03068nas a2200469   4500000000100000000000100001008004100002260001200043653001200055653002500067653001000092653001300102653001100115653001100126653001400137653002000151653002700171653002500198653002400223100001800247700002400265700001500289700002200304700001700326700002900343700002200372700001600394700002200410700001700432700001900449700001800468700002300486700002300509700001900532700002200551700001700573245009300590300001200683490000800695520188100703022001402584       2019                            d  c2019-1010aAnimals10aBiological Evolution10aBrain10aGenomics10aHumans10aMacaca10aorganoids10aPan troglodytes10aPluripotent Stem Cells10aSingle-Cell Analysis10aSpecies Specificity1 aSabina Kanton1 aMichael James Boyle1 aZhisong He1 aMalgorzata Santel1 aAnne Weigert1 aFátima Sanchís-Calleja1 aPatricia Guijarro1 aLeila Sidow1 aJonas Simon Fleck1 aDingding Han1 aZhengzong Qian1 aMichael Heide1 aWieland B. Huttner1 aPhilipp Khaitovich1 aSvante Pääbo1 aBarbara Treutlein1 aJ. Gray Camp00aOrganoid single-cell genomic atlas uncovers human-specific features of brain development  a418-4220 v5743 aThe human brain has undergone substantial change since humans diverged from chimpanzees and the other great apes1,2. However, the genetic and developmental programs that underlie this divergence are not fully understood. Here we have analysed stem cell-derived cerebral organoids using single-cell transcriptomics and accessible chromatin profiling to investigate gene-regulatory changes that are specific to humans. We first analysed cell composition and reconstructed differentiation trajectories over the entire course of human cerebral organoid development from pluripotency, through neuroectoderm and neuroepithelial stages, followed by divergence into neuronal fates within the dorsal and ventral forebrain, midbrain and hindbrain regions. Brain-region composition varied in organoids from different iPSC lines, but regional gene-expression patterns remained largely reproducible across individuals. We analysed chimpanzee and macaque cerebral organoids and found that human neuronal development occurs at a slower pace relative to the other two primates. Using pseudotemporal alignment of differentiation paths, we found that human-specific gene expression resolved to distinct cell states along progenitor-to-neuron lineages in the cortex. Chromatin accessibility was dynamic during cortex development, and we identified divergence in accessibility between human and chimpanzee that correlated with human-specific gene expression and genetic change. Finally, we mapped human-specific expression in adult prefrontal cortex using single-nucleus RNA sequencing analysis and identified developmental differences that persist into adulthood, as well as cell-state-specific changes that occur exclusively in the adult brain. Our data provide a temporal cell atlas of great ape forebrain development, and illuminate dynamic gene-regulatory features that are unique to humans.  a1476-4687