Oregon Health & Science University (OHSU) researchers just published results from a study focused on identifying and characterizing low-lying autism spectrum disorder genetic mutations that may have been missed in previous research, given these mutations are only present in a fraction of the bulk DNA of an individual. The work was published yesterday in The American Journal of Human Genetics.
The scientists compared genetic sequencing data from the Simons Simplex Collection and determined that approximately 11% of previously reported postzygotic mosaic mutations (PMMs) affecting a single DNA base, which was thought to have been present at the time of human conception, actually show evidence of the mutation occurring during the development process.
"This initial finding told us that, generally, these mosaic mutations are much more common than previously believed. We thought this might be the tip of a genetic iceberg waiting to be explored," said the study's principal investigator Brian O'Roak, Ph.D., an assistant professor of molecular and medical genetics in the OHSU School of Medicine.
To check this possibility, researchers developed a custom approach to identify the low-level mutations and validate that they were real. By doing this, they found that the rate of PMMs increased to 22% of the new mutations present in children.
By comparing the rates of PMMs that result in different predicted effects on the genome in affected children and their unaffected siblings, the scientists were lead to finding "silent" mosaic mutations. These mutations were enriched in the affected children, contributing risk to approximately 2% of the individuals with autism in this cohort. These types of mutations were thought to be neutral, but the team found that actually, they might be altering genetic messages.
The study also found evidence that mosaic mutations that alter the protein code of genes essential for development, or genes that resist mutations, are enriched in individuals with autism and added a 1 to 2% risk. Many of the PMMs occurred in some of the most highly validated autism risk genes identified to date, which suggested that these mutations are contributing to autism genetic risk. Due to this, the research team believes that overall, mosaic mutations may contribute to autism risk in 3 to 4% of this cohort.
By leveraging the unique family design of the Simons Simplex Collection cohort, O'Roak's team analyzed the parents' genomes and discovered that 6.8% of the supposedly "new" mutations present in children at conception could actually be traced back to a PMM that occurred early in the development of their parent. These mutations were generally present in 20 to 75% of the parents' blood cells, providing indirect evidence that many of the PMMs occurring in children did, in fact, happen very early during development and that they likely contribute mosaicism across the body, including in the brain.
"In addition to a need for broader research focused on the role that mosaicism plays in autism and related disorders, our data argue that physicians should be requiring more sensitive testing of both children and parents, when a new disorder-related genetic mutation is identified," O'Roak said. "These mutation[s] can go from being in a few percent of the cells of a parent to 100% of the cells of a child. If present, at even low levels in the parents, the risk of additional children receiving this mutation is dramatically increased."