High-coverage sequencing of 79 (wild and captive) individuals representing all six non-human great ape species has identified over 88 million single nucleotide polymorphisms providing insight into ape genetic variation and evolutionary history and enabling comparison with human genetic diversity. In an effort to provide insights into great ape genetic variation, the authors sequence 79 wild- and captive-born individuals from across all six great ape species and seven subspecies. Their data and analyses shed light on population structure and gene flow, inbreeding, inferred dynamics of effective population sizes and the differences in the rate of gene loss among the great apes. This new catalogue of great ape genome diversity provides a valuable resource for evolutionary and conservation studies. Most great ape genetic variation remains uncharacterized1,2; however, its study is critical for understanding population history3,4,5,6, recombination7, selection8 and susceptibility to disease9,10. Here we sequence to high coverage a total of 79 wild- and captive-born individuals representing all six great ape species and seven subspecies and report 88.8 million single nucleotide polymorphisms. Our analysis provides support for genetically distinct populations within each species, signals of gene flow, and the split of common chimpanzees into two distinct groups: Nigeria–Cameroon/western and central/eastern populations. We find extensive inbreeding in almost all wild populations, with eastern gorillas being the most extreme. Inferred effective population sizes have varied radically over time in different lineages and this appears to have a profound effect on the genetic diversity at, or close to, genes in almost all species. We discover and assign 1,982 loss-of-function variants throughout the human and great ape lineages, determining that the rate of gene loss has not been different in the human branch compared to other internal branches in the great ape phylogeny. This comprehensive catalogue of great ape genome diversity provides a framework for understanding evolution and a resource for more effective management of wild and captive great ape populations.

INTRODUCTION: The brain is responsible for cognition, behavior, and much of what makes us uniquely human. The development of the brain is a highly complex process, and this process is reliant on precise regulation of molecular and cellular events grounded in the spatiotemporal regulation of the transcriptome. Disruption of this regulation can lead to neuropsychiatric disorders.RATIONALE: The regulatory, epigenomic, and transcriptomic features of the human brain have not been comprehensively compiled across time, regions, or cell types. Understanding the etiology of neuropsychiatric disorders requires knowledge not just of endpoint differences between healthy and diseased brains but also of the developmental and cellular contexts in which these differences arise. Moreover, an emerging body of research indicates that many aspects of the development and physiology of the human brain are not well recapitulated in model organisms, and therefore it is necessary that neuropsychiatric disorders be understood in the broader context of the developing and adult human brain.RESULTS: Here we describe the generation and analysis of a variety of genomic data modalities at the tissue and single-cell levels, including transcriptome, DNA methylation, and histone modifications across multiple brain regions ranging in age from embryonic development through adulthood. We observed a widespread transcriptomic transition beginning during late fetal development and consisting of sharply decreased regional differences. This reduction coincided with increases in the transcriptional signatures of mature neurons and the expression of genes associated with dendrite development, synapse development, and neuronal activity, all of which were temporally synchronous across neocortical areas, as well as myelination and oligodendrocytes, which were asynchronous. Moreover, genes includingMEF2C,SATB2, andTCF4,with genetic associations to multiple brain-related traits and disorders, converged in a small number of modules exhibiting spatial or spatiotemporal specificity.CONCLUSION: We generated and applied our dataset to document transcriptomic and epigenetic changes across human development and then related those changes to major neuropsychiatric disorders. These data allowed us to identify genes, cell types, gene coexpression modules, and spatiotemporal loci where disease risk might converge, demonstrating the utility of the dataset and providing new insights into human development and disease. Spatiotemporal dynamics of human brain development and neuropsychiatric risks.: Human brain development begins during embryonic development and continues through adulthood (top). Integrating data modalities (bottom left) revealed age- and cell type–specific properties and global patterns of transcriptional dynamics, including a late fetal transition (bottom middle). We related the variation in gene expression (brown, high; purple, low) to regulatory elements in the fetal and adult brains, cell type–specific signatures, and genetic loci associated with neuropsychiatric disorders (bottom right; gray circles indicate enrichment for corresponding features among module genes). Relationships depicted in this panel do not correspond to specific observations. CBC, cerebellar cortex; STR, striatum; HIP, hippocampus; MD, mediodorsal nucleus of thalamus; AMY, amygdala.

INTRODUCTION: Improved understanding of how the developing human nervous system differs from that of closely related nonhuman primates is fundamental for teasing out human-specific aspects of behavior, cognition, and disorders. RATIONALE: The shared and unique functional properties of the human nervous system are rooted in the complex transcriptional programs governing the development of distinct cell types, neural circuits, and regions. However, the precise molecular mechanisms underlying shared and unique features of the developing human nervous system have been only minimally characterized. RESULTS: We generated complementary tissue-level and single-cell transcriptomic datasets from up to 16 brain regions covering prenatal and postnatal development in humans and rhesus macaques ( Macaca mulatta ), a closely related species and the most commonly studied nonhuman primate. We created and applied TranscriptomeAge and TempShift algorithms to age-match developing specimens between the species and to more rigorously identify temporal differences in gene expression within and across the species. By analyzing regional and temporal patterns of gene expression in both the developing human and macaque brain, and comparing these patterns to a complementary dataset that included transcriptomic information from the adult chimpanzee, we identified shared and divergent transcriptomic features of human brain development. Furthermore, integration with single-cell and single-nucleus transcriptomic data covering prenatal and adult periods of both species revealed that the developmental divergence between humans and macaques can be traced to distinct cell types enriched in different developmental times and brain regions, including the prefrontal cortex, a region of the brain associated with distinctly human aspects of cognition and behavior. We found two phases of prominent species differences: embryonic to late midfetal development and adolescence/young adulthood. This evolutionary cup-shaped or hourglass-like pattern, with high divergence in prenatal development and adolescence/young adulthood and lower divergence in early postnatal development, resembles the developmental cup-shaped pattern described in the accompanying study by Li et al . Even though the developmental (ontogenetic) and evolutionary (phylogenetic) patterns have similar profiles, the overlap of genes driving these two patterns is not substantial, indicating the existence of different molecular mechanisms and constraints for regional specification and species divergence. Notably, we also identified numerous genes and gene coexpression modules exhibiting human-distinct patterns in either temporal (heterochronic) or spatial (heterotopic) gene expression, as well as genes with human-distinct developmental expression, linked to autism spectrum disorder, schizophrenia, and other neurological or psychiatric diseases. This finding potentially suggests mechanistic underpinnings of these disorders. CONCLUSION: Our study provides insights into the evolution of gene expression in the developing human brain and may shed some light on potentially human-specific underpinnings of certain neuropsychiatric disorders. Concerted ontogenetic and phylogenetic transcriptomic divergence in human and macaque brain.: Left: Human and macaque brain regions spanning both prenatal and postnatal development were age-matched using TranscriptomeAge. Right: Phylogenetic transcriptomic divergence between humans and macaques resembles the developmental (ontogenetic) cup-shaped pattern of each species, with high divergence in prenatal development and adolescence/young adulthood and lower divergence during the early postnatal period (from perinatal to adolescence). Single-cell transcriptomics revealed shared and divergent transcriptomic features of distinct cell types.

Lipid rafts are cholesterol- and sphingomyelin-enriched microdomains that provide a highly saturated and viscous physicochemical microenvironment to promote protein-lipid and protein-protein interactions. We purified lipid rafts from human frontal cortex from normal, early motor stages of Parkinson's disease (PD) and incidental Parkinson's disease (iPD) subjects and analyzed their lipid composition. We observed that lipid rafts from PD and iPD cortices exhibit dramatic reductions in their contents of n-3 and n-6 long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (22:6-n3) and arachidonic acid (20:4n-6). Also, saturated fatty acids (16:0 and 18:0) were significantly higher than in control brains. Paralleling these findings, unsaturation and peroxidability indices were considerably reduced in PD and iPD lipid rafts. Lipid classes were also affected in PD and iPD lipid rafts. Thus, phosphatidylserine and phosphatidylinositol were increased in PD and iPD, whereas cerebrosides and sulfatides and plasmalogen levels were considerably diminished. Our data pinpoint a dramatic increase in lipid raft order due to the aberrant biochemical structure in PD and iPD and indicate that these abnormalities of lipid rafts in the frontal cortex occur at early stages of PD pathology. The findings correlate with abnormal lipid raft signaling and cognitive decline observed during the development of these neurodegenerative disorders.