More Extensive Analysis Casts Doubt On Portion Of The Public Project's Human Genome Paper

Steven L. Salzberg, Ph.D., Owen White, Ph.D., Jeremy Peterson, and Jonathan A. Eisen, Ph.D., report in "Microbial genes in the human genome: lateral transfer or gene loss?" on the results of a study conducted at TIGR that reexamined the claim made by the IHGSC that a significant number of bacterial genes were laterally transferred to the human genome. The original report identified a set of 223 proteins as having "significant similarity to proteins from bacteria, but no comparable similarity to proteins from yeast, worm, fly and mustard weed…" Based on this evidence, the earlier study concluded that these genes were likely transferred directly from bacteria into an ancestral vertebrate species.

TIGR scientists reanalyzed the 31,780 genes that were the focus of the IHGSC report, and also analyzed the 26,544 genes reported in the human genome paper published in Science (Feb. 16, 2001). They compared these human genes to a larger sample of genes from other organisms, including thousands of genes from partially sequenced genomes. Conducting a more detailed analysis built a stronger case against the claim of lateral transfer: with each new piece of analysis, the number of genes found only in humans and bacteria grew smaller and smaller.

"Our results suggest that many of the shared genes were simply lost by other eukaryotes, with variations in different organisms' rates of evolution and the effects of sample size also affecting the outcome," said Salzberg.

"Recent comparative genomics studies have revealed that lateral gene transfer plays an important role in evolution of microbial species (see the paper published by K.E. Nelson, et al., "Evidence for lateral gene transfer between Archaea and bacteria from genome sequence of Thermotoga maritima," Nature, 399:323-9, May 27, 1999)," said Claire Fraser, Ph.D., president of TIGR. "The initial report of lateral gene transfer between bacteria and humans generated a great deal of interest here at TIGR. However, based on our subsequent reanalysis of the data, the assertion of such transfer cannot be substantiated."

"We are not calling into question the occurrence of lateral gene transfer," said Jonathan A. Eisen, an evolutionary biologist at TIGR. "What we are saying is that the specific gene transfers proposed by the authors of the human genome paper are based on inappropriate scientific assumptions and are likely incorrect."

In the TIGR study, researchers found just 41 genes that are exclusively shared by humans and bacteria, rather than the 223 cited in the original report. These 41 genes, they argue, could all have been lost from the four non-vertebrate genomes examined in the Nature paper. Alternatively, some of the genes could be present, but might have mutated sufficiently that sequence similarity programs cannot detect them.

"Our conclusion is that few if any genes have been laterally transferred from bacteria directly into vertebrates," said Salzberg, "Our analysis shows that as you include more and more non-vertebrates in the analysis, the pool of genes remaining grows smaller and smaller. We expect that this pool will shrink to zero when another dozen or so non-vertebrate genomes have been sequenced."

Definition

Horizontal (Lateral) gene transfer: transfer of genetic material from an individual of one species to an individual of a different species.

ABOUT TIGR

The Institute for Genomic Research (TIGR) is a not-for-profit research institute founded in 1992 with interests in structural, functional and comparative analysis of genomes and gene products from a wide variety of organisms including viruses, eubacteria (both pathogens and non-pathogens), Archaea (the so-called third domain of life), and eukaryotes (plants, animals, fungi and protists such as the malarial parasite). The first two complete genome sequences of free-living organisms (the bacteria Haemophilus influenzae and Mycoplasma genitalium) were determined at TIGR in 1995, as was the first complete genome sequence of an Archaea (Methanococcus jannaschii, in 1996). TIGR recently completed the sequencing of its 25th microbial genome. TIGR also completed the first sequence of a chromosome from the malarial parasite, Plasmodium falciparum, and from the model plant species, Arabidopsis thaliana. Additional information about TIGR is available at http://www.tigr.org.