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

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

Memeli yaşlanması esnasında transkriptom korunmasında meydana gelen önemli azalış.

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. M.S. - Master of Scienc

FEN BİLİMLERİ ENSTİTÜSÜ/LİSANSÜSTÜ TEZ PROJESİ

YAŞLANMA VE STRESİN BEYİN TRANSKRİPTOMU ÜZERİNDE ETKİLER

Determining the role of mutation load in mammalian senescence

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

Yeni nesil moleküler veri analizi yoluyla genom ve transkriptom evriminin incelenmesi

Tüm genom dizileme verisi, genom çapında veya ekzom çapında polimorfizm verisi, mikrodizin ve RNA-dizileme verisi, GC-MS metabolit verisi gibi geniş çaplı moleküler veri setlerinin hesaplamalı analizi yoluyla uzun zamandır biyologları meşgul eden çok sayıda sorunun cevaplanması bugün mümkün hale gelmiştir. Araştırma grubumuzda genom ve transkriptom evrimi üzerine şu soruları gelecek yıl içinde cevaplayamaya çalışacağız:- Primatlar arasında testis transkriptomu niye ve nasıl evrilmektedir? - Türler arasında transkriptom farkları arasında en anlamlı olanlar nasıl tespit edilir?- Genom çapında kısa nükleotit homopolimerleri oluşturan mutasyonların insan popülasyonu içinde hızlı yayılmasının sebepleri nelerdir? - Yaşlanma sırasında metabolit ve gen ifadesi değişimlerinin sebepleri nedir?- Anadolu insan popülasyonunda Neandertal karışımı başka popülasyonlardan farklı olabilir mi?- Anadolu’da geçmiş göç örüntüleri nelerdir?- Mesane kanserinde görülen senkronize tümörler akraba mıdır

Somatic copy number variant load in neurons of healthy controls and Alzheimer’s disease patients

Abstract The possible role of somatic copy number variations (CNVs) in Alzheimer’s disease (AD) aetiology has been controversial. Although cytogenetic studies suggested increased CNV loads in AD brains, a recent single-cell whole-genome sequencing (scWGS) experiment, studying frontal cortex brain samples, found no such evidence. Here we readdressed this issue using low-coverage scWGS on pyramidal neurons dissected via both laser capture microdissection (LCM) and fluorescence activated cell sorting (FACS) across five brain regions: entorhinal cortex, temporal cortex, hippocampal CA1, hippocampal CA3, and the cerebellum. Among reliably detected somatic CNVs identified in 1301 cells obtained from the brains of 13 AD patients and 7 healthy controls, deletions were more frequent compared to duplications. Interestingly, we observed slightly higher frequencies of CNV events in cells from AD compared to similar numbers of cells from controls (4.1% vs. 1.4%, or 0.9% vs. 0.7%, using different filtering approaches), although the differences were not statistically significant. On the technical aspects, we observed that LCM-isolated cells show higher within-cell read depth variation compared to cells isolated with FACS. To reduce within-cell read depth variation, we proposed a principal component analysis-based denoising approach that significantly improves signal-to-noise ratios. Lastly, we showed that LCM-isolated neurons in AD harbour slightly more read depth variability than neurons of controls, which might be related to the reported hyperploid profiles of some AD-affected neurons