New mutations occur at an increasing rate in the mitochondrial genomes of developing oocytes in aging rhesus monkeys, but increases appear to plateau at a certain age and are not as large as in nonreproductive cells such as muscle and liver. A new study using an incredibly accurate DNA sequencing method suggests there may be a protective mechanism that keeps the mutation rate in reproductive cells relatively low compared to other tissues in primates, a fact linked to primate propensity – and related to that of humans – could reproduce at a later age.
“Because of the human diseases caused by mutations in the mitochondrial genome and the trend in modern human societies to have children at older ages, it is important to understand how mutations accumulate with age,” said Kateryna Makova, Verne M. Willaman Chair of Life Sciences at Penn State and leader of the research team.
“My lab has long had an interest in studying mutations – including mutations in mitochondrial DNA. We’re also interested in evolution, so we wanted to see how mutations in mitochondrial DNA accumulate in reproductive cells because those mutations can be passed on to the next generation.” A paper describing the study, led by Penn State researchers will appear online in the week of April 4, 2022 The Proceedings of the National Academy of Sciences.
Mitochondria are cellular organelles — often referred to as the cell’s powerhouses because of their role in energy production — that have their own genome, separate from the cell’s “nuclear genome,” which resides in the cell’s nucleus and is what we often think of as “the.” genome. Mutations in mitochondrial DNA contribute to several human diseases, but studying new mutations is challenging because true mutations are difficult to distinguish from sequencing errors, which are more common compared to the mutation rates of most sequencing technologies.
“To overcome this difficulty, we used a method called ‘duplex sequencing,'” said Barbara Arbeithuber, a postdoctoral fellow at Penn State at the time of the research, who is now a research group leader at Johannes Kepler University Linz in Austria. “DNA consists of two complementary strands, but most sequencing techniques only look at the sequences of one strand at a time. In duplex sequencing, we create consensus sequences for each strand individually and then compare the two. Errors are extremely unlikely to happen at the same place on both strands, so if we see changes on both strands we can be sure it’s a real mutation.”
The team sequenced the mitochondrial genome of muscle cells, liver cells and oocytes – progenitor cells in the ovary that can become oocytes – in rhesus monkeys aged 1 to 23 years. This age range covers almost the entire reproductive lifespan of monkeys. Tissues for the study were collected opportunistically from primate research centers over a number of years when animals died of natural causes or were killed due to non-reproductive diseases. Oocytes and no sperm cells were used since mitochondria are inherited exclusively through the maternal line.
Overall, as the macaques aged, the researchers saw an increase in the frequency of mutations in all tissues tested. Liver cells experienced the most dramatic change, with a 3.5-fold increase in mutation frequency over about 20 years. The frequency of mutations in muscle increased 2.8-fold over the same period. The mutation frequency in oocytes increased 2.5-fold up to the age of nine years and then remained constant.
“From a reproductive biology perspective, oocytes are really interesting and special cells,” said Francisco Diaz, associate professor of reproductive biology at Penn State University. “They are created before birth and sit in the ovary for years, and then some of them are activated in each reproductive cycle. So you would expect them to accumulate a lot of mutations in that time, but instead we see them accumulating mutations for a while and then stop. This seems to indicate that the germline — reproductive cells like the egg and sperm — may be more resilient than we thought.”
In addition to changes in mutation rate over time, the research team also identified variations in mutation frequency in the mitochondrial genome, including multiple hotspots where mutations occurred much more frequently than would be randomly expected, which varied by tissue. One of the hotspots was in the region responsible for copying mitochondrial genomes.
“Although it is very difficult to do such a study in humans, using a primate model species gives us a good approximation,” Makova said. “Our results suggest that primate oocytes may have a mechanism to protect or repair their mitochondrial DNA, an adaptation that helps enable later reproduction. The exact mechanism leading to the plateau in mutation frequency in oocytes remains enigmatic, but it may act at the level of elimination of defective mitochondria or oocytes.”
New mutations accumulate in reproductive cells of older mice
Advanced age increases the frequency of de novo mitochondrial 2 mutations in macaque oocytes and somatic tissues, Proceedings of the National Academy of Sciences (2022). doi.org/10.1073/pnas.2118740119
Provided by Pennsylvania State University
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