Tuesday, March 31, 2015

Iceland’s Giant Genome Project: Are there really Genes we can live without?

Nearly 20 years ago a controversial proposal was made to sequence the genomes of the nation of Iceland.  The effort, underwritten by Amgen's deCODE Genetics, a biopharmaceutical company based in Reykjavik, Iceland, hoped to provide scientists insight to the human genome that would expand their ability to investigate the genetic bases of human diseases. Originally the project was granted permission by the Parliament of Iceland, but intervening court cases, citing a right to privacy, limited the unfettered access to patient samples. Despite the privacy concern, the vast majority of the population supported the decode project and over half the population donated blood samples.  Members of this small progressive thinking island nation decided that the scientific benefits of the study to society outweighed any potential prejudice associated with the finding of genetic mutations in individuals.

This small island county is pretty much ideal for genetic studies in that the population is more or less genetically uniform and has been more or less isolated since the first settlers arrived centuries ago.  Equally important is the fact that the health care system of the country maintains health records on all of its citizens.  By sequencing the full genomes of 2,500 Icelanders and comparing the results with less extensive genotype data from more than 104,000 other Icelanders teams of researchers identified 20 million genetic variants.  Keep in mind that the population of Iceland is only 325,000, so nearly 1/3 of the population took part in this study; quite an example of societal cooperation. The researchers then cross-checked that information against Iceland's extensive genealogical and healthcare information records to investigate how diseases might exist through generations of a given family.

The work, published as four papers in the 25 March 2015 issue of the journal Nature Genetics has yielded insights into a number of different areas of genetics, including new insights regarding the common human ancestor for the male Y chromosome or the mutation in the ABCA7 gene, which doubles the risk of Alzheimer’s disease in populations dominated by Icelandic or European ancestry.  One of the more interesting findings was the number of gene deletions or “knockouts” that were found.  More than 1000 genetic knockouts were identified and more than 8,000 Icelanders were identified as having lost the function of at least one gene. Genes responsible for our ability to discriminate smells being the most common knockout, while genes expressed in the brain having far fewer.  While these data seem to demonstrate the redundancy of human genetic architecture, the comparison of phenotypic data with the knockouts can potentially provide information regarding alternative biochemical pathways currently unknown.  Of course the lay-press is now asking whether or not these genes are necessary.

These data have application beyond Iceland.  For example, scientists at deCODE were able to zero in on their new anti-heart-attack compound. It's based on a gene known as LTA4H, first seen in mice, which governs the production of an enzyme called leukotriene A4 hydrolase. The enzyme plays a role in inflammation, a key factor in heart disease, and also encourages the buildup of cholesterol on blood-vessel walls.  Icelanders with a particular variant of the LTA4H gene turn out to be 40% more likely than average to have heart attacks.

While there still exists an ethical conundrum regarding the use of genetic information, it is also obvious that to do nothing with the information might be unethical as well.  How to best use this treasure trove of information to improve their health care is up to the citizens of Iceland.

What do you think of the use of individual genetic information to guide personalized medicine?


By: BioTek Instruments, Paul Held, PhD., Laboratory Manager

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