Tuesday, December 18, 2007

Losses Of Long-established Genes Contribute To Human Evolution

Finding: While it is well understood that the evolution of new genes leads to adaptations that help species survive, gene loss may also afford a selective advantage. A group of scientists has investigated this less-studied idea, carrying out the first systematic computational analysis to identify long-established genes that have been lost across millions of years of evolution leading to the human species.

The idea that gene losses might contribute to adaptation has been kicked around, but not well studied.

To find gene losses a software program called TransMap. The program compared the mouse and human genomes, searching for genes having changes significant enough to render them nonfunctional somewhere during the 75 million years since the divergence of the mouse and the human.

Genes can be lost in many ways. This study focused on losses caused by mutations that disrupt the open reading frame (ORF-disrupting mutations). These are either point mutations, where events such as the insertion or substitution of a DNA base alter the instructions delivered by the DNA, or changes that occur when a large portion of a gene is deleted altogether or moves to a new place on the genome.

Using the Dog Genome
The dog genome was used as an out-group to filter out false positives because the dog diverged from our ancient common ancestor earlier than the mouse. So if a gene is still living in both dog and mouse but not in human, it was probably living in the common ancestor and then lost in the human lineage.

Using this process, they identified 26 losses of long-established genes, including 16 that were not previously known.

The gene loss candidates found in the study do not represent a complete list of gene losses of long-established genes in the human lineage, because the analysis was designed to produce more false negatives than false positives.

The study compares multiple genomes
Next they compared the identified genes in the complete genomes of the human, chimpanzee, rhesus monkey, mouse, rat, dog, and opossum to estimate the amount of time the gene was functional before it was lost. This refined the timing of the gene loss and also served as a benchmark for whether the gene in question was long-established, and therefore probably functional, or merely a loss of a redundant gene copy. Through this process, they found 6 genes that were lost only in the human.

The ACYL3 Protein - A loss From many to none
One previously unknown loss, the gene for acyltransferase-3 (ACYL3), was particularly important. This is an ancient protein that exists throughout the whole tree of life. Multiple copies of the ACYL3 gene are encoded in the fly and worm genomes. In the mammalian clade there is only one copy left, and somewhere along primate evolution, that one copy was lost to the primate clan.

Next it was found that this gene contains a nonsense mutation in both human and chimp, and it appears to still look functional in rhesus. Further, they found that the mutation is not present in the orangutan, so the gene is probably still functional in that species. On the evolutionary tree leading to human, on the branch between chimp and orangutan sits gorilla. Knowing if the gene was still active in gorilla would narrow down the timing of the loss.

The gorilla DNA sequence showed the gene intact, without the mutation, so the loss likely occurred between the speciation of gorilla and chimpanzee.

Other Functional Losses
Acyltransferase-3 was not the only lost gene that doesn't have any close functional homologues in the human genome. A highlight of the research was that they were able to find a list of these orphan losses. Some of them have been functional for more than 300 million years, and they were the last copies left in the human genome. While the copies of these genes remaining in the human genome appear to be nonfunctional, functional copies of all of them exist in the mouse genome.

These orphan genes may be interesting candidates for experimental biologists to explore. It will be interesting to find out what was the biological effect of these losses. Once their function is well characterized in species that still have active copies, we could maybe speculate about their effects on human evolution.

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