NEW YORK (GenomeWeb) – The Icelandic population, long valued by geneticists due to its homogeneity and the country's extensive genealogical records, has become an even more robust research resource with the completion of whole-genome sequences for thousands of Icelanders.
As they reported in the first of four new studies out today in Nature Genetics, researchers from Decode Genetics, the University of Iceland, and elsewhere described efforts to sequence and start analyzing the genomes on 2,636 individuals from Iceland.
"Basically, what we have is a fairly detailed insight into the sequence of a genome of an entire nation," senior author Kari Stefansson, Decode's founder and CEO, told reporters during a telephone press briefing this week.
"This is, I think, a reasonably large step towards putting us in a position to understand how human diversity is dictated by the diversity and the sequence of DNA," added Stefansson, who is also affiliated with the University of Iceland.
He and his colleagues have already used the genomes to assess common SNPs in the population, impute additional variants, and document new genetic ties for traits and diseases in the population.
Whereas studies done over nearly two decades have mainly focused on variants involved in disease risk or protection, Stefansson noted, current papers offer broader clues to human mutation rates and, consequently, human population history.
The team also got a glimpse at rarer forms of genetic variation, including loss-of-function mutations affecting both alleles of a gene, which turned up in a significant proportion of Iceland's population.
"We have, now, insight into how many of our fellow countrymen have a gene knocked out: it's about 7 percent or 8 percent of the population who have loss-of-function mutations in both alleles of 1,170 genes," Stefansson noted.
For instance, findings so far suggest that double allele disrupting alterations are relatively rare for genes that are highly expressed in human brain tissue, while olfactory receptor gene knockouts were more common.
The researchers are currently gearing up to do detailed phenotypic studies of individuals carrying loss-of-function gene mutations in the hopes of finding out which, if any, have an impact on human traits.
"We now have this database of human knockouts — which is something that people have aspired to develop over the past few years — and we can turn the tables," Stefansson explained. "Instead of going from a phenotype to a variant in a genome, we can go from a variant in a genome to a phenotype."
Based on what they've already been able to glean from the Icelandic genome sequences, Stefansson predicted that the country is poised to consider implementing the sort of personalized medicine outlined in President Obama's recently proposed precision medicine program in the US.
The team used Illumina technology to sequence the genomes, which were covered to an average minimum depth of 10-fold apiece. The medium depth came in at around 20-fold per genome, on average, with 909 of the genomes exceeding 30-fold average coverage.
The genome sequences contained nearly 20 million SNPs, along with almost 1.5 million small insertions and deletions, the researchers reported. Through imputation in another 104,220 individuals from Iceland, they narrowed in on variants with minor allele frequencies as low as 0.1 percent.
When the group considered genetic factors coinciding with various human traits or clinical features, it uncovered ABCB4 alterations that bump up liver disease risk, along with a recessively inherited frameshift mutation in the MYL4 gene that appears to dial up risk of a heart condition called early-onset atrial fibrillation.
Similarly, the data made it possible to find maternally inherited variants in non-coding, intervening sequences in the GNAS gene that are associated with higher-than-usual levels of the thyroid-stimulating hormone.
Still other findings, described in one of the accompanying Nature Genetics papers, pointed to loss-of-function glitches in the ABCA7 gene that seem to more than double the risk of Alzheimer's disease in the Icelandic population.
Using data from 753 fully sequenced Icelandic men, meanwhile, the researchers found new clues about the age and apparent mutation rate of the Y chromosome.
The team estimated that the Y chromosome emerged roughly 239,000 years ago. That would make the male sex chromosome somewhat younger than estimated in a previous study, but roughly the same age as the maternally inherited mitochondrial genome, noted Agnar Helgason, first author of the Y chromosome-focused analysis.
Helgason, an anthropology researcher at the University of Iceland, is also employed by Decode Genetics, which was acquired by biopharmaceutical firm Amgen in late 2012.