Image by Spencer Phillips
DNA helix
Whole-exome sequencing (WES) may routinely miss genetic variations associated with leukemia and other diseases, according to research published in Scientific Reports.
The study revealed 832 genes that have low coverage across multiple WES platforms.
These genes are associated with leukemia, psoriasis, heart failure, and other diseases, and they may be missed by researchers using WES to study these diseases.
“Although it was known that coverage—the average number of times a given piece of DNA is read during sequencing—could be uneven in whole-exome sequencing, our new methods are the first to really quantify this,” said study author Santhosh Girirajan, MBBS, PhD, of The Pennsylvania State University, University Park.
“Adequate coverage—often as many as 70 or more reads for each piece of DNA—increases our confidence that the sequence is accurate, and, without it, it is nearly impossible to make confident predictions about the relationship between a mutation in a gene and a disease.”
“In our study, we found 832 genes that have systematically low coverage across 3 different sequencing platforms, meaning that these genes would be missed in disease studies.”
The researchers said low-coverage regions may result from limited precision in WES technologies due to certain genomic features.
Highly repetitive stretches of DNA can prevent the sequencer from reading the DNA properly. The study showed that at least 60% of low-coverage genes occur near DNA repeats.
“One solution to this problem is for researchers to use whole-genome sequencing, which examines all base pairs of DNA instead of just the regions that contain genes,” Dr Girirajan said. “Our study found that whole-genome data had significantly fewer low-coverage genes than whole-exome data, and its coverage is more uniformly distributed across all parts of the genome.”
“However, the costs of whole-exome sequencing are still significantly lower than whole-genome sequencing. Until the costs of whole-genome sequencing is no longer a barrier, human genetics researchers should be aware of these limitations in whole-exome sequencing technologies.”
