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Primate cell fusion disentangles gene regulatory divergence in neurodevelopment.

ABSTRACT: Among primates, humans display a unique trajectory of development that is responsible for the many traits specific to our species. However, the inaccessibility of primary human and chimpanzee tissues has limited our ability to study human evolution. Comparative in vitro approaches using primate-derived induced pluripotent stem cells have begun to reveal species differences on the cellular and molecular levels^1,2. In particular, brain organoids have emerged as a promising platform to study primate neural development in vitro^3-5, although cross-species comparisons of organoids are complicated by differences in developmental timing and variability of differentiation^6,7. Here we develop a new platform to address these limitations by fusing human and chimpanzee induced pluripotent stem cells to generate a panel of tetraploid hybrid stem cells. We applied this approach to study species divergence in cerebral cortical development by differentiating these cells into neural organoids. We found that hybrid organoids provide a controlled system for disentangling cis- and trans-acting gene-expression divergence across cell types and developmental stages, revealing a signature of selection on astrocyte-related genes. In addition, we identified an upregulation of the human somatostatin receptor 2 gene (SSTR2), which regulates neuronal calcium signalling and is associated with neuropsychiatric disorders^8,9. We reveal a human-specific response to modulation of SSTR2 function in cortical neurons, underscoring the potential of this platform for elucidating the molecular basis of human evolution.

SUBMITTER: Agoglia RM

PROVIDER: S-EPMC8719633 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Primate cell fusion disentangles gene regulatory divergence in neural development

Project description:Among primates, humans display a unique trajectory of development responsible for the many traits specific to our species. However, the inaccessibility of human and chimpanzee primary tissues has limited our ability to study human evolution. Comparative in vitro approaches using primate-derived induced pluripotent stem cells have begun to reveal species differences on the cellular and molecular levels. In particular, brain organoids have emerged as a promising platform to study primate neural development in vitro, although cross-species comparisons of organoids are complicated by differences in developmental timing and variability of differentiation. Here, we developed a new platform to address these limitations. We first generated a panel of tetraploid hybrid stem cells by fusing human and chimpanzee induced pluripotent stem cells. We next applied this approach to study species divergence in cerebral cortical development by differentiating them into neural organoids. We found that hybrid organoids provide a controlled system for disentangling cis- and trans-acting gene expression divergence across cell types and developmental stages, revealing a signature of selection on astrocyte-related genes. In addition, we identified an up-regulation of human somatostatin receptor 2 (SSTR2), which regulates neuronal calcium signaling and is associated with neuropsychiatric disorders. We discovered a human-specific response to modulation of SSTR2 function in cortical neurons, underscoring the potential of this unique platform to reveal the molecular basis of human evolution.

2020-11-17 | GSE144825 | GEO

Primate cell fusion disentangles gene regulatory divergence in neural development

Project description:Primate cell fusion disentangles gene regulatory divergence in neural development

| PRJNA605139 | ENA

Next-generation museomics disentangles one of the largest primate radiations.

Project description:Guenons (tribe Cercopithecini) are one of the most diverse groups of primates. They occupy all of sub-Saharan Africa and show great variation in ecology, behavior, and morphology. This variation led to the description of over 60 species and subspecies. Here, using next-generation DNA sequencing (NGS) in combination with targeted DNA capture, we sequenced 92 mitochondrial genomes from museum-preserved specimens as old as 117 years. We infer evolutionary relationships and estimate divergence times of almost all guenon taxa based on mitochondrial genome sequences. Using this phylogenetic framework, we infer divergence dates and reconstruct ancestral geographic ranges. We conclude that the extraordinary radiation of guenons has been a complex process driven by, among other factors, localized fluctuations of African forest cover. We find incongruences between phylogenetic trees reconstructed from mitochondrial and nuclear DNA sequences, which can be explained by either incomplete lineage sorting or hybridization. Furthermore, having produced the largest mitochondrial DNA data set from museum specimens, we document how NGS technologies can "unlock" museum collections, thereby helping to unravel the tree-of-life.

| S-EPMC3676678 | biostudies-literature

Gain, loss and divergence in primate zinc-finger genes: a rich resource for evolution of gene regulatory differences between species.

Project description:The molecular changes underlying major phenotypic differences between humans and other primates are not well understood, but alterations in gene regulation are likely to play a major role. Here we performed a thorough evolutionary analysis of the largest family of primate transcription factors, the Krüppel-type zinc finger (KZNF) gene family. We identified and curated gene and pseudogene models for KZNFs in three primate species, chimpanzee, orangutan and rhesus macaque, to allow for a comparison with the curated set of human KZNFs. We show that the recent evolutionary history of primate KZNFs has been complex, including many lineage-specific duplications and deletions. We found 213 species-specific KZNFs, among them 7 human-specific and 23 chimpanzee-specific genes. Two human-specific genes were validated experimentally. Ten genes have been lost in humans and 13 in chimpanzees, either through deletion or pseudogenization. We also identified 30 KZNF orthologs with human-specific and 42 with chimpanzee-specific sequence changes that are predicted to affect DNA binding properties of the proteins. Eleven of these genes show signatures of accelerated evolution, suggesting positive selection between humans and chimpanzees. During primate evolution the most extensive re-shaping of the KZNF repertoire, including most gene additions, pseudogenizations, and structural changes occurred within the subfamily homininae. Using zinc finger (ZNF) binding predictions, we suggest potential impact these changes have had on human gene regulatory networks. The large species differences in this family of TFs stands in stark contrast to the overall high conservation of primate genomes and potentially represents a potent driver of primate evolution.

| S-EPMC3126818 | biostudies-literature

Pinpointing the <i>PRDM9-PRDM7</i> Gene Duplication Event During Primate Divergence.

Project description:Studies on the function of PRDM9 in model systems and its evolution during vertebrate divergence shed light on the basic molecular mechanisms of hybrid sterility and its evolutionary consequences. However, information regarding PRDM9-homolog, PRDM7, whose origin is placed in the primate evolutionary tree, as well as information about the fast-evolving DNA-binding zinc finger array of strepsirrhine PRDM9 are scarce. Thus, we aimed to narrow down the date of the duplication event leading to the emergence of PRDM7 during primate evolution by comparing the phylogenetic tree reconstructions of representative primate samples of PRDM orthologs and paralogs. To confirm our PRDM7 paralogization pattern, database-deposited sequences were used to test the presence/absence patterns expected from the paralogization timing. In addition, we extended the existing phylogenetic tree of haplorrhine PRDM9 zinc fingers with their strepsirrhine counterparts. The inclusion of strepsirrhine zinc fingers completes the PRDM9 primate phylogeny. Moreover, the updated phylogeny of PRDM9 zinc fingers showed distinct clusters of strepsirrhine, tarsier, and anthropoid degenerated zinc fingers. Here, we show that PRDM7 emerged on the branch leading to the most recent common ancestor of catarrhines; therefore, its origin is more recent than previously expected. A more detailed character evolutionary study suggests that PRDM7 may have evolved differently in Cercopithecoidea as compared to Hominoidea: it lacks the first four exons in Old World monkeys orthologs and exon 10 in Papionini orthologs. Dating the origin of PRDM7 is essential for further studies investigating why Hominoidea representatives need another putative histone methyltransferase in the testis.

| S-EPMC7943923 | biostudies-literature

Viral and developmental cell fusion mechanisms: conservation and divergence.

Project description:Membrane fusion is a fundamental requirement in numerous developmental, physiological, and pathological processes in eukaryotes. So far, only a limited number of viral and cellular fusogens, proteins that fuse membranes, have been isolated and characterized. Despite the diversity in structures and functions of known fusogens, some common principles of action apply to all fusion reactions. These can serve as guidelines in the search for new fusogens, and may allow the formulation of a cross-species, unified theory to explain divergent and convergent evolutionary principles of membrane fusion.

| S-EPMC3549671 | biostudies-literature

Functional divergence of the two Elongator subcomplexes during neurodevelopment.

Project description:The highly conserved Elongator complex is a translational regulator that plays a critical role in neurodevelopment, neurological diseases, and brain tumors. Numerous clinically relevant variants have been reported in the catalytic Elp123 subcomplex, while no missense mutations in the accessory subcomplex Elp456 have been described. Here, we identify ELP4 and ELP6 variants in patients with developmental delay, epilepsy, intellectual disability, and motor dysfunction. We determine the structures of human and murine Elp456 subcomplexes and locate the mutated residues. We show that patient-derived mutations in Elp456 affect the tRNA modification activity of Elongator in vitro as well as in human and murine cells. Modeling the pathogenic variants in mice recapitulates the clinical features of the patients and reveals neuropathology that differs from the one caused by previously characterized Elp123 mutations. Our study demonstrates a direct correlation between Elp4 and Elp6 mutations, reduced Elongator activity, and neurological defects. Foremost, our data indicate previously unrecognized differences of the Elp123 and Elp456 subcomplexes for individual tRNA species, in different cell types and in different key steps during the neurodevelopment of higher organisms.

| S-EPMC9260213 | biostudies-literature

Patterns of divergence in the vCXCL and vGPCR gene clusters in primate cytomegalovirus genomes.

Project description:Primate cytomegalovirus (CMV) genomes contain tandemly repeated gene clusters putatively encoding divergent CXC chemokine ligand-like proteins (vCXCLs) and G protein-coupled receptor-like proteins (vGPCRs). In human, chimpanzee and rhesus CMVs, respectively, the vCXCL cluster contains two, three and six genes, and the vGPCR cluster contains two, two and five genes. We report that (i) green monkey CMV strains fall into two groups, containing either eight and five genes or seven and six genes in the respective clusters, and (ii) owl monkey CMV has two and zero genes. Phylogenetic analysis suggested that the vCXCL cluster evolved from a CXCL chemokine gene (probably GRO-alpha) that was captured in an incompletely spliced form by an ancestor of Old and New World primate CMVs, and that the vGPCR cluster evolved from a GPCR gene captured by an Old World primate CMV. Both clusters appear to have evolved via complex duplication and deletion events.

| S-EPMC2846823 | biostudies-literature

Birth, decay, and reconstruction of an ancient TRIMCyp gene fusion in primate genomes.

Project description:TRIM5 is a host antiviral gene with an evolutionary history of genetic conflict with retroviruses. The TRIMCyp gene encodes a protein fusion of TRIM5 effector domains with the capsid-binding ability of a retrotransposed CyclophilinA (CypA), resulting in novel antiviral specificity against lentiviruses. Previous studies have identified two independent primate TRIMCyp fusions that evolved within the past 6 My. Here, we describe an ancient primate TRIMCyp gene (that we call TRIMCypA3), which evolved in the common ancestor of simian primates 43 Mya. Gene reconstruction shows that CypA3 encoded an intact, likely active, TRIMCyp antiviral gene, which was subject to selective constraints for at least 10 My, followed by pseudogenization or loss in all extant primates. Despite its decayed status, we found TRIMCypA3 gene fusion transcripts in several primates. We found that the reconstructed "newly born" TrimCypA3 encoded robust and broad retroviral restriction activity but that this broad activity was lost via eight amino acid changes over the course of the next 10 My. We propose that TRIMCypA3 arose in response to a viral pathogen encountered by ancestral primates but was subsequently pseudogenized or lost due to a lack of selective pressure. Much like imprints of ancient viruses, fossils of decayed genes, such as TRIMCypA3, provide unique and specific insight into paleoviral infections that plagued primates deep in their evolutionary history.

| S-EPMC3574956 | biostudies-literature

Regulatory divergence between parental alleles determines gene expression patterns in hybrids.

Project description:Both hybridization and allopolyploidization generate novel phenotypes by conciliating divergent genomes and regulatory networks in the same cellular context. To understand the rewiring of gene expression in hybrids, the total expression of 21,025 genes and the allele-specific expression of over 11,000 genes were quantified in interspecific hybrids and their parental species, Coffea canephora and Coffea eugenioides using RNA-seq technology. Between parental species, cis- and trans-regulatory divergences affected around 32% and 35% of analyzed genes, respectively, with nearly 17% of them showing both. The relative importance of trans-regulatory divergences between both species could be related to their low genetic divergence and perennial habit. In hybrids, among divergently expressed genes between parental species and hybrids, 77% was expressed like one parent (expression level dominance), including 65% like C. eugenioides. Gene expression was shown to result from the expression of both alleles affected by intertwined parental trans-regulatory factors. A strong impact of C. eugenioides trans-regulatory factors on the upregulation of C. canephora alleles was revealed. The gene expression patterns appeared determined by complex combinations of cis- and trans-regulatory divergences. In particular, the observed biased expression level dominance seemed to be derived from the asymmetric effects of trans-regulatory parental factors on regulation of alleles. More generally, this study illustrates the effects of divergent trans-regulatory parental factors on the gene expression pattern in hybrids. The characteristics of the transcriptional response to hybridization appear to be determined by the compatibility of gene regulatory networks and therefore depend on genetic divergences between the parental species and their evolutionary history.

| S-EPMC4419803 | biostudies-literature

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