By David N. Leff

They¿re at it again.

The day after Nature, dated May 17, 2001, ran a ¿brief communication¿ impugning the accuracy of the fruit fly genomic sequence published by Celera Genomics, of Rockville, Md., today¿s issue of Science, dated May 18, 2001, carries a lengthier article by Steven Salzberg and co-authors at The Institute for Genomic Research (TIGR), also of Rockville. Its title: ¿Microbial genes in the human genome: Lateral transfer or gene loss?¿ Evolutionary biologist Jonathan Eisen, an assistant investigator at TIGR, answered that question in an interview with BioWorld Today:

¿Our Science article,¿ Eisen began, ¿is a reanalysis of the big, 62-page International Human Genome Consortium paper in Nature, dated Feb. 15, 2001, announcing total sequencing of the human genome. In one section of that paper, on lateral gene transfer between species, the authors presented an analysis that we think was flawed. Their conclusion was that there had likely been lateral transfer of genes from free-living bacteria into the human genome some time during the course of vertebrate evolution, hundreds of millions of years ago.

¿This would be surprising,¿ Eisen continued, ¿because it would mean the genes were transferred into some multicellular vertebrate-like organism during evolution, and somehow made it not just into the host¿s somatic cells but into its germ-line cells as well.

¿One of the first flaws is how the international consortium analyzed the data. They took the 31,780 predicted proteins in the human genome, and compared them to a database of proteins from other species. This included lots of complete genomes as well as some incomplete ones. And the authors asked a very simple question: Is this protein found in bacteria but not in non-vertebrate species?¿ Of those 31,780 genes, they found 223 genes that met this criterion.

¿Then the Nature authors concluded,¿ Eisen went on, ¿that the fact that these genes were shared between humans and bacteria, but not in non-vertebrates, meant that the gene was transferred from bacteria into the vertebrate lineage, sometime during evolution. There¿s no valid reason to make that conclusion, as our paper spells out.¿

Jumping Off Evolution¿s Family Tree

¿For example,¿ he proposed, ¿let¿s consider a common ancestral protein of all organisms ¿ say, some metabolic enzyme that¿s needed by lots of organisms. When the prokaryotic bacteria and the common ancestor of all eukaryotes split off from the evolutionary family tree, they both had this enzyme¿s gene. Then some non-vertebrate lineages branched off ¿ including C. elegans, one of the big genomes they looked at, and fruit flies and yeast and Arabidopsis thaliana, a plant.

¿We think a much more straightforward and likely explanation,¿ Eisen suggested, ¿is that those genes are absent from the non-vertebrates simply because they¿ve been lost from those lineages. The reason we think this is more likely,¿ he added, ¿is that there are hundreds if not thousands of research papers showing that these exact non-vertebrate species that the Nature authors analyzed have lost thousands of genes in their recent evolution. Now you add a few more hundred million years of evolution, and it¿s clear that these lineages that branched off could have lost up to 30 [percent] or 40 percent of the genes that they had when they started splitting.

¿Gene loss is an incredibly common phenomenon,¿ Eisen pointed out. ¿All you have to do is incur a certain percentage of lost genes to end up with 223 genes. Only 1 percent of the genes in the entire human genome had this pattern. The Nature paper,¿ he went on, ¿made a lot of over-speculative statements. Its authors looked at the putative functions of these genes and said, Wow! It¿s interesting that some of these genes are neurobiological genes,¿ and tried to guess some ideas of how a human brain gene would have come from bacteria. There¿s no reason to ask that question,¿ Eisen asserted, ¿because they didn¿t come from bacteria.

¿The genes that tend to be exchanged between species,¿ he observed, ¿are very important biologically. The first evidence for this came in the 1940s and ¿50s, looking for bacterial genes that confer resistance to antibiotics. And we know that very distantly related bacteria pass genes to each other that code for antibiotic resistance ¿ which has enormous medical implications. It means if you¿re infected with a Streptococcus pneumoniae pathogen, which is resistant to vancomycin or another antibiotic, and simultaneously you¿re infected with some other bacterium that is not resistant to that antibiotic, it is possible for that antibiotic resistance gene to switch between species.

¿We also know, again in microbes, that genes with toxin resistance for pathogeniticty ¿ such as a certain strain of E. coli that can cause fatal food poisoning ¿ are in part due to the fact that they¿re stolen genes from other species.¿

Eisen pointed out, ¿In multicellular eukaryotes, lateral gene transfer is of a different general genre ¿ a different phenomenon. In these higher forms of life, a very important type of LGT is involved ¿ the transfer of genes from the organellar genomes into the host cell¿s nucleus. Thus the mitochondria in all eukaryotes, and chloroplasts in plants, originally were free-living bacteria.¿

Human Genes Also Find Way Into Microbes

That gene transfer cuts both ways: ¿We know for example that viruses do this to humans,¿ Eisen said. ¿Viruses inject their genes into the human cells and take over some of their metabolism. Sometimes, humans have similar genes in their genome. But even in that case there is very little evidence that viruses have transferred genes into the human germ line. The reason that viruses share genes is that they stole them from humans, not the other way around. And if bacteria could potentially do that with humans, we would be more inclined to believe their story, if Nature had proposed human-to-bacteria gene transfer.¿

Eisen recalled, ¿We wrote an e-mail to Eric Lander, the Nature paper¿s principal author, the day last February when they had their press conference. We suggested he might want to look more carefully at that one LGT section more carefully, because we think it¿s flawed. He didn¿t get back to us, but has subsequently continued to defend their analysis. He still thinks their method is good. We disagree.¿

No Comments