Single-cell epigenomics and spatiotemporal transcriptomics reveal human cerebellar development.

Human cerebellar development is orchestrated by molecular regulatory networks to achieve cytoarchitecture and coordinate motor and cognitive functions. Here, we combined single-cell transcriptomics, spatial transcriptomics and single cell chromatin accessibility states to systematically depict an integrative spatiotemporal landscape of human fetal cerebellar development. We revealed that combinations of transcription factors and cis-regulatory elements (CREs) play roles in governing progenitor differentiation and cell fate determination along trajectories in a hierarchical manner, providing a gene expression regulatory map of cell fate and spatial information for these cells. We also illustrated that granule cells located in different regions of the cerebellar cortex showed distinct molecular signatures regulated by different signals during development. Finally, we mapped single-nucleotide polymorphisms (SNPs) of disorders related to cerebellar dysfunction and discovered that several disorder-associated genes showed spatiotemporal and cell type-specific expression patterns only in humans, indicating the cellular basis and possible mechanisms of the pathogenesis of neuropsychiatric disorders.

Transcriptome dynamics of hippocampal neurogenesis in macaques across the lifespan and aged humans.

Whether adult hippocampal neurogenesis (AHN) persists in adult and aged humans continues to be extensively debated. A major question is whether the markers identified in rodents are reliable enough to reveal new neurons and the neurogenic trajectory in primates. Here, to provide a better understanding of AHN in primates and to reveal more novel markers for distinct cell types, droplet-based single-nucleus RNA sequencing (snRNA-seq) is used to investigate the cellular heterogeneity and molecular characteristics of the hippocampi in macaques across the lifespan and in aged humans. All of the major cell types in the hippocampus and their expression profiles were identified. The dynamics of the neurogenic lineage was revealed and the diversity of astrocytes and microglia was delineated. In the neurogenic lineage, the regulatory continuum from adult neural stem cells (NSCs) to immature and mature granule cells was investigated. A group of primate-specific markers were identified. We validated ETNPPL as a primate-specific NSC marker and verified STMN1 and STMN2 as immature neuron markers in primates. Furthermore, we illustrate a cluster of active astrocytes and microglia exhibiting proinflammatory responses in aged samples. The interaction analysis and the comparative investigation on published datasets and ours imply that astrocytes provide signals inducing the proliferation, quiescence and inflammation of adult NSCs at different stages and that the proinflammatory status of astrocytes probably contributes to the decrease and variability of AHN in adults and elderly individuals.

Emission patterns of biogenic volatile organic compounds from dominant forest species in Beijing, China.

Biogenic volatile organic compounds (BVOCs) have significant effects on atmospheric chemistry, ozone formation and secondary organic aerosol formation. Considering few investigations about BOVCs emissions in north China where is facing serious air pollution in recent years, emissions of various BVOCs from 24 dominant forest species in Beijing were measured from June to September in 2018, using a dynamic headspace sampling method. More than one hundred BVOCs in the collected samples were identified by using an automatic thermal desorption-gas chromatography/mass spectrometry, and their emission rates based on leaf biomass were calculated. Isoprene and monoterpenes were verified to be the dominant BVOCs emitted from the tree species, accounting for more than 50% of the total BVOCs. Generally, broad-leaved species displayed high isoprene emission rates, especially the Platanus occidentalis (21.36 µg/(g⋅hr)), Robinia pseudoacacia (11.55 µg/(g⋅hr)), and Lonicera maackii (9.17 µg/(g⋅hr)), while coniferous species emitted high rates of monoterpenes, such as Platycladus orientalis (27.18 µg/(g⋅hr)), Pinus griffithii (23.11 µg/(g⋅hr)), and Pinus armandii (7.42 µg/(g⋅hr)). High emission rates of monoterpenes from the broad-leaved species of Buxus megistophylla (13.07 µg/(g⋅hr)) and Ligustrum vicaryi (5.74 µg/(g⋅hr)), and high isoprene emission rate from the coniferous tree of Taxus cuspidata (5.86 µg/(g⋅hr)) were also observed. The emission rates of sesquiterpenes from each tree were usually 10-100 times smaller than those of isoprene and monoterpenes. Additionally, relatively high emission rates of oxygenated volatile organic compounds and other alkenes than isoprene and monoterpenes were also found for several tree species.

Update on the predictability of tall stature from DNA markers in Europeans.

Predicting adult height from DNA has important implications in forensic DNA phenotyping. In 2014, we introduced a prediction model consisting of 180 height-associated SNPs based on data from 10,361 Northwestern Europeans enriched with tall individuals (770 > 1.88 standard deviation), which yielded a mid-ranged accuracy (AUC = 0.75 for binary prediction of tall stature and R2 = 0.12 for quantitative prediction of adult height). Here, we provide an update on DNA-based height predictability considering an enlarged list of subsequently-published height-associated SNPs using data from the same set of 10,361 Europeans. A prediction model based on the full set of 689 SNPs showed an improved accuracy relative to previous models for both tall stature (AUC = 0.79) and quantitative height (R2 = 0.21). A feature selection analysis revealed a subset of 412 most informative SNPs while the corresponding prediction model retained most of the accuracy (AUC = 0.76 and R2 = 0.19) achieved with the full model. Over all, our study empirically exemplifies that the accuracy for predicting human appearance phenotypes with very complex underlying genetic architectures, such as adult height, can be improved by increasing the number of phenotype-associated DNA variants. Our work also demonstrates that a careful sub-selection allows for a considerable reduction of the number of DNA predictors that achieve similar prediction accuracy as provided by the full set. This is forensically relevant due to restrictions in the number of SNPs simultaneously analyzable with forensically suitable DNA technologies in the current days of targeted massively parallel sequencing in forensic genetics.

Predicting adult height from DNA variants in a European-Asian admixed population.

Accurate genomic profiling for adult height is of high practical relevance in forensics genetics. Adult height is a classical reference trait in the field of human complex trait genetics characterized by highly polygenic nature and relatively high heritability. A meta-analysis of genome-wide association studies by the Genetic Investigation of Anthropocentric Traits (GIANT) consortium has identified 697 DNA variants associated with adult height in Europeans; however, whether these variants will still be informative in non-Europeans is still in question. The present study investigated the predictive power of these 697 height-associated SNPs in 687 Uyghurs of European-Asian admixed origin. Among all GIANT SNPs, 11% showed nominally significant association (6.78 × 10-4 < p < 0.05) with adult height in the Uyghur population and among the significant SNPs 77% of allele effects were in the same direction as those in Europeans reported in the GIANT study. Fitting linear and logistic models using a polygenic score consisting of all GIANT SNPs resulted in an 80-20 cross-validated mean R2 of 10.08% (95% CI 3.16-18.40%) for quantitative height prediction and a mean AUC value of 0.65 (95% CI 0.57-0.72%) for qualitative "above average" prediction. Fine-tuning the SNP set using their association p values considerably improved the prediction results (number of SNPs = 62, R2 = 15.59%, 95% CI 6.80-25.71%; AUC = 0.70, 95% CI 62-0.77) in the Uyghurs. Overall, our findings demonstrate substantial differences between the European and Asian populations in the genetics of adult height, emphasizing the importance of population heterogeneity underlying the genetic architecture of adult height.

Genome-wide compound heterozygote analysis highlights alleles associated with adult height in Europeans.

Adult height is the most widely genetically studied common trait in humans; however, the trait variance explainable by currently known height-associated single nucleotide polymorphisms (SNPs) identified from the previous genome-wide association studies (GWAS) is yet far from complete given the high heritability of this complex trait. To exam if compound heterozygotes (CH) may explain extra height variance, we conducted a genome-wide analysis to screen for CH in association with adult height in 10,631 Dutch Europeans enriched with extremely tall people, using our recently developed method implemented in the software package CollapsABEL. The analysis identified six regions (3q23, 5q35.1, 6p21.31, 6p21.33, 7q21.2, and 9p24.3), where multiple pairs of SNPs as CH showed genome-wide significant association with height (P < 1.67 × 10-10). Of those, 9p24.3 represents a novel region influencing adult height, whereas the others have been highlighted in the previous GWAS on height based on analysis of individual SNPs. A replication analysis in 4080 Australians of European ancestry confirmed the significant CH-like association at 9p24.3 (P < 0.05). Together, the collapsed genotypes at these six loci explained 2.51% of the height variance (after adjusting for sex and age), compared with 3.23% explained by the 14 top-associated SNPs at 14 loci identified by traditional GWAS in the same data set (P < 5 × 10-8). Overall, our study empirically demonstrates that CH plays an important role in adult height and may explain a proportion of its "missing heritability". Moreover, our findings raise promising expectations for other highly polygenic complex traits to explain missing heritability identifiable through CH-like associations.