Notable decrease in transcriptome conservation during mammalian aging

Turan, Zeliha Gözde
Aging is a complex process that causes decline in organisms’ reproductive capacity and chance of survival. Even though aging tends to reduce fitness, it is not eliminated by natural selection and is observed in many multicellular species, and this leads to an evolutionary paradox. The mutation accumulation theory states that due to the declining force of natural selection with age, old-age-expressed deleterious mutations will not be effectively eliminated, and can contribute to the aging phenotype. A limited number of empirical studies showed effects consistent with the mutation accumulation theory with controversial results, but this theory has not been tested using transcriptomic data. One prediction of mutation accumulation theory would be that genes highly expressed later in life would be less conserved than those expressed early. In this study, I performed a meta-analysis of 35 microarray gene-expression datasets including 8 tissues from 4 mammalian species, and studied the protein sequence conservation of genes expressed at different levels during adulthood. Age-related decrease in transcriptome conservation was detected in brain, liver, and lung, with the contribution of both genes having increased expression with age and low conservation, and genes having decreased expression with age and high conservation. Meanwhile, no such trend was observed in muscle tissues. To find functional groups associated with decrease in transcriptome conservation with age, I then performed Gene Ontology (GO) analysis. GO analysis revealed that genes showing increased expression and low conservation tend to be associated with apoptosis across different tissues. These results may indicate that genes highly expressed at old age and with low sequence conservation may contribute to the senescence phenotype in different mammalian species, consistent with the mutation accumulation theory.