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How to Compare Us to Our Hairy Cousins? New Papers Provide Techniques

NEW YORK, March 4 - To illuminate the genomic gap between knuckle draggers and Nobel laureates, primate genome researchers have been forced to develop novel techniques.


In one paper, published in last week's Science, researchers at the DOE's Joint Genome Institute and Lawrence Berkeley National Laboratory describe how they successfully applied a method called phylogenetic shadowing toward comparisons of the genomes of multiple primates.


In the second paper, which appears in this month's Genome Research, a group at Perlegen Sciences used microarrays to compare a long stretch of sequence on the human chromosome 21 to the comparable chromosomes in numerous primates. They found that the human sequence was separated from that of our primate cousins by rearrangements of large stretches of sequence rather than single base pair changes.


This new work might help scientists to better understand what -- genomically speaking -- makes us human.

The phylogenetic shadowing technique described in Science was developed by Edward Rubin, Lior Pachter, and colleagues at JGI and Berkeley in order to glean subtle similarities and differences between closely related species, as opposed to the more obvious differences between the previously compared genomes of human and mouse.


It involves sampling data from select regions of many different related species, and then comparing them within the context of their phylogenetic relationships. In the research described in the Science paper, Rubin and colleagues sampled 17 primate species closely related to human and spanning 40 million years of evolution -- insufficient time for significant genetic divergence to have taken place.


According to Rubin, phylogenetic shadowing compensates for the failure of traditional comparative genomics techniques, which "invariably miss recent changes in DNA sequence that account for primate-specific biological traits." The approach overcomes the primary challenge of comparing genomes of closely related species: the difficulty in distinguishing functional from nonfunctional sequences. By pooling specific segments of the genomes of multiple species, the researchers found enough small differences in the nonhuman primates to combine them into a phylogenetic "shadow" that they could then compare to the human genome.


The phylogenetic shadow that Rubin and his colleagues created was distinct enough for them to see the boundaries between exons and introns for several genes. In addition, they report in their paper that they were able to identify regulatory elements for the apo(a) gene, which is found in humans, apes, and Old World Monkeys, but not in other mammals.


Perls of Wisdom?


In their paper, "Genomic DNA insertions and deletions occur frequently between humans and nonhuman primates," the Perlegen scientists hybridized a 27kb region of human chromosome 21 to Affymetrix microarrays, then did the same for the comparable stretch of chimpanzee sequence. They found that there were 57 deletions and insertions ranging from 100 to 800 bp, distributed at genic intervals.


The researchers then compared about 9 Mb of sequence with orangutan, rhesus macaque, and wooley monkey, and found 57 additional insertions and deletions. In this group of rearrangements, they found one deletion that is believed to inactivate a beta-galactosyltransferase gene in the wooley monkey.


Perlegen CSO David Cox called the findings "a very surprising and important discovery of the fundamental basis of structural genomic differences between humans and other primates."


The Perlegen researchers used special high-density genomic tiling arrays, which are manufactured by Affymetrix and which the company has used to tile through the human genome to find common SNPs linked to disease.


"This study illustrates the power and versatility of Perlegen's high-density array technology in the detection of DNA rearrangements," said Kelly Frazer, the Perlegen scientist who was the paper's lead author.


The company, a 2000 spinoff of Affymetrix, uses these arrays in ongoing research collaborations with Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Pfizer, and Unilever.

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