Temporal changes in the gene expression heterogeneity during brain development and aging

Cells in largely non-mitotic tissues such as the brain are prone to stochastic (epi-)genetic alterations that may cause increased variability between cells and individuals over time. Although increased interindividual heterogeneity in gene expression was previously reported, whether this process starts during development or if it is restricted to the aging period has not yet been studied. The regulatory dynamics and functional significance of putative aging-related heterogeneity are also unknown. Here we address these by a meta-analysis of 19 transcriptome datasets from three independent studies, covering diverse human brain regions. We observed a significant increase in inter-individual heterogeneity during aging (20 + years) compared to postnatal development (0 to 20 years). Increased heterogeneity during aging was consistent among different brain regions at the gene level and associated with lifespan regulation and neuronal functions. Overall, our results show that increased expression heterogeneity is a characteristic of aging human brain, and may influence aging-related changes in brain functions

Accelerated aging-related transcriptome changes in the female prefrontal cortex

Human female life expectancy is higher than that of males. Intriguingly, it has been reported that women display faster rates of age-related cognitive decline and a higher prevalence of Alzheimers disease (AD). To assess the molecular bases of these contradictory trends, we analyzed differences in expression changes with age between adult males and females, in four brain regions. In the superior frontal gyrus (SFG), a part of the prefrontal cortex, we observed manifest differences between the two sexes in the timing of age-related changes, that is, sexual heterochrony. Intriguingly, age-related expression changes predominantly occurred earlier, or at a faster pace, in females compared to men. These changes included decreased energy production and neural function and up-regulation of the immune response, all major features of brain aging. Furthermore, we found that accelerated expression changes in the female SFG correlated with expression changes observed in AD, as well as stress effects in the frontal cortex. Accelerated aging-related changes in the female SFG transcriptome may provide a link between a higher stress exposure or sensitivity in women and the higher prevalence of AD

Determining the origin of synchronous multifocal bladder cancer by exome sequencing

Background: Synchronous multifocal tumours are commonly observed in urothelial carcinomas of the bladder. The origin of these physically independent tumours has been proposed to occur by either intraluminal migration (clonal) or spontaneous transformation of multiple cells by carcinogens (field effect). It is unclear which model is correct, with several studies supporting both hypotheses. A potential cause of this uncertainty may be the small number of genetic mutations previously used to quantify the relationship between these tumours. Methods: To better understand the genetic lineage of these tumours we conducted exome sequencing of synchronous multifocal pTa urothelial bladder cancers at a high depth, using multiple samples from three patients. Results: Phylogenetic analysis of high confidence single nucleotide variants (SNV) demonstrated that the sequenced multifocal bladder cancers arose from a clonal origin in all three patients (bootstrap value 100 %). Interestingly, in two patients the most common type of tumour-associated SNVs were cytosine mutations of TpC*dinucleotides (Fisher's exact test p < 10-41), likely caused by APOBEC-mediated deamination. Incorporating these results into our clonal model, we found that TpC*type mutations occurred 2-5× more often among SNVs on the ancestral branches than in the more recent private branches (p < 10-4) suggesting that TpC*mutations largely occurred early in the development of the tumour. Conclusions: These results demonstrate that synchronous multifocal bladder cancers frequently arise from a clonal origin. Our data also suggests that APOBEC-mediated mutations occur early in the development of the tumour and may be a driver of tumourigenesis in non-muscle invasive urothelial bladder cancer. © 2015 Acar et al

Evolution of Neuronal and Endothelial Transcriptomes in Primates

The study of gene expression evolution in vertebrates has hitherto focused on the analysis of transcriptomes in tissues of different species. However, because a tissue is made up of different cell types, and cell types differ with respect to their transcriptomes, the analysis of tissues offers a composite picture of transcriptome evolution. The isolation of individual cells from tissue sections opens up the opportunity to study gene expression evolution at the cell type level. We have stained neurons and endothelial cells in human brains by antibodies against cell type-specific marker proteins, isolated the cells using laser capture microdissection, and identified genes preferentially expressed in the two cell types. We analyze these two classes of genes with respect to their expression in 62 different human tissues, with respect to their expression in 44 human “postmortem” brains from different developmental stages and with respect to between-species brain expression differences. We find that genes preferentially expressed in neurons differ less across tissues and developmental stages than genes preferentially expressed in endothelial cells. We also observe less expression differences within primate species for neuronal transcriptomes. In stark contrast, we see more gene expression differences between humans, chimpanzees, and rhesus macaques relative to within-species differences in genes expressed preferentially in neurons than in genes expressed in endothelial cells. This suggests that neuronal and endothelial transcriptomes evolve at different rates within brain tissue

Gene expression reversal toward pre-adult levels in the aging human brain and age-related loss of cellular identity

It was previously reported that mRNA expression levels in the prefrontal cortex at old age start to resemble pre-adult levels. Such expression reversals could imply loss of cellular identity in the aging brain, and provide a link between aging-related molecular changes and functional decline. Here we analyzed 19 brain transcriptome age-series datasets, comprising 17 diverse brain regions, to investigate the ubiquity and functional properties of expression reversal in the human brain. Across all 19 datasets, 25 genes were consistently up-regulated during postnatal development and down-regulated in aging, displaying an "up-down" pattern that was significant as determined by random permutations. In addition, 113 biological processes, including neuronal and synaptic functions, were consistently associated with genes showing an up-down tendency among all datasets. Genes up-regulated during in vitro neuronal differentiation also displayed a tendency for up-down reversal, although at levels comparable to other genes. We argue that reversals may not represent aging-related neuronal loss. Instead, expression reversals may be associated with aging-related accumulation of stochastic effects that lead to loss of functional and structural identity in neurons. © 2017 The Author(s)

New insights on commemoration of the dead through mortuary and architectural use of pigments at Neolithic Çatalhöyük, Turkey

The cultural use of pigments in human societies is associated with ritual activities and the creation of social memory. Neolithic Çatalhöyük (Turkey, 7100–5950 cal BC) provides a unique case study for the exploration of links between pigments in burials, demographic data and colourants in contemporary architectural contexts. This study presents the first combined analysis of funerary and architectural evidence of pigment use in Neolithic Anatolia and discusses the possible social processes underlying the observed statistical patterns. Results reveal that pigments were either applied directly to the deceased or included in the grave as a burial association. The most commonly used pigment was red ochre. Cinnabar was mainly applied to males and blue/green pigment was associated with females. A correlation was found between the number of buried individuals and the number of painted layers in the buildings. Mortuary practices seem to have followed specific selection processes independent of sex and age-at-death of the deceased. This study offers new insights about the social factors involved in pigment use in this community, and contributes to the interpretation of funerary practices in Neolithic Anatolia. Specifically, it suggests that visual expression, ritual performance and symbolic associations were elements of shared long-term socio-cultural practices

Whole genome sequencing of Turkish genomes reveals functional private alleles and impact of genetic interactions with Europe, Asia and Africa

Background: Turkey is a crossroads of major population movements throughout history and has been a hotspot of cultural interactions. Several studies have investigated the complex population history of Turkey through a limited set of genetic markers. However, to date, there have been no studies to assess the genetic variation at the whole genome level using whole genome sequencing. Here, we present whole genome sequences of 16 Turkish individuals resequenced at high coverage (32 × -48×). Results: We show that the genetic variation of the contemporary Turkish population clusters with South European populations, as expected, but also shows signatures of relatively recent contribution from ancestral East Asian populations. In addition, we document a significant enrichment of non-synonymous private alleles, consistent with recent observations in European populations. A number of variants associated with skin color and total cholesterol levels show frequency differentiation between the Turkish populations and European populations. Furthermore, we have analyzed the 17q21.31 inversion polymorphism region (MAPT locus) and found increased allele frequency of 31.25% for H1/H2 inversion polymorphism when compared to European populations that show about 25% of allele frequency. Conclusion: This study provides the first map of common genetic variation from 16 western Asian individuals and thus helps fill an important geographical gap in analyzing natural human variation and human migration. Our data will help develop population-specific experimental designs for studies investigating disease associations and demographic history in Turkey. © 2014 Alkan et al

New insights on commemoration of the dead through mortuary and architectural use of pigments at Neolithic Çatalhöyük, Turkey.

The cultural use of pigments in human societies is associated with ritual activities and the creation of social memory. Neolithic Çatalhöyük (Turkey, 7100-5950 cal BC) provides a unique case study for the exploration of links between pigments in burials, demographic data and colourants in contemporary architectural contexts. This study presents the first combined analysis of funerary and architectural evidence of pigment use in Neolithic Anatolia and discusses the possible social processes underlying the observed statistical patterns. Results reveal that pigments were either applied directly to the deceased or included in the grave as a burial association. The most commonly used pigment was red ochre. Cinnabar was mainly applied to males and blue/green pigment was associated with females. A correlation was found between the number of buried individuals and the number of painted layers in the buildings. Mortuary practices seem to have followed specific selection processes independent of sex and age-at-death of the deceased. This study offers new insights about the social factors involved in pigment use in this community, and contributes to the interpretation of funerary practices in Neolithic Anatolia. Specifically, it suggests that visual expression, ritual performance and symbolic associations were elements of shared long-term socio-cultural practices