• Mutations across animal kingdom shed new

    From ScienceDaily@1:317/3 to All on Wed Apr 13 22:30:44 2022
    Mutations across animal kingdom shed new light on aging
    Quantity of mutations acquired similar over lifetime of 16 species,
    despite vast differences in lifespan and body mass

    Date:
    April 13, 2022
    Source:
    Wellcome Trust Sanger Institute
    Summary:
    A new study compares the accumulation of mutations across many
    animal species and has shed new light on decades-old questions about
    the role of these genetic changes in ageing and cancer. Researchers
    found that despite huge variation in lifespan and size, different
    animal species end their natural life with similar numbers of
    genetic changes.



    FULL STORY ==========================================================================
    The first study to compare the accumulation of mutations across many
    animal species has shed new light on decades-old questions about the
    role of these genetic changes in ageing and cancer. Researchers from the Wellcome Sanger Institute found that despite huge variation in lifespan
    and size, different animal species end their natural life with similar
    numbers of genetic changes.


    ==========================================================================
    The study, published today (13 April 2022) in Nature, analysed genomes
    from 16 species of mammal, from mice to giraffes. The authors confirmed
    that the longer the lifespan of a species, the slower the rate at which mutations occur, lending support to the long-standing theory that somatic mutations play a role in ageing.

    Genetic changes, known as somatic mutations, occur in all cells throughout
    the life of an organism. This is a natural process, with cells acquiring
    around 20 to 50 mutations per year in humans. Most of these mutations
    will be harmless, but some of them can start a cell on the path to cancer
    or impair the normal functioning of the cell.

    Since the 1950s, some scientists have speculated that these mutations may
    play a role in ageing. But the difficulty of observing somatic mutations
    has made it challenging to study this possibility. In the last few years, technological advances have finally allowed genetic changes to be observed
    in normal tissues, raising hopes of answering this question1.

    Another long-standing question is Peto's paradox. Since cancers develop
    from single cells, species with larger bodies (and therefore more cells)
    should theoretically have a much higher risk of cancer. Yet cancer
    incidence across animals is independent of body size. Animal species with
    large bodies are believed to have evolved superior mechanisms to prevent cancer. Whether one such mechanism is a reduction in the accumulation
    of genetic changes in their tissues has remained untested.

    In this study, researchers at the Wellcome Sanger Institute set out to
    test these theories by using new methods to measure somatic mutation
    in 16 mammalian species, covering a wide range of lifespans and body
    masses2. This included species such as human, mouse, lion, giraffe,
    tiger, and the long-lived, highly cancer-resistant naked mole-rat, with
    samples provided by a number of organisations including the Zoological
    Society of London.



    ========================================================================== Whole-genome sequences were generated from 208 intestinal crypts3 taken
    from 48 individuals, to measure mutation rates in single intestinal
    stem cells.

    Analysis of the patterns of mutations (or mutational signatures) provided information on the processes at work. The researchers found that somatic mutations accumulated linearly over time and that they were caused by
    similar mechanisms across all species, including humans, despite their
    very different diets and life histories.

    Evidence of a possible role of somatic mutations in ageing was provided
    by the researchers' discovery that the rate of somatic mutation decreased
    as the lifespan of each species increased.

    Dr Alex Cagan, a first author of the study from the Wellcome Sanger
    Institute, 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." The search for an answer to Peto's paradox
    goes on, however. After accounting for lifespan, the authors found no significant association between somatic mutation rate and body mass,
    indicating that other factors must be involved in larger animals'
    ability to reduce their cancer risk relative to their size.



    ==========================================================================
    Dr Adrian Baez-Ortega, a first author of the study from the Wellcome
    Sanger Institute, 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." Despite vast differences in lifespan
    and body mass between the 16 species studied, the quantity of somatic
    mutations acquired over each animal's lifetime was relatively similar. On average a giraffe is 40,000 times bigger than a mouse, and a human lives
    30 times longer, but the difference in 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." Understanding
    the exact causes of ageing remains an unsolved question and an area of
    active investigation. Ageing is likely to be caused by the accumulation
    of multiple types of damage to our cells and tissues throughout life,
    including somatic mutations, protein aggregation and epigenetic changes,
    among others.

    Comparing the rates of these processes across species with very different lifespans can shed light on their role in 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."

    ========================================================================== Story Source: Materials provided by Wellcome_Trust_Sanger_Institute. Note: Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Alex Cagan, Adrian Baez-Ortega, Natalia Brzozowska, Federico
    Abascal, Tim
    H. H. Coorens, Mathijs A. Sanders, Andrew R. J. Lawson, Luke M. R.

    Harvey, Shriram Bhosle, David Jones, Raul E. Alcantara, Timothy M.

    Butler, Yvette Hooks, Kirsty Roberts, Elizabeth Anderson,
    Sharna Lunn, Edmund Flach, Simon Spiro, Inez Januszczak, Ethan
    Wrigglesworth, Hannah Jenkins, Tilly Dallas, Nic Masters, Matthew
    W. Perkins, Robert Deaville, Megan Druce, Ruzhica Bogeska, Michael
    D. Milsom, Bjo"rn Neumann, Frank Gorman, Fernando Constantino-Casas,
    Laura Peachey, Diana Bochynska, Ewan St. John Smith, Moritz
    Gerstung, Peter J. Campbell, Elizabeth P.

    Murchison, Michael R. Stratton, In~igo Martincorena. Somatic
    mutation rates scale with lifespan across mammals. Nature, 2022;
    DOI: 10.1038/ s41586-022-04618-z ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/04/220413131155.htm

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