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. 


Determining the role of mutation load in mammalian senescence
Somel, Mehmet; Özer, Füsun; Turan, Zeliha Gözde; Koptekin, Dilek; Ghalichi, Ayshin(2016-12-31)
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 suppo...
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 (2019-08-01)
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...
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 ...
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...
Widespread splicing changes in human brain development and aging
Mazin, Pavel; Xiong, Jieyi; Liu, Xiling; Yan, Zheng; Zhang, Xiaoyu; Li, Mingshuang; He, Liu; Somel, Mehmet; Yuan, Yuan; Chen, Yi-Ping Phoebe; Li, Na; Hu, Yuhui; Fu, Ning; Ning, Zhibin; Zeng, Rong; Yang, Hongyi; Chen, Wei; Gelfand, Mikhail; Khaitovich, Philipp (EMBO, 2013-01-01)
While splicing differences between tissues, sexes and species are well documented, little is known about the extent and the nature of splicing changes that take place during human or mammalian development and aging. Here, using high-throughput transcriptome sequencing, we have characterized splicing changes that take place during whole human lifespan in two brain regions: prefrontal cortex and cerebellum. Identified changes were confirmed using independent human and rhesus macaque RNA-seq data sets, exon ar...
Citation Formats
Z. G. Turan, “Notable decrease in transcriptome conservation during mammalian aging,” M.S. - Master of Science, Middle East Technical University, 2016.