NEW YORK — Researchers at Oregon Health and Science University (OHSU) and elsewhere have mapped post-zygotic mutations (PZM) from multiple post-mortem tissue samples of 948 human donors.
Post-zygotic mutations begin to arise in the genome soon after fertilization and are thought to be key contributors to aging and aging-related diseases.
"PZMs are very difficult to ascertain because they can happen anywhere in the genome and [in] any cell of the body," said co-corresponding author Donald Conrad, chief of the division of genetics at the primate center at OHSU.
For their study published in Science on Thursday, Conrad and his colleagues used RNA-seq data from 17,382 samples derived from 948 donors across 54 diverse tissues and cell types from the Genotype-Tissue Expression (GTEx) project. Previously, most PZM research has focused on easily accessible tissues, such as blood, liver, skin, and colon samples, but this study examined additional tissue types.
To analyze that data, the researchers developed a suite of methods they dubbed Lachesis to identify single-nucleotide PZMs from bulk RNA-seq data and to predict when the mutations arose during development and aging.
"We used the logic that RNA is a copy of DNA, so any PZMs present in the DNA of these tissues would get copied in the RNA," Conrad said. "These PZMs can provide a signpost for other researchers on how PZMs contribute to aging," he added.
The atlas contains around 56,000 mutations. Since the researchers relied on RNA data, they were only able to detect mutations in expressed genes. "This is a small, but important, fraction of the human genome," said co-corresponding author Nicole Rockweiler, a computational researcher at the Broad Institute.
The number of mutations found in each tissue varied, though brain regions had the lowest number of mutations, whereas the liver, skin, blood, and esophagus had some of the highest.
The researchers also reported that while half the variation in PMZ burden among tissue samples can be attributed to measured technical and biological effects, about 9 percent can be attributed to donor-specific effects. "This finding is exciting because it tells you that there is something potentially inherent to a person that could be measured," said Conrad.
Meanwhile, the data also showed that most prenatal mutations occurred during gastrulation and the early formation of the brain. "I found these results surprising because I would have thought the human body would need the genomes for cells involved in these processes to be error-free. Instead, it looks like the body is OK with errors during these periods," said Rockweiler.
According to the researchers, the PMZ atlas they developed can also help scientists understand which mutations can lead to diseases. "Our findings tell us which are normal post-zygotic mutations among people to help understand which ones are abnormal," Rockweiler added.