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Alternative splicing (AS) is pervasive in mammalian genomes, yet cross-species comparisons have been largely restricted to adult tissues and the functionality of most AS events remains unclear. We assessed AS patterns across pre- and postnatal development of seven organs in six mammals and a bird. Our analyses revealed that developmentally dynamic AS events, which are especially prevalent in the brain, are substantially more conserved than nondynamic ones. Cassette exons with increasing inclusion frequencies during development show the strongest signals of conserved and regulated AS. Newly emerged cassette exons are typically incorporated late in testis development, but those retained during evolution are predominantly brain specific. Our work suggests that an intricate interplay of programs controlling gene expression levels and AS is fundamental to organ development, especially for the brain and heart. In these regulatory networks, AS affords substantial functional diversification of genes through the generation of tissue- and time-specific isoforms from broadly expressed genes. Analysis of RNA-seq datasets from seven organs across seven species generates an alternative splicing (AS) atlas and shows that AS events provide functional gene diversification through generation of tissue- and time-specific transcript isoforms.

Lipids are essential to brain functions, yet they remain largely unexplored. Here we investigated the lipidome composition of prefrontal cortex gray matter in 396 cognitively healthy individuals with ages spanning 100 years, as well as 67 adult individuals diagnosed with autism (ASD), schizophrenia (SZ), and Down syndrome (DS). Of the 5024 detected lipids, 95% showed significant age-dependent concentration differences clustering into four temporal stages, and resulting in a gradual increase in membrane fluidity in individuals ranging from newborn to nonagenarian. Aging affects 14% of the brain lipidome with late-life changes starting predominantly at 50–55 years of age—a period of general metabolic transition. All three diseases alter the brain lipidome composition, leading—among other things—to a concentration decrease in glycerophospholipid metabolism and endocannabinoid signaling pathways. Lipid concentration decreases in SZ were further linked to genetic variants associated with disease, indicating the relevance of the lipidome changes to disease progression.

Developmental trajectories of gene expression may reverse in their direction during ageing, a phenomenon previously linked to cellular identity loss. Our analysis of cerebral cortex, lung, liver, and muscle transcriptomes of 16 mice, covering development and ageing intervals, revealed widespread but tissue-specific ageing-associated expression reversals. Cumulatively, these reversals create a unique phenomenon: mammalian tissue transcriptomes diverge from each other during postnatal development, but during ageing, they tend to converge towards similar expression levels, a process we term Di vergence followed by Co nvergence (DiCo). We found that DiCo was most prevalent among tissue-specific genes and associated with loss of tissue identity, which is confirmed using data from independent mouse and human datasets. Further, using publicly available single-cell transcriptome data, we showed that DiCo could be driven both by alterations in tissue cell-type composition and also by cell-autonomous expression changes within particular cell types.

Lipids are the most abundant but poorly explored components of the human brain. Here, we present a lipidome map of the human brain comprising 75 regions, including 52 neocortical ones. The lipidome composition varies greatly among the brain regions, affecting 93% of the 419 analyzed lipids. These differences reflect the brain’s structural characteristics, such as myelin content (345 lipids) and cell type composition (353 lipids), but also functional traits: functional connectivity (76 lipids) and information processing hierarchy (60 lipids). Combining lipid composition and mRNA expression data further enhances functional connectivity association. Biochemically, lipids linked with structural and functional brain features display distinct lipid class distribution, unsaturation extent, and prevalence of omega-3 and omega-6 fatty acid residues. We verified our conclusions by parallel analysis of three adult macaque brains, targeted analysis of 216 lipids, mass spectrometry imaging, and lipidome assessment of sorted murine neurons. While our brain is primarily composed of lipids, their functions have largely remained unexplored. Here, authors show that specific lipids can be linked to the structural organization and functional hierarchy of the human and macaque brain.

Changes in gene expression are thought to underlie many of the phenotypic differences between species. However, large-scale analyses of gene expression evolution were until recently prevented by technological limitations. Here we report the sequencing of polyadenylated RNA from six organs across ten species that represent all major mammalian lineages (placentals, marsupials and monotremes) and birds (the evolutionary outgroup), with the goal of understanding the dynamics of mammalian transcriptome evolution. We show that the rate of gene expression evolution varies among organs, lineages and chromosomes, owing to differences in selective pressures: transcriptome change was slow in nervous tissues and rapid in testes, slower in rodents than in apes and monotremes, and rapid for the X chromosome right after its formation. Although gene expression evolution in mammals was strongly shaped by purifying selection, we identify numerous potentially selectively driven expression switches, which occurred at different rates across lineages and tissues and which probably contributed to the specific organ biology of various mammals. Gene expression and species difference Genome analyses can uncover protein-coding changes that potentially underlie the differences between species, but many of the phenotypic differences between species are the result of regulatory mutations affecting gene expression. Brawand et al . use high-throughput RNA sequencing to study the evolutionary dynamics of mammalian transcriptomes in six major tissues (cortex, cerebellum, heart, kidney, liver and testis) from ten species from all major mammalian lineages. Among the findings is the extent of transcriptome variation between organs and species, as well as the identification of potentially selectively driven expression switches that may have shaped specific organ biology.

By sectioning and sequencing the prefrontal cortex of humans, chimpanzees and macaques, He et al. compiled comprehensive transcriptome atlases of cortical layers. The study provides scores of previously uncharacterized layer-marker genes and more than a hundred human-specific genes, implying that the human neocortex has evolved more than was previously appreciated. While human cognitive abilities are clearly unique, underlying changes in brain organization and function remain unresolved. Here we characterized the transcriptome of the cortical layers and adjacent white matter in the prefrontal cortexes of humans, chimpanzees and rhesus macaques using unsupervised sectioning followed by RNA sequencing. More than 20% of detected genes were expressed predominantly in one layer, yielding 2,320 human layer markers. While the bulk of the layer markers were conserved among species, 376 switched their expression to another layer in humans. By contrast, only 133 of such changes were detected in the chimpanzee brain, suggesting acceleration of cortical reorganization on the human evolutionary lineage. Immunohistochemistry experiments further showed that human-specific expression changes were not limited to neurons but affected a broad spectrum of cortical cell types. Thus, despite apparent histological conservation, human neocortical organization has undergone substantial changes affecting more than 5% of its transcriptome.

Lipids are essential structural and functional components of cells. Little is known, however, about the evolution of lipid composition in different tissues. Here, we report a large-scale analysis of the lipidome evolution in six tissues of 32 species representing primates, rodents, and bats. While changes in genes’ sequence and expression accumulate proportionally to the phylogenetic distances, <2% of the lipidome evolves this way. Yet, lipids constituting this 2% cluster in specific functions shared among all tissues. Among species, human show the largest amount of species-specific lipidome differences. Many of the uniquely human lipidome features localize in the brain cortex and cluster in specific pathways implicated in cognitive disorders.

Microscopic green algae are active producers of beneficial compounds, particularly those containing nitrogen. However, the metabolism of nitrogen-containing compounds is diverse and depends on the conditions of the nitrogen source. As a result, the approach to studying the metabolism of nitrogen-containing compounds becomes more complicated. This work demonstrates the metabolic changes in the high-productive green algae Neochlorella semenenkoi IPPAS C-1210 under conditions of nitrogen starvation and subsequent reintake, using high-performance liquid chromatography–mass spectrometry (HPLC–MS) with 15N isotopic labeling. The presented results include semi-quantitative chromatography–mass spectrometric analysis for 17 amino acids, a metabolomic profile of over 40 isotopically labeled compounds, an assessment of metabolic flux via isotopic incorporation, and an analysis of cellular lipid composition under varying growth conditions. The findings indicate that this strain can utilize ammonium acetate as a nitrogen source, consuming nitrogen in the ammonium form. The degree of isotopic labeling in compounds often diverged significantly from their quantitative changes (concentrations and chromatographic peak areas), suggesting that isotopic analysis may offer advantages over purely quantitative analysis for biological systems. Furthermore, in vivo biological isotopic labeling is shown to assist in identifying compounds absent from standard mass spectrometric databases.

Background Changes in gene expression levels during brain development are thought to have played an important role in the evolution of human cognition. With the advent of high-throughput sequencing technologies, changes in brain developmental expression patterns, as well as human-specific brain gene expression, have been characterized. However, interpreting the origin of evolutionarily advanced cognition in human brains requires a deeper understanding of the regulation of gene expression, including the epigenomic context, along the primate genome. Here, we used chromatin immunoprecipitation sequencing (ChIP-seq) to measure the genome-wide profiles of histone H3 lysine 4 trimethylation (H3K4me3) and histone H3 lysine 27 acetylation (H3K27ac), both of which are associated with transcriptional activation in the prefrontal cortex of humans, chimpanzees, and rhesus macaques. Results We found a discrete functional association, in which H3K4me3 HP gain was significantly associated with myelination assembly and signaling transmission, while H3K4me3 HP loss played a vital role in synaptic activity. Moreover, H3K27ac HP gain was enriched in interneuron and oligodendrocyte markers, and H3K27ac HP loss was enriched in CA1 pyramidal neuron markers. Using strand-specific RNA sequencing (ssRNA-seq), we first demonstrated that approximately 7 and 2% of human-specific expressed genes were epigenetically marked by H3K4me3 HP and H3K27ac HP, respectively, providing robust support for causal involvement of histones in gene expression. We also revealed the co-activation role of epigenetic modification and transcription factors in human-specific transcriptome evolution. Mechanistically, histone-modifying enzymes at least partially contribute to an epigenetic disturbance among primates, especially for the H3K27ac epigenomic marker. In line with this, peaks enriched in the macaque lineage were found to be driven by upregulated acetyl enzymes. Conclusions Our results comprehensively elucidated a causal species-specific gene-histone-enzyme landscape in the prefrontal cortex and highlighted the regulatory interaction that drove transcriptional activation.

With few exceptions, current methods for short read mapping make use of simple seed heuristics to speed up the search. Most of the underlying matching models neglect the necessity to allow not only mismatches, but also insertions and deletions. Current evaluations indicate, however, that very different error models apply to the novel high-throughput sequencing methods. While the most frequent error-type in Illumina reads are mismatches, reads produced by 454's GS FLX predominantly contain insertions and deletions (indels). Even though 454 sequencers are able to produce longer reads, the method is frequently applied to small RNA (miRNA and siRNA) sequencing. Fast and accurate matching in particular of short reads with diverse errors is therefore a pressing practical problem. We introduce a matching model for short reads that can, besides mismatches, also cope with indels. It addresses different error models. For example, it can handle the problem of leading and trailing contaminations caused by primers and poly-A tails in transcriptomics or the length-dependent increase of error rates. In these contexts, it thus simplifies the tedious and error-prone trimming step. For efficient searches, our method utilizes index structures in the form of enhanced suffix arrays. In a comparison with current methods for short read mapping, the presented approach shows significantly increased performance not only for 454 reads, but also for Illumina reads. Our approach is implemented in the software segemehl available at http://www.bioinf.uni-leipzig.de/Software/segemehl/.