What makes humans unique? Thanks to an exhaustive comparison of extra and missing genes within the genomes of humans and nine other primates, researchers now have a host of new clues to probe this perplexing question. The findings offer intriguing insights into disease, longevity, and even the origin of endurance running.
Geneticists have long known that extra or missing copies of genes can cause diseases like Down syndrome or conditions like color blindness, but "copy number variation" recently has moved into the spotlight because of two factors. One is the sequencing of human, chimpanzee, macaque, and other genomes, which allows unprecedented comparisons of gene copy numbers both within and between species. The other is the application of a technique originally developed for cancer studies called comparative genomic hybridization, or CGH, which can detect copy number variations that are missed in genome analyses. CGH was the main tool used by genome researcher James Sikela of the University of Colorado at Denver and Health Sciences Center in Aurora and colleagues to assess copy number variation in humans and our closest relatives.
As Sikela and co-workers explain in a paper published online 31 July in Genome Research, they compared the DNA from more than 24,000 known human genes to the DNA from chimpanzees, gorillas, bonobos, orangutans, gibbons, macaques, baboons, lemurs, and marmosets. Applying CGH, researchers take one stretch of DNA as a target--in this case, each human gene--and then check which complementary strands of DNA will stick to it. "We don't think anyone has looked this comprehensively at gene gain and loss over time," says Sikela.
All told, the researchers found more than 4000 genes that showed lineage-specific changes in copy number, with the numbers steadily increasing over evolutionary time. Humans, for example, only had 84 genes with increased copy numbers over those of our closet relatives. In contrast, lemurs, which have evolved for 60 million years, have 1180 genes with extra copies. "This is further evidence that genomic differences between humans and other primates is far, far more complex than we originally imagined they might be," says Ajit Varki, who studies human/chimpanzee differences at the University of California, San Diego. "However, many of the differences may or may not be relevant for explaining 'humanness.'"
Jonathan Sebat, a geneticist at Cold Spring Harbor Laboratory in New York state who specializes in copy number variation, considers the results "quite tantalizing" but also feels that the report takes "extreme liberties in speculating about the biological effects." Sikela says the paper is meant to be "hypothesis generating" and hopes the speculation "at least points to some genes that could be investigated further."
One of those genes is aquaporin 7. Humans have five copies of this gene, whereas the other primates have just two, and the researchers suggest that the gene may be involved in exercise-induced sweating and endurance running, a unique feature of humans. Similarly, gorillas have many extra genes in the gamma-glutamyltransferase family, which is thought to play a role in the removal of toxins. This is significant because gorillas eat about 100 plants that are high in toxins.
The researchers identify regions of chromosomes in various species that seem particularly prone to gene duplication and loss, and argue that these "gene nurseries" are hot spots for evolution. "It's a double-edged sword," says Sikela. "It could easily lead to a disease, but the upside is it increases variation that evolution can use. It's more evolutionary fuel." As the researchers note, the family of genes that may broaden the gorilla's diet are shortchanged in humans and linked to a disease called DiGeorge syndrome that causes heart problems and other ailments.
Sunil Ahuja, who discovered in his lab at the University of Texas Health Science Center at San Antonio a copy number variation that strongly protects people from HIV, says proving the link between extra or missing genes and function ultimately will require much more detailed work. "These are the initial Google maps," says Ahuja, who studied DNA from more than 5000 people to nail down his discovery. "Now we have to go down and see what each building looks like."