From mouse to human to giraffe, species accrue similar numbers of genetic mutations during lifetime, Wellcome Sanger Institute finds
A study of 16 species, from mice to humans to giraffes, has found that they all end their life with similar numbers of genetic changes.
Researchers at the Wellcome Sanger Institute found that the longer the lifespan of a species, the slower the rate at which mutations occur.
This lends weight to the theory held since the 1950s that genetic changes, or ‘somatic mutations’, play a role in ageing.
In humans, cells naturally acquire about 20 to 50 mutations per year. Most are harmless, but some can start a cell on a path to cancer or impair its normal function.
Technological advances have finally allowed researchers to observe these changes in normal tissues.
In this study, which also explored the genomes of lions, tigers and the long-lived, highly cancer-resistant naked mole-rat, samples were provided by organisations including the Zoological Society of London.
Whole-genome sequences were generated from 208 intestinal crypts taken from 48 individuals in order to measure mutation rates in single intestinal stem cells.
Analysing the mutational signatures, the researchers found somatic mutations accumulated linearly over time and were caused by similar mechanisms across all species
First author Dr Alex Cagan said: “To find a similar pattern of genetic changes in animals as different from one another as a mouse and a tiger was surprising. But the most exciting aspect of the study has to be finding that lifespan is inversely proportional to the somatic mutation rate. This suggests that somatic mutations may play a role in ageing, although alternative explanations may be possible. Over the next few years, it will be fascinating to extend these studies into even more diverse species, such as insects or plants.”
But the search for an answer to Peto’s paradox goes on. This describes the mystery of why cancers, which develop from single cells, are not more likely to be found in species with larger bodies and therefore more cells.
First author Dr Adrian Baez-Ortega said: “The fact that differences in somatic mutation rate seem to be explained by differences in lifespan, rather than body size, suggests that although adjusting the mutation rate sounds like an elegant way of controlling the incidence of cancer across species, evolution has not actually chosen this path.
“It is quite possible that every time a species evolves a larger size than its ancestors – as in giraffes, elephants and whales – evolution might come up with a different solution to this problem. We will need to study these species in greater detail to find out.”
A giraffe is 40,000 times bigger than a mouse and a human lives 30 times longer, but the number of somatic mutations per cell at the end of lifespan between the three species only varied by around a factor of three.
Dr Simon Spiro, ZSL (Zoological Society of London) wildlife veterinary pathologist, said: “Animals often live much longer in zoos than they do in the wild, so our vets’ time is often spent dealing with conditions related to old age. The genetic changes identified in this study suggest that diseases of old age will be similar across a wide range of mammals, whether old age begins at seven months or 70 years, and will help us keep these animals happy and healthy in their later years.”
Accumulation of multiple types of damage to our cells and tissues throughout life, including somatic mutations, protein aggregation, epigenetic changes and others, are likely to be responsible for ageing.
Dr Inigo Martincorena, senior author of the study from the Wellcome Sanger Institute, said: “Ageing is a complex process, the result of multiple forms of molecular damage in our cells and tissues. Somatic mutations have been speculated to contribute to ageing since the 1950s, but studying them had remained difficult. With the recent advances in DNA sequencing technologies, we can finally investigate the roles that somatic mutations play in ageing and in multiple diseases. That this diverse range of mammals end their lives with a similar number of mutations in their cells is an exciting and intriguing discovery.”
The study was published in Nature.
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