SummaryThe archaeological documentation of the development of sedentary farming societies in Anatolia is not yet mirrored by a genetic understanding of the human populations involved, in contrast to the spread of farming in Europe [1, 2, 3]. Sedentary farming communities emerged in parts of the Fertile Crescent during the tenth millennium and early ninth millennium calibrated (cal) BC and had appeared in central Anatolia by 8300 cal BC [4]. Farming spread into west Anatolia by the early seventh millennium cal BC and quasi-synchronously into Europe, although the timing and process of this movement remain unclear. Using genome sequence data that we generated from nine central Anatolian Neolithic individuals, we studied the transition period from early Aceramic (Pre-Pottery) to the later Pottery Neolithic, when farming expanded west of the Fertile Crescent. We find that genetic diversity in the earliest farmers was conspicuously low, on a par with European foraging groups. With the advent of the Pottery Neolithic, genetic variation within societies reached levels later found in early European farmers. Our results confirm that the earliest Neolithic central Anatolians belonged to the same gene pool as the first Neolithic migrants spreading into Europe. Further, genetic affinities between later Anatolian farmers and fourth to third millennium BC Chalcolithic south Europeans suggest an additional wave of Anatolian migrants, after the initial Neolithic spread but before the Yamnaya-related migrations. We propose that the earliest farming societies demographically resembled foragers and that only after regional gene flow and rising heterogeneity did the farming population expansions into Europe occur.

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.

Aging is the largest risk factor for a variety of noncommunicable diseases. Model organism studies have shown that genetic and chemical perturbations can extend both lifespan and healthspan. Aging is a complex process, with parallel and interacting mechanisms contributing to its aetiology, posing a challenge for the discovery of new pharmacological candidates to ameliorate its effects. In this study, instead of a target‐centric approach, we adopt a systems level drug repurposing methodology to discover drugs that could combat aging in human brain. Using multiple gene expression data sets from brain tissue, taken from patients of different ages, we first identified the expression changes that characterize aging. Then, we compared these changes in gene expression with drug‐perturbed expression profiles in the Connectivity Map. We thus identified 24 drugs with significantly associated changes. Some of these drugs may function as antiaging drugs by reversing the detrimental changes that occur during aging, others by mimicking the cellular defence mechanisms. The drugs that we identified included significant number of already identified prolongevity drugs, indicating that the method can discover de novo drugs that meliorate aging. The approach has the advantages that using data from human brain aging data, it focuses on processes relevant in human aging and that it is unbiased, making it possible to discover new targets for aging studies.

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. Aging is a complex process characterized by a gradual decline in maintenance and repair mechanisms, accompanied by an increase in genetic and epigenetic mutations, and oxidative damage to nucleic acids, protein and lipids 1,2. The human brain experiences dramatic structural and functional changes in the course of aging. These include decline in gray matter and white matter volumes 3 , increase in axonal bouton dynamics 4 and reduced synaptic plasticity, all processes that may be associated with decline in cognitive functions 5. Changes during brain aging are suggested to be a result of stochastic processes, unlike changes associated with postnatal neuronal development that are known to be primarily controlled by adaptive regulatory processes 6-8. The molecular mechanisms underlying age-related alteration of regulatory processes and eventually leading to aging-related phenotypes, however, are little understood. Over the past decade, a number of transcriptome studies focusing on age-related changes in human brain gene expression profiles were published 2,9-12. These studies report aging-related differential expression patterns in many functions, including synaptic functions, energy metabolism, inflammation, stress response, and DNA repair. By analyzing age-related change in gene expression profiles in diverse brain regions, we previously showed that for many genes, gene expression changes occur in opposite directions during postnatal development (pre-20 years of age) and aging (post-20 years of age), which may be associated with aging-related phenotypes in healthy brain aging 13. While different brain regions are associated with specific, and often independent, gene expression profiles 9,10,12 , these studies also show that age-related alteration of gene expression profiles during aging is a widespread effect across different brain regions. One of the suggested effects of aging is increased variability between indivi...

We present genome-wide data from 40 individuals dating to c.16,900 to 550 years ago in northeast Asia. We describe hitherto unknown gene flow and admixture events in the region, revealing a complex population history. While populations east of Lake Baikal remained relatively stable from the Mesolithic to the Bronze Age, those from Yakutia and west of Lake Baikal witnessed major population transformations, from the Late Upper Paleolithic to the Neolithic, and during the Bronze Age, respectively. We further locate the Asian ancestors of Paleo-Inuits, using direct genetic evidence. Last, we report the most northeastern ancient occurrence of the plague-related bacterium, Yersinia pestis. Our findings indicate the highly connected and dynamic nature of northeast Asia populations throughout the Holocene.

Advancing age is the dominant risk factor for most of the major killer diseases in developed countries. Hence, ameliorating the effects of ageing may prevent multiple diseases simultaneously. Drugs licensed for human use against specific diseases have proved to be effective in extending lifespan and healthspan in animal models, suggesting that there is scope for drug repurposing in humans. New bioinformatic methods to identify and prioritise potential anti-ageing compounds for humans are therefore of interest. In this study, we first used drug-protein interaction information, to rank 1,147 drugs by their likelihood of targeting ageing-related gene products in humans. Among 19 statistically significant drugs, 6 have already been shown to have pro-longevity properties in animal models (p < 0.001). Using the targets of each drug, we established their association with ageing at multiple levels of biological action including pathways, functions and protein interactions. Finally, combining all the data, we calculated a ranked list of drugs that identified tanespimycin, an inhibitor of HSP-90, as the top-ranked novel anti-ageing candidate. We experimentally validated the pro-longevity effect of tanespimycin through its HSP-90 target in Caenorhabditis elegans.

Age is a common risk factor in many diseases, but the molecular basis for this relationship is elusive. In this study we identified 4 disease clusters from 116 diseases in the UK Biobank data, defined by their age-of-onset profiles, and found that diseases with the same onset profile are genetically more similar, suggesting a common etiology. This similarity was not explained by disease categories, co-occurrences or disease cause-effect relationships. Two of the four disease clusters had an increased risk of occurrence from age 20 and 40 years respectively. They both showed an association with known aging-related genes, yet differed in functional enrichment and evolutionary profiles. Moreover, they both had age-related expression and methylation changes. We also tested mutation accumulation and antagonistic pleiotropy theories of aging and found support for both.

Neanderthals contributed genetic material to modern humans via multiple admixture events. Initial admixture events presumably occurred in Western Asia shortly after humans migrated out of Africa. Despite being a focal point of admixture, earlier studies indicate lower Neanderthal introgression rates in some Western Asian populations as compared with other Eurasian populations. To better understand the genome-wide and phenotypic impact of Neanderthal introgression in the region, we sequenced whole genomes of nine present-day Europeans, Africans, and the Western Asian Druze at high depth, and analyzed available whole genome data from various other populations, including 16 genomes from present-day Turkey. Our results confirmed previous observations that contemporary Western Asian populations, on an average, have lower levels of Neanderthal-introgressed DNA relative to other Eurasian populations. Modern Western Asians also show comparatively high variability in Neanderthal ancestry, which may be attributed to the complex demographic history of the region. We further replicated the previously described depletion of putatively functional sequences among Neanderthal-introgressed haplotypes. Still, we find dozens of common Neanderthal-introgressed haplotypes in the Turkish sample associated with human phenotypes, including anthropometric and metabolic traits, as well as the immune response. One of these haplotypes is unusually long and harbors variants that affect the expression of members of the CCR gene family and are associated with celiac disease. Overall, our results paint a complex first picture of the genomic impact of Neanderthal introgression in the Western Asian populations.