Molecular footprint of Medawar's mutation accumulation process in mammalian aging

Turan, Zeliha Gozde
Parvizi, Poorya
Donertas, Handan Melike
Tung, Jenny
Khaitovich, Philipp
Somel, Mehmet
Medawar's mutation accumulation hypothesis explains aging by the declining force of natural selection with age: Slightly deleterious germline mutations expressed in old age can drift to fixation and thereby lead to aging-related phenotypes. Although widely cited, empirical evidence for this hypothesis has remained limited. Here, we test one of its predictions that genes relatively highly expressed in old adults should be under weaker purifying selection than genes relatively highly expressed in young adults. Combining 66 transcriptome datasets (including 16 tissues from five mammalian species) with sequence conservation estimates across mammals, here we report that the overall conservation level of expressed genes is lower at old age compared to young adulthood. This age-related decrease in transcriptome conservation (ADICT) is systematically observed in diverse mammalian tissues, including the brain, liver, lung, and artery, but not in others, most notably in the muscle and heart. Where observed, ADICT is driven partly by poorly conserved genes being up-regulated during aging. In general, the more often a gene is found up-regulated with age among tissues and species, the lower its evolutionary conservation. Poorly conserved and up-regulated genes have overlapping functional properties that include responses to age-associated tissue damage, such as apoptosis and inflammation. Meanwhile, these genes do not appear to be under positive selection. Hence, genes contributing to old age phenotypes are found to harbor an excess of slightly deleterious alleles, at least in certain tissues. This supports the notion that genetic drift shapes aging in multicellular organisms, consistent with Medawar's mutation accumulation hypothesis.


Notable decrease in transcriptome conservation during mammalian aging
Turan, Zeliha Gözde; Somel, Mehmet; Department of Biology (2016)
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 limite...
Işıldak, Ulaş; Somel, Mehmet; Department of Biology (2022-9-1)
Aging is a complex process associated with the accumulation of stochastic genetic and epigenetic alterations, leading to functional decline and increased risk for disease and death. Although some previous studies demonstrated a tendency towards increased inter-individual heterogeneity during aging, whether it is a function of time that starts at the beginning of life is unknown. Its functional consequences and regulations have also not been systematically studied. In this study, I addressed these questions ...
MicroRNA-Driven Developmental Remodeling in the Brain Distinguishes Humans from Other Primates
Somel, Mehmet; Tang, Lin; Yan, Zheng; Hu, Haiyang; Guo, Song; Jiang, Xi; Zhang, Xiaoyu; Xu, Guohua; Xie, Gangcai; Li, Na; Hu, Yuhui; Chen, Wei; Paeaebo, Svante; Khaitovich, Philipp (2011-12-01)
While multiple studies have reported the accelerated evolution of brain gene expression in the human lineage, the mechanisms underlying such changes are unknown. Here, we address this issue from a developmental perspective, by analyzing mRNA and microRNA (miRNA) expression in two brain regions within macaques, chimpanzees, and humans throughout their lifespan. We find that constitutive gene expression divergence (species differences independent of age) is comparable between humans and chimpanzees. However, ...
Biochemical characterization of recombinant 20s proteasome from thermoplasma volcanium and cloning of it's regulatory subunit gene
Baydar, Gözde; Kocabıyık, Semra; Department of Biotechnology (2006)
In this study, we have characterized some biochemical and electrophoretic features of recombinant 20S Proteasome from a thermoacidophilic archaeon Thermoplasma volcanium. As revealed by SDS-PAGE the 20S Proteasome was composed of two subunits, ?- and β- subunits with estimated molecular masses of 24 kDa and 23 kDa, respectively. The highest chymotryptic activity was observed over an alkaline pH range (pH 8.0 ا pH 9.0) and the optimum temperature for the activity was determined as 85oC. The heat stability of...
Evolution of Primate Gene Expression: Drift and Corrective Sweeps?
Chaix, R.; Somel, Mehmet; Kreil, D. P.; Khaitovich, P.; Lunter, G. A. (Genetics Society of America, 2008-11-01)
Changes in gene expression play an important: role in species' evolution. Earlier studies uncovered evidence that the effect of mutations on expression levels within the primate order is skewed, with many small downregulations balanced by fewer but larger upregulations. In addition, brain-expressed genes appeared to show an increased rate of evolution on the branch leading to human. However, the lack of a mathematical model adequately describing the evolution of gene expression precluded the rigorous establ...
Citation Formats
Z. G. Turan, P. Parvizi, H. M. Donertas, J. Tung, P. Khaitovich, and M. Somel, “Molecular footprint of Medawar’s mutation accumulation process in mammalian aging,” AGING CELL, pp. 0–0, 2019, Accessed: 00, 2020. [Online]. Available: