NEW YORK – By digging into detailed structural variant (SV) profiles produced using long-read sequencing on thousands of individuals from Iceland, a team led by investigators at the Amgen subsidiary Decode Genetics has identified rare SVs linked to traits and conditions in the population.
"We are confident that the long-read sequencing applied at population level is going to help us to find much of the missing sequence diversity that we must have to fully understand how diversity in the sequence of the genome accounts for human diversity," Decode Founder and CEO Kari Stefansson, who is also affiliated with the University of Iceland, said in a statement.
As they reported in Nature Genetics on Monday, Stefansson and his colleagues did Oxford Nanopore Technologies' long-read sequencing on DNA from 3,524 whole blood and 102 heart tissue samples from more than 3,600 Icelandic individuals already profiled with short-read sequencing and genotyping arrays, including members of more than 400 parent-child trios. With the resulting whole-genome sequences, and a handful of analytical pipelines, they uncovered large insertions, deletions, inversions, translocations, and other SVs that were missed using available short-read sequence data.
"This technology and algorithms we developed enable us to characterize almost all structural variants reliably and consistently on a population scale," co-senior and co-corresponding author Bjarni Halldorsson, head of sequence analysis at Decode Genetics and a technology researcher at Reykjavik University, said in a statement.
From a set of nearly 133,900 SV alleles found in this group — including a median of some 13,353 insertions and almost 9,500 deletions per person — the team went on to impute tens of thousands of SVs apiece in another 166,281 Icelanders with available array-based genotyping, searching for direct ties to human traits and conditions as well as SV alleles in linkage disequilibrium with variants found in prior genome-wide association studies.
Among the new associations, the researchers flagged a rare deletion spanning more than 14,000 base pairs in the first exon of the low-density lipoprotein (LDL) cholesterol regulator-coding gene PCSK9 that appeared to coincide with reduced LDL cholesterol levels in the blood. They also reported on almost a dozen SV alleles in the ACAN gene that appeared to influence height in the Icelandic population, depending on the number of repeats present in the gene's exon.
Using the long-read sequencing-based imputation strategy, the team was also able to find individuals who were homozygous for SV alleles linked to autosomal recessively inherited conditions such as the lysosomal storage disorder cystinosis or an inherited nervous condition called Krabbe disease.
When the researchers took a closer look at SVs in linkage disequilibrium with GWAS variants, meanwhile, they highlighted SV alleles in or around loci linked to psoriasis, diabetes, age-related macular degeneration, and other traits or conditions.
The study's authors noted that structural variants falling in parts of the genome that affect protein function are relatively rare, suggesting "large-scale SV studies will be essential to characterize their role in the genetics of disease."
"[Long-read sequencing] technology and accompanying data analysis methods are still being developed and can be improved upon," they explained, noting that the current study "did not attempt to discover all forms of SVs."