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Icelanders, a diverse bunch?
By Bijal P. Trivedi

Nords and Celts began settling in Iceland in 870 AD.

The population of Iceland was thought to be genetically fairly homogeneous. But a letter to the editor in the August issue of Nature Genetics suggests that Icelanders are as heterogeneous as many populations in Europe. This letter challenges the presumptions of gene hunters, like those at deCODE genetics, who postulated that the limited gene pool and extensive genealogical records of Iceland would make it easy to search for genes involved in common diseases.

Whether Icelanders are or are not notably homogeneous is an interesting question to which there is no simple answer. Even if Icelanders are not as genetically alike as we have been led to believe, they may nonetheless be a particularly valuable population for certain types of disease-related research.

The controversy seems to be both a scientific and political problem. Kári Stefánsson, president and CEO of deCODE genetics, claims that the report has many scientific flaws and that the author, Einar Árnason, of the University of Iceland, has "written the report for political purposes and has gone on the record throwing mud at our company." Árnason is vice chairman of Mannvernd, a group opposed to the database of medical, genealogical and genetic information, which will be established and run by deCODE.

Researchers have suggested that gene-seeking would be fast and efficient in "isolated" populations such as the Icelanders. The Icelanders are said to have essentially the same genes and the same variations of each gene, which they inherited from the country's founders 1,100 years ago. For instance, those genes that caused multiple sclerosis, schizophrenia and stroke in Iceland's founders are presumably the same ones causing the disease now, albeit in a much expanded population. Some scientists reasoned that if all Icelanders essentially have the same genetic background, then the major genetic differences among people should be those associated with various diseases.

Einar Árnason and his colleagues of the University of Iceland now present evidence that the original founding population was genetically quite diverse. Árnason disputes the notion that Icelanders really do have a less diverse genetic background than people in other European countries.

Árnason's group used a study of 11 blood groups and enzymes published in 1973 to calculate the level of genetic diversity in Iceland, which they found to be comparable to Denmark, Scotland, England, or Norway.

It is preposterous that Icelanders are more heterogeneous than the French—Stefánsson

By contrast, in a response to Árnason's letter, which has been submitted to Nature Genetics, Jeff Gulcher, Agnar Helgason and Kári Stefánsson, all of deCODE, provide an analysis of 14 genetic marker sequences that show that Icelanders have the lowest average heterozygosity of ten European populations.

Calculating genetic diversity, or heterozygosity, is an indicator of whether a population contains many or few variants of each gene. When a population has been isolated since its founding, the number of variations of each gene will depend on the number of founding members and their ethnic backgrounds. Isolated populations are more homogeneous because the population intermarries and the genes are re-circulated within a confined group. By contrast, heterozygous populations arise in countries like the United States where there is a mixing of different ethnic groups that brings in a continuous inflow of gene variants.

"We are very heterogeneous, much more than they [deCODE] claim. Iceland falls right in line with other countries in Europe," says Árnason. According to his calculation based on 300 marker sequences, Icelanders have a heterozygosity of 0.75 compared to 0.70 for France, suggesting that Icelanders were genetically more diverse than the French.

Iceland's founders were more than just a couple of Vikings

Stefánsson and colleagues take the position that the method Árnason used to calculate heterozygosity was flawed because he chose 300 of the most heterozygous markers, which skewed the results, giving Iceland's population an inflated heterozygosity value of 0.75. Stefánsson also points out that Árnason quotes the French population having a heterozygosity of 0.70—a value that was calculated based on 5,264 marker sequences. "The two numbers are not comparable," says Stefánsson. "It is preposterous to suggest that the Icelandic population, which has been living in isolation for 1,100 years, is more heterozygous than the French population, which has been in the middle of so many migrations," he says.

On the other hand, Leonid Kruglyac, of the Fred Hutchinson Cancer Center in Seattle, says, "The idea that the genetic effects stand out more clearly in this population is nonsense." History supports the idea that Iceland's founders were more than just a couple of Vikings. About 60 to 80 percent of the founders were from Nordic countries and the rest were Celtic stock from the British Isles. "It's nice to see this report coming out now, which is consistent with historical reports published in the 70s," says Krugylac.

When a small number of people colonize a country their chromosomes are passed down from the founders to future generations. If there is little or no immigration then the expanded population many generations later will all derive their genetic make-up from a few people; this population would be homogeneous because there would be only a few variants of each gene circulating in the population. A large founding population would introduce more heterogeneity.

The danger in treating the Icelanders as a homogeneous population is that the technique used to search for disease genes is more likely to generate false positives, pointing to specific regions of the chromosomes that are unrelated to the disease, says Árnason, an argument that deCODE does not find persuasive.

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Árnason, E. et al. Genetic homogeneity of Icelanders: fact or fiction? Nat Gen 25, 373-374 (August 2000).

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