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Researchers Challenge Recent Claim That Humans Acquired 223
Bacterial Genes During Evolution
 
By
Edward R. Winstead



Featured article.

A new study demonstrates that humans have relatively few, if any, genes passed directly from bacteria during evolution. Fewer than 50 human genes may have been transferred from bacteria to vertebrates at some point in time, according to an analysis of human, bacterial and nonvertebrate genomes published this week in Science Express.

None of these genes is likely to have been acquired outright from bacteria, say investigators at The Institute for Genomic Research (TIGR) in Rockville, Maryland, who conducted the study. Rather, they suggest that some proteins may appear to exist only in humans and bacteria due to the loss of genes among nonvertebrate species and the failure to detect human and bacterial genes that are present but mutated in nonvertebrate species.


Genes shared by humans and prokaryotes after removing successive proteome sets from 5 nonvertebrates and a collection of miscellaneous nonvertebrates ("Other"). Left: Ensembl protein set. Right: Celera protein set. View larger

"My colleagues and I did not find any bacterial genes that appear to be in humans due to what is called lateral transfer," says Steven L. Salzberg, senior director of bioinformatics at TIGR.

The TIGR team repeated an analysis reported three months ago with the publication of the human genome sequences. The conclusion of that study in Nature is that humans have acquired 223 genes from bacteria, some of which may have been transferred to vertebrates during bacterial infections.

For the reanalysis, Salzberg's team used the set of proteins from the publicly funded genome sequence, but they also screened proteins predicted by the Celera human genome sequence for matches with bacterial proteins that are not present in other species.

"There are 41 genes in the public data and 46 in the Celera data that are shared by humans and bacteria but were not found in the invertebrates we screened," says Salzberg. "However, I could not argue that they are there due to lateral gene transfer."


‘Changing people’s impressions is difficult. All we can do is try to correct the record.’

The transfer of genes horizontally, or laterally, between species is a well-documented phenomenon in nature. Bacteria can transfer genes to other bacteria. And mitochondria, organelles in human cells that once were free-living bacteria, have transferred genes to humans.

But there is no strong evidence that bacteria genes have been transferred to vertebrates, say many evolutionary biologists. It was therefore big news that more than one hundred human proteins are likely to have "entered the vertebrate (or prevertebrate) lineage by horizontal transfer from bacteria," as the International Human Genome Sequencing Consortium proposed in Nature.

"I was reading about this in the German newspapers," says William Martin, a researcher at the University of Duesseldorf who studies lateral gene transfer. "But when I saw the statement, I knew the number was wrong. Those of us in the field have seen these claims before. I don't even believe the 40 genes in the new study are real examples of lateral transfer."

"The TIGR paper shows that the claim of lateral transfer is at least an overstatement, very probably a gross exaggeration and possibly altogether erroneous," says Martin, who is not affiliated with either research team. "Furthermore, TIGR's research methods are sound."


Detail of phylogenetic tree of homologs of three human hyaluronan synthase (HAS) proteins that were proposed as lateral transfers from bacteria to vertebrates. View full

Others in the field now say that the original number of 223 human proteins acquired from bacteria is probably too high. Recent refinements in the sequence data had already eliminated some protein candidates prior to this week's publication of the reanalysis in Science Express.

In a commentary that accompanies this study, W. Ford Doolittle, of Dalhousie University, in Halifax, Nova Scotia, and two colleagues say the original number of 223 human proteins "is probably overenthusiastic." They do not exclude the possibility that lateral gene transfer has occurred between bacteria and vertebrates and provide evidence for one "probable case," a protein called N-acetylneuraminate lyase.

For evolutionary biologists working on lateral gene transfer, Doolittle and colleagues write: "The most exciting news from the human genome sequencing project has been the claim by the 'public effort' that between 113 and 223 genes have been transferred from bacteria to humans over the course of vertebrate evolution."

The claim implies that humans can acquire genes through bacterial infection and pass them to offspring. This is the kind of thing people remember, observes Martin. "The concept of lateral gene transfer is so simple that the person on the street can understand it," he says. "But straightening out the misconception created by the original report is so complex that the same person might not understand it."


Detail of phylogeny of the gene encoding N-acetylneuraminate lyase (Ensemb ID IGI_M1_ctg1425_20). View full

The process of lateral gene transfer involves a series of steps. For starters, a gene has to migrate somehow to the nucleus of the 'germ' cells that give rise to sperm and eggs. Otherwise it will not be passed on. How a gene successfully infiltrates the human genome is not clear, say researchers. Unlike bacteria, humans have relatively sheltered DNA. Further, a transferred gene must be in or get in a format that allows long-term maintenance and replication.

"It's readily accepted that gene transfer from mitochondria has occurred in the past and continues to occur," says Jonathan Eisen, an evolutionary biologist at TIGR. The claim that a pathogen infected a vertebrate early in vertebrate evolution means both that a bacterial gene entered the nucleus of a host cell, and that the infected cell was part of the reproductive system.

Many evolutionary biologists regard lateral gene transfer as an extraordinary event. "You need strong evidence to explain extraordinary events," says Salzberg.

Proving that no bacterial genes have been transferred to vertebrates, on the other hand, is at present impossible. Instead, the TIGR researchers attempted to show that the existing genomic data do not support the original statement.

Proteome sizes and number of genes shared with each of the human protein sets, using a Blast cutoff of 10-10.

Organism
Number of proteins
Number matching Ensembl proteome
Number matching Celera proteome
Human
--
31,780
26,544
Bacteria/Archaea
85,824
4,388
3,915
Yeast
9,030
7,508
7,103
C. elegans
19,400
13,770
12,660
D. melanogaster
14,080
15,324
14,302
A. thaliana
25,470
9,151
9,081
Parasites
11,606
5,146
4,756


Like the authors of the Nature paper, the TIGR researchers used bioinformatic tools to search across species for genes with unusual 'distribution patterns.' A gene that shows up in a particular species through lateral gene transfer in theory should be identifiable by its presence or absence in multiple species. For example, a gene may be present in certain bacteria and all plants but not in other bacteria or vertebrates.

The strategy involves identifying genes with similar sequences in different species. "Sequence similarity is a very powerful tool, but you have to be careful how you use it," says Salzberg. "Similarity means the two proteins are likely to have a common ancestor and may have a similar function, but the similarity does not tell you when they diverged."

This approach "can be effective but is frequently misleading," says Jonathan Eisen of TIGR. Abnormal distribution patterns can result from the loss of genes or the 'apparent' loss of a gene that is present but has mutated beyond recognition. Eisen reviewed the methods for analyzing lateral gene transfer last year in Current Opinion in Genetics & Development.

"The biggest evolutionary problem with the original study was that it assumes there was no loss of genes in the non-vertebrate genomes," says Eisen. "There are hundreds if not thousands of studies saying that gene loss is very common, particularly among small genomes. And small genomes are the ones we have sequenced."

One way to eliminate false positives is include more data in a sample. According to the Nature paper, the human proteins predicted by the public human genome sequence were compared to those of four sequenced nonvertebrates, as well as to "any other (nonvertebrate) eukaryote." The four nonvertebrate species were yeast, worms, flies, and the plant Arabidopsis.

The TIGR data set included virtually all publicly available genomic data, including partial genes identified in hundreds of nonvertebrate species, the researchers say. "We found 21 human genes in the original set matching invertebrate organisms such as sponge, soybean, and jellyfish," says Salzberg. "All I can conclude is that somehow the initial analysis missed these genes."

Doolittle and colleagues note that the TIGR group obtained "a downward trend" by adding additional data: "The reanalysis demonstrates that the calculation of the number of bacterial genes in the human genome is highly dependent on how many nonvertebrate genomes were screened against the human genome."

"The TIGR paper nicely makes the point that you get additional insights by comparing a large number of species," says Charles F. Delwiche, of the University of Maryland, College Park, and a researcher on lateral gene transfer in plants. "The reanalysis does a good job casting doubt on the original number. For the genomics community, the paper's subtext is: Don't stop sequencing organisms now."


Part of the only figure in Darwin's Origin of Species. View larger

The two studies together show the value of publishing research, adds Delwiche. "Here is a good example of how science proceeds, with researchers checking and double-checking each other's work," he says. "I don't think anyone should be embarrassed about this."

Salzberg is less upbeat. He notes that the original statement made headlines three months ago when the publication of the human genome sequence captured the imaginations of many people. "Changing people's impressions is difficult," he says. "As researchers, all we can do is try to correct the record."

Having more genomes to compare may help answer some of today's questions. But even now researchers seem to agree that lateral gene transfer has played a limited role in vertebrate evolution. "We expect…that the vast majority of these transfer events happened before the evolution of multicellularity," concludes the commentary in Science Express. "Our multicellularity probably saved us from participating in the dirty business of lateral gene transfer so beloved by microbes."

Even if the human genome has several hundred genes of bacterial origin, the number is insignificant, says Eisen. "There are 25,000 genes in the human genome, and they found one percent that may have come into vertebrate lineage over the course of 600 million to a billion years, including the human lineage," he says. "To be honest, the number is not all that interesting."

. . .

Salzberg, S.L. et al. Microbial genes in the human genome: lateral transfer or gene loss? Science Express (May 17, 2001).

 

Andersson, J.O. & Nesbø, C.L. Are there bugs in our genome? Science Express (May 17, 2001).

 

Lander, E.S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860-921 (February 15, 2001).

 
Eisen, J.A. Horizontal gene transfer among microbial genomes: new insights from complete genome analysis. Curr Opin Genet Dev 10, 606-611 (December 2000).
 

Doolittle, W.F. Phylogenetic classification and the universal tree. Science 284, 2124-2128 (June 25, 1999).

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