Induced pluripotent stem-cell characterization reveals phenotypical differences between humans and non-human primates (NHPs): gene expression analysis shows differences in the regulation of long interspersed element-1 (L1) transposons, and in the expression of L1-restricting genes APOBEC3B and PIWIL2, correlating with higher L1 mobility in NHPs; this indicates that L1 mobility differences may have differentially shaped the human and NHP genomes. This paper reports the derivation and characterization of induced pluripotent stem (iPS) cells from chimpanzees and bonobos, and the use of the resulting iPS cells to study phenotypical differences between human and non-human primates (NHPs). Comparative gene expression analysis reveals greater expression of long interspersed element-1 (L1) in chimpanzees and bonobos than in humans. Differential expression of two genes (APOBEC3B and PIWIL2) between humans and the NHPs correlates with L1 transposon mobility and endogenous L1 messenger RNA levels. The authors propose that differences in L1 mobility may have differentially shaped the genomes of humans and NHPs and could have ongoing adaptive significance. Identifying cellular and molecular differences between human and non-human primates (NHPs) is essential to the basic understanding of the evolution and diversity of our own species. Until now, preserved tissues have been the main source for most comparative studies between humans, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus)1,2. However, these tissue samples do not fairly represent the distinctive traits of live cell behaviour and are not amenable to genetic manipulation. We propose that induced pluripotent stem (iPS) cells could be a unique biological resource to determine relevant phenotypical differences between human and NHPs, and that those differences could have potential adaptation and speciation value. Here we describe the generation and initial characterization of iPS cells from chimpanzees and bonobos as new tools to explore factors that may have contributed to great ape evolution. Comparative gene expression analysis of human and NHP iPS cells revealed differences in the regulation of long interspersed element-1 (L1, also known as LINE-1) transposons. A force of change in mammalian evolution, L1 elements are retrotransposons that have remained active during primate evolution3,4,5. Decreased levels of L1-restricting factors APOBEC3B (also known as A3B)6 and PIWIL2 (ref. 7) in NHP iPS cells correlated with increased L1 mobility and endogenous L1 messenger RNA levels. Moreover, results from the manipulation of A3B and PIWIL2 levels in iPS cells supported a causal inverse relationship between levels of these proteins and L1 retrotransposition. Finally, we found increased copy numbers of species-specific L1 elements in the genome of chimpanzees compared to humans, supporting the idea that increased L1 mobility in NHPs is not limited to iPS cells in culture and may have also occurred in the germ line or embryonic cells developmentally upstream to germline specification during primate evolution. We propose that differences in L1 mobility may have differentially shaped the genomes of humans and NHPs and could have continuing adaptive significance.

A human neurodevelopmental model fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain. Individuals with the neurodevelopmental disorder Williams syndrome (WS) lack a region of about 25 genes on chromosome 7. The condition is characterized by hypersociability and a range of cognitive and behavioural impairments, but how specific genes contribute to the neuroanatomical and functional alterations is not known. Alysson Muotri and colleagues have used cellular reprogramming technologies to generate induced pluripotent stem cells (iPSCs) from individuals with WS and controls. iPSC-derived neural progenitor cells from individuals with WS had increased apoptosis owing to haploinsufficiency of the gene FZD9. In addition, iPSC-derived WS cortical neurons displayed altered activity and morphological changes, some of which matched those seen in postmortem brains of individuals with WS. This human iPSC model may provide insights into the molecular and cellular mechanisms underlying the various features of the disorder. Williams syndrome is a genetic neurodevelopmental disorder characterized by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. Nearly all clinically diagnosed individuals with Williams syndrome lack precisely the same set of genes, with breakpoints in chromosome band 7q11.23 (refs 1, 2, 3, 4, 5). The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioural pathologies in humans, remains largely unexplored. Here we investigate neural progenitor cells and cortical neurons derived from Williams syndrome and typically developing induced pluripotent stem cells. Neural progenitor cells in Williams syndrome have an increased doubling time and apoptosis compared with typically developing neural progenitor cells. Using an individual with atypical Williams syndrome6,7, we narrowed this cellular phenotype to a single gene candidate, frizzled 9 (FZD9). At the neuronal stage, layer V/VI cortical neurons derived from Williams syndrome were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in neurons from Williams syndrome were validated after Golgi staining of post-mortem layer V/VI cortical neurons. This model of human induced pluripotent stem cells8 fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain.

Significance: Three-dimensional systems enable the formation of tissue-mimetic architectures and promote more realistic physiological responses than conventional 2D systems. Here we report a previously unidentified layered 3D culture system to assay migration and maturation of human induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) and reveal a genotype-specific effect of methyl-CpG-binding protein-2 (MeCP2) dysfunction on iPSC-derived neuronal migration and maturation in 3D layered hydrogels. Using this platform, we identified a migration defect in MeCP2-mutant iPSC-derived NPCs and confirmed previous observations that neurons derived from these cells have reduced neurite outgrowth and fewer synapses. Meanwhile, 3D hydrogel culture accelerates neuronal differentiation of iPSC-derived NPCs.

Brain organoids with Neanderthal genes: The genomes of Neanderthals and modern humans are overall very similar. To understand the impact of genetic variants that are specific to modern humans, Trujillo et al. performed a genome-wide analysis to identify 61 coding variants in protein-coding genes. Identifying the gene encoding the RNA-binding protein NOVA1 as a top candidate for functional analyses, they introduced the archaic gene variant into human pluripotent stem cells and generated brain organoids. These organoids showed alterations in gene expression and splicing as well as morphology and synaptogenesis, suggesting that this method could be used to explore other genetic changes that underlie the phenotypic traits separating our species from extinct relatives. Science , this issue p. eaax2537

We present the sequencing and annotation of the Leishmania (Leishmania) amazonensis genome, an etiological agent of human cutaneous leishmaniasis in the Amazon region of Brazil. L. (L.) amazonensis shares features with Leishmania (L.) mexicana but also exhibits unique characteristics regarding geographical distribution and clinical manifestations of cutaneous lesions (e.g. borderline disseminated cutaneous leishmaniasis). Predicted genes were scored for orthologous gene families and conserved domains in comparison with other human pathogenic Leishmania spp. Carboxypeptidase, aminotransferase, and 3′-nucleotidase genes and ATPase, thioredoxin, and chaperone-related domains were represented more abundantly in L. (L.) amazonensis and L. (L.) mexicana species. Phylogenetic analysis revealed that these two species share groups of amastin surface proteins unique to the genus that could be related to specific features of disease outcomes and host cell interactions. Additionally, we describe a hypothetical hybrid interactome of potentially secreted L. (L.) amazonensis proteins and host proteins under the assumption that parasite factors mimic their mammalian counterparts. The model predicts an interaction between an L. (L.) amazonensis heat-shock protein and mammalian Toll-like receptor 9, which is implicated in important immune responses such as cytokine and nitric oxide production. The analysis presented here represents valuable information for future studies of leishmaniasis pathogenicity and treatment.