousand positions simultaneously. When the data from dogs with a given disease, for instance lymphoma, are compared to those from dogs without the disease, we can quickly pinpoint regions of the genome where disease genes are likely to lie.
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