Losses Of Long-established Genes Contribute To Human Evolution

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Losses Of Long-established Genes Contribute To Human Evolution

http://www.sciencedaily.com/releases/2007/12/071214094129.htm

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 at the University of

California, Santa Cruz led by biomolecular engineering professor

Haussler 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.

Haussler and five others in his group--postdoc Jingchun Zhu,

graduate students Zack Sanborn and Craig Lowe, technical projects

manager Mark Diekhans, and evolutionary biologist Tom Pringle--are

co-authors on the paper*.

" The idea that gene losses might contribute to adaptation has been

kicked around, but not well studied, " said Zhu, who is first author

of the paper. " We found three examples in the literature, and all of

them could have medical implications. "

To find gene losses, Zhu employed a software program called TransMap

that Diekhans had developed. 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.

" This is the first study designed to search the entire genome for

recent loss of genes that do not have any near-duplicate copies

elsewhere in the genome, " said Haussler. " These are likely to be the

more important gene losses. "

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.

" We used the dog genome as an out-group to filter out false

positives, " Sanborn explained, because the dog diverged from our

ancient common ancestor earlier than the mouse. " 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 this 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.

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.

One previously unknown loss, the gene for acyltransferase-3 (ACYL3),

particularly caught their attention. " This is an ancient protein

that exists throughout the whole tree of life, " said Zhu. 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 copy was lost. "

" In our analysis, we found that this gene contains a nonsense

mutation in human and chimp, and it appears to still look functional

in rhesus, " said Sanborn. 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, " explained Sanborn. Knowing if the

gene was still active in gorilla would narrow down the timing of the

loss.

Sanborn took to the wet laboratory to sequence the corresponding

region in a DNA sample from a gorilla. The gorilla DNA sequence

showed the gene intact, without the mutation, so the loss likely

occurred between the speciation of gorilla and chimpanzee.

" Acyltransferase-3 was not the only lost gene that doesn't have any

close functional homologues in the human genome. A highlight of our

research was that we were able to find a list of these 'orphan

losses,' " said Zhu. " 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, " said Zhu. " It would 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. "

*Their findings appear in the December 14 issue of PLoS

Computational Biology.

This research was funded by the National Human Genome Research

Institute, the National Institutes of Health, the National Cancer

Institute, and the Medical Institute.