A new study of the full genetic code of a common human virus by researchers at the University of Wisconsin-Madison dramatically confirms of the “out-of-Africa” pattern of human migration previously documented by anthropologists, and studies of the human genome.
The virus under study, herpes simplex virus type 1 (HSV-1), usually causes nothing more severe than cold sores around the mouth notes Curtis Brandt, a professor of medical microbiology and ophthalmology at UW-Madison. Brandt is senior author of the study, now online in the journal PLOS ONE.
When Dr. Brandt and co-authors UW-Madison Research Specialist Aaron Kolb and Associate professor in the Departments of Statistics and Botany Cécile Ané compared 31 strains of HSV-1 collected in North America, Europe, Africa and Asia, “the result was fairly stunning,” says Dr. Brandt.
“The viral strains sort exactly as you would predict based on sequencing of human genomes. We found that all of the African isolates cluster together, all the virus from the Far East, Korea, Japan, China clustered together, all the viruses in Europe and America, with one exception, clustered together,” Dr. Brandt notes in a UW-Madison release. “What we found follows exactly what the anthropologists have told us, and the molecular geneticists who have analyzed the human genome have told us, about where humans originated and how they spread across the planet.”
The UW-Madison release notes that geneticists explore how organisms are related by studying changes in the sequence of bases, or “letters” on their genes. From knowledge of how quickly a particular genome changes, they can construct a “family tree” that shows when particular variants had their last common ancestor. Studies of human genomes have shown that our ancestors emerged from Africa roughly 150,000 to 200,000 years ago, and then spread eastward toward Asia, and westward toward Europe.
Scientists have previously studied herpes simplex virus type 1 by looking at a single gene, or a small cluster of genes, but Brandt notes that this approach can be misleading. “Scientists have come to realize that the relationships you get back from a single gene, or a small set of genes, are not very accurate.”
The PLOS ONE study used high-capacity genetic sequencing and advanced bioinformatics to analyze the massive amount of data from the 31 genomes.
“Our results clearly support the anthropological data, and other genetic data, that explain how humans came from Africa into the Middle East and started to spread from there.” comments Dr. Brandt.
The PLOS ONE research article “Using HSV-1 Genome Phylogenetics to Track Past Human Migrations,” (Kolb AW, Ané C, Brandt CR (2013) PLoS ONE 8(10): e76267. doi:10.1371/journal.pone.0076267) co-authors explain that they compared 31 complete and nearly complete globally derived HSV-1 genomic sequences using HSV-2 HG52 as an outgroup to investigate their phylogenetic relationships and looked for evidence of recombination. The East African derived viruses contained the greatest amount of genetic diversity and formed four o six clades identified. (A clade a group consisting of an ancestor and all its descendants, living and extinct). East Asian and European/North American derived viruses formed separate clades. HSV-1 strains E07, E22 and E03 were highly divergent and may each represent an individual clade.
The study expands the previously described HSV-1 three clade phylogenetic structures to a minimum of six and shows that the clade structure also mirrors global human migrations. Given that HSV-1 has co-evolved with its host, sequencing HSV-1 isolated from various populations could serve as a surrogate biomarker to study human population structure and migration patterns.
The technology of simultaneously comparing the entire genomes of related viruses could also be useful in exploring why certain strains of a virus are so much more lethal than others. In a tiny percentage of cases, for example, HSV-1 can cause a deadly brain infection, Dr. Brandt notes. “We’d like to understand why these few viruses are so dangerous, when the predominant course of herpes is so mild. We believe that a difference in the gene sequence is determining the outcome, and we are interested in sorting this out.”
For studies of influenza virus in particular, Dr. Brandt continues, “people are trying to come up with virulence markers that will enable us to predict what a particular strain of virus will do.”
The researchers broke the HSV-1 genome into 26 pieces, made family trees for each piece and then combined each of the trees into one network tree of the whole genome, Brandt says. “Cécile Ané did a great job in coming up with a new way to look at these trees, and identifying the most probable grouping.” It was this grouping that paralleled existing analyses of human migration.
The new analysis could even detect some intricacies of migration. Every HSV-1 sample from the United States except one matched the European strains, but one strain that was isolated in Texas looked Asian. “How did we get an Asian-related virus in Texas?” Kolb asks. Either the sample had come from someone who had travelled from the Far East, or it came from a native American whose ancestors had crossed the “land bridge” across the Bering Strait roughly 15,000 years ago.
“What we found follows exactly what the anthropologists have told us, and the molecular geneticists … have told us, about where humans originated and how they spread across the planet,” says Dr. Brandt “We found support for the land bridge hypothesis because the date of divergence from its most recent Asian ancestor was about 15,000 years ago. The dates match, so we postulate that this was an Amerindian virus.”
Herpes simplex virus type 1 was an ideal virus for the study because it is easy to collect, usually not lethal, and able to form lifelong latent infections. Because HSV-1 is spread by close contact, kissing or saliva, it tends to run in families. “You can think of this as a kind of external genome,” Dr. Brandt says.
Moreover, HSV-1 is much simpler than the human genome, which cuts the cost of sequencing, yet its genome is much larger than another virus that also has been used for this type of study. Genetics often comes down to a numbers game; larger numbers produce stronger evidence, so a larger genome produces much more detail.
But what really jumped out of the study, Brandt says, “was clear support for the out-of-Africa hypothesis. Our results clearly support the anthropological data, and other genetic data, that explain how humans came from Africa into the Middle East and started to spread from there.”
The correspondence with anthropology even extends, as before, to the details. In the virus, as in human genomes, a small human population entered the Middle East from Africa. “There is a population bottleneck between Africa and the rest of the world; very few people were involved in the initial migration from Africa,” says Dr. Brandt. “When you look at the phylogenetic tree from the virus, it’s exactly the same as what the anthropologists have told us.”
University of Wisconsin-Madison
Kolb AW, Ané C, Brandt CR (2013) Using HSV-1 Genome Phylogenetics to Track Past Human Migrations. PLoS ONE 8(10): e76267. doi:10.1371/journal.pone.0076267
University of Wisconsin-Madison