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Determining the role of mutation load in mammalian senescence

Somel, Mehmet
Kılınç, Gülşah Merve
Özer, Füsun
Turan, Zeliha Gözde
Koptekin, Dilek
Ghalichi, Ayshin
In most multicellular species, aging is accompanied by an increasing risk of disease and mortality, a process termed senescence. The evolutionary causes and genetic bases of senescence are little understood. Senescence is usually associated with accumulating cellular damage, although a number of theories suggest that harmful mutations that are expressed only at late age could also contribute to the aging phenotype. Analyzing primate brain transcriptome data, we recently identified a pattern that would support this latter notion: genes expressed at high levels in old individuals, compared to genes expressed at high levels in young adults, tend to be evolutionarily less conserved, suggesting that they might harbor a higher proportion of deleterious mutations. This result suggests that a deleterious mutation load may indeed play a role in senescence. In this project, we will use a wide array of transcriptome datasets across multiple tissues and mammalian species, to identify the generality of this pattern. Using a new metric, for the first time, we will measure the decrease in negative selection pressure with age. The results will shed light into one highly debated mechanism of senescence.