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Publications in Biomedical Research by NOMIS researchers

Adaptable toolbox to characterize Alzheimer’s disease pathology in mouse models

NOMIS Researcher(s)

Published in

December 16, 2022

Here, we describe a highly adaptable toolbox for characterizing and analyzing molecular and histopathological changes in Alzheimer’s disease (AD) mouse models. We detail optimized and streamlined approaches from sample preparation to image analysis to facilitate reproducible analyses. We also describe the extraction and measurement of the soluble Aβ level by sandwich ELISA in the cortex and hippocampus of AD mouse models before and after plaque deposition. Finally, we outline the steps for image quantification and analysis using Imaris and ImageJ. For complete details on the use and execution of this protocol, please refer to Huang et al. (2021).1

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1016/j.xpro.2022.101891

SepN is a septal junction component required for gated cell–cell communication in the filamentous cyanobacterium Nostoc

NOMIS Researcher(s)

Published in

December 1, 2022

Multicellular organisms require controlled intercellular communication for their survival. Strains of the filamentous cyanobacterium Nostoc regulate cell–cell communication between sister cells via a conformational change in septal junctions. These multi-protein cell junctions consist of a septum spanning tube with a membrane-embedded plug at both ends, and a cap covering the plug on the cytoplasmic side. The identities of septal junction components are unknown, with exception of the protein FraD. Here, we identify and characterize a FraD-interacting protein, SepN, as the second component of septal junctions in Nostoc. We use cryo-electron tomography of cryo-focused ion beam-thinned cyanobacterial filaments to show that septal junctions in a sepN mutant lack a plug module and display an aberrant cap. The sepN mutant exhibits highly reduced cell–cell communication rates, as shown by fluorescence recovery after photobleaching experiments. Furthermore, the mutant is unable to gate molecule exchange through septal junctions and displays reduced filament survival after stress. Our data demonstrate the importance of controlling molecular diffusion between cells to ensure the survival of a multicellular organism.

Research field(s)
Health Sciences, Biomedical Research, Microbiology

DOI
10.1038/s41467-022-34946-7

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

NOMIS Researcher(s)

Published in

December 1, 2022

Background: The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. Methods: We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer’s disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. Results: We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. Conclusions: Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1186/s13073-022-01035-9

Brain aging is faithfully modelled in organotypic brain slices and accelerated by prions

NOMIS Researcher(s)

Published in

December 1, 2022

Mammalian models are essential for brain aging research. However, the long lifespan and poor amenability to genetic and pharmacological perturbations have hindered the use of mammals for dissecting aging-regulatory molecular networks and discovering new anti-aging interventions. To circumvent these limitations, we developed an ex vivo model system that faithfully mimics the aging process of the mammalian brain using cultured mouse brain slices. Genome-wide gene expression analyses showed that cultured brain slices spontaneously upregulated senescence-associated genes over time and reproduced many of the transcriptional characteristics of aged brains. Treatment with rapamycin, a classical anti-aging compound, largely abolished the time-dependent transcriptional changes in naturally aged brain slice cultures. Using this model system, we discovered that prions drastically accelerated the development of age-related molecular signatures and the pace of brain aging. We confirmed this finding in mouse models and human victims of Creutzfeldt-Jakob disease. These data establish an innovative, eminently tractable mammalian model of brain aging, and uncover a surprising acceleration of brain aging in prion diseases.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1038/s42003-022-03496-5

An arrayed genome-wide perturbation screen identifies the ribonucleoprotein Hnrnpk as rate-limiting for prion propagation

NOMIS Researcher(s)

Published in

December 1, 2022

A defining characteristic of mammalian prions is their capacity for self-sustained propagation. Theoretical considerations and experimental evidence suggest that prion propagation is modulated by cell-autonomous and non-autonomous modifiers. Using a novel quantitative phospholipase protection assay (QUIPPER) for high-throughput prion measurements, we performed an arrayed genome-wide RNA interference (RNAi) screen aimed at detecting cellular host-factors that can modify prion propagation. We exposed prion-infected cells in high-density microplates to 35,364 ternary pools of 52,746 siRNAs targeting 17,582 genes representing the majority of the mouse protein-coding transcriptome. We identified 1,191 modulators of prion propagation. While 1,151 modified the expression of both the pathological prion protein, PrPSc, and its cellular counterpart, PrPC, 40 genes selectively affected PrPSc. Of the latter 40 genes, 20 augmented prion production when suppressed. A prominent limiter of prion propagation was the heterogeneous nuclear ribonucleoprotein Hnrnpk. Psammaplysene A (PSA), which binds Hnrnpk, reduced prion levels in cultured cells and protected them from cytotoxicity. PSA also reduced prion levels in infected cerebellar organotypic slices and alleviated locomotor deficits in prion-infected Drosophila melanogaster expressing ovine PrPC. Hence, genome-wide QUIPPER-based perturbations can discover actionable cellular pathways involved in prion propagation. Further, the unexpected identification of a prion-controlling ribonucleoprotein suggests a role for RNA in the generation of infectious prions.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.15252/embj.2022112338

Serological fingerprints link antiviral activity of therapeutic antibodies to affinity and concentration

NOMIS Researcher(s)

Published in

December 1, 2022

The effectiveness of therapeutic monoclonal antibodies (mAbs) against variants of the SARS-CoV-2 virus is highly variable. As target recognition of mAbs relies on tight binding affinity, we assessed the affinities of five therapeutic mAbs to the receptor binding domain (RBD) of wild type (A), Delta (B.1.617.2), and Omicron BA.1 SARS-CoV-2 (B.1.1.529.1) spike using microfluidic diffusional sizing (MDS). Four therapeutic mAbs showed strongly reduced affinity to Omicron BA.1 RBD, whereas one (sotrovimab) was less impacted. These affinity reductions correlate with reduced antiviral activities suggesting that affinity could serve as a rapid indicator for activity before time-consuming virus neutralization assays are performed. We also compared the same mAbs to serological fingerprints (affinity and concentration) obtained by MDS of antibodies in sera of 65 convalescent individuals. The affinities of the therapeutic mAbs to wild type and Delta RBD were similar to the serum antibody response, indicating high antiviral activities. For Omicron BA.1 RBD, only sotrovimab retained affinities within the range of the serum antibody response, in agreement with high antiviral activity. These results suggest that serological fingerprints provide a route to evaluating affinity and antiviral activity of mAb drugs and could guide the development of new therapeutics.

Research field(s)
Health Sciences, Biomedical Research, Biochemistry & Molecular Biology

DOI
10.1038/s41598-022-22214-z

Genomic and metabolic adaptations of biofilms to ecological windows of opportunity in glacier-fed streams

NOMIS Researcher(s)

Published in

December 1, 2022

In glacier-fed streams, ecological windows of opportunity allow complex microbial biofilms to develop and transiently form the basis of the food web, thereby controlling key ecosystem processes. Using metagenome-assembled genomes, we unravel strategies that allow biofilms to seize this opportunity in an ecosystem otherwise characterized by harsh environmental conditions. We observe a diverse microbiome spanning the entire tree of life including a rich virome. Various co-existing energy acquisition pathways point to diverse niches and the exploitation of available resources, likely fostering the establishment of complex biofilms during windows of opportunity. The wide occurrence of rhodopsins, besides chlorophyll, highlights the role of solar energy capture in these biofilms while internal carbon and nutrient cycling between photoautotrophs and heterotrophs may help overcome constraints imposed by oligotrophy in these habitats. Mechanisms potentially protecting bacteria against low temperatures and high UV-radiation are also revealed and the selective pressure of this environment is further highlighted by a phylogenomic analysis differentiating important components of the glacier-fed stream microbiome from other ecosystems. Our findings reveal key genomic underpinnings of adaptive traits contributing to the success of complex biofilms to exploit environmental opportunities in glacier-fed streams, which are now rapidly changing owing to global warming.

Research field(s)
Health Sciences, Biomedical Research, Microbiology

DOI
10.1038/s41467-022-29914-0

The microbiome of cryospheric ecosystems

NOMIS Researcher(s)

Published in

December 1, 2022

The melting of the cryosphere is among the most conspicuous consequences of climate change, with impacts on microbial life and related biogeochemistry. However, we are missing a systematic understanding of microbiome structure and function across cryospheric ecosystems. Here, we present a global inventory of the microbiome from snow, ice, permafrost soils, and both coastal and freshwater ecosystems under glacier influence. Combining phylogenetic and taxonomic approaches, we find that these cryospheric ecosystems, despite their particularities, share a microbiome with representatives across the bacterial tree of life and apparent signatures of early and constrained radiation. In addition, we use metagenomic analyses to define the genetic repertoire of cryospheric bacteria. Our work provides a reference resource for future studies on climate change microbiology.

Research field(s)
Health Sciences, Biomedical Research, Microbiology

DOI
10.1038/s41467-022-30816-4

The SARS-CoV-2 nucleocapsid phosphoprotein forms mutually exclusive condensates with RNA and the membrane-associated M protein

NOMIS Researcher(s)

Published in

December 1, 2022

The multifunctional nucleocapsid (N) protein in SARS-CoV-2 binds the ~30 kb viral RNA genome to aid its packaging into the 80–90 nm membrane-enveloped virion. The N protein is composed of N-terminal RNA-binding and C-terminal dimerization domains that are flanked by three intrinsically disordered regions. Here we demonstrate that the N protein’s central disordered domain drives phase separation with RNA, and that phosphorylation of an adjacent serine/arginine rich region modulates the physical properties of the resulting condensates. In cells, N forms condensates that recruit the stress granule protein G3BP1, highlighting a potential role for N in G3BP1 sequestration and stress granule inhibition. The SARS-CoV-2 membrane (M) protein independently induces N protein phase separation, and three-component mixtures of N + M + RNA form condensates with mutually exclusive compartments containing N + M or N + RNA, including annular structures in which the M protein coats the outside of an N + RNA condensate. These findings support a model in which phase separation of the SARS-CoV-2 N protein contributes both to suppression of the G3BP1-dependent host immune response and to packaging genomic RNA during virion assembly.

Research field(s)
Health Sciences, Biomedical Research, Virology

DOI
10.1038/s41467-020-20768-y

Recursive Editing improves homology-directed repair through retargeting of undesired outcomes

NOMIS Researcher(s)

Published in

December 1, 2022

CRISPR-Cas induced homology-directed repair (HDR) enables the installation of a broad range of precise genomic modifications from an exogenous donor template. However, applications of HDR in human cells are often hampered by poor efficiency, stemming from a preference for error-prone end joining pathways that yield short insertions and deletions. Here, we describe Recursive Editing, an HDR improvement strategy that selectively retargets undesired indel outcomes to create additional opportunities to produce the desired HDR allele. We introduce a software tool, named REtarget, that enables the rational design of Recursive Editing experiments. Using REtarget-designed guide RNAs in single editing reactions, Recursive Editing can simultaneously boost HDR efficiencies and reduce undesired indels. We also harness REtarget to generate databases for particularly effective Recursive Editing sites across the genome, to endogenously tag proteins, and to target pathogenic mutations. Recursive Editing constitutes an easy-to-use approach without potentially deleterious cell manipulations and little added experimental burden.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1038/s41467-022-31944-7

Adenine base editing efficiently restores the function of Fanconi anemia hematopoietic stem and progenitor cells

NOMIS Researcher(s)

Published in

December 1, 2022

Fanconi Anemia (FA) is a debilitating genetic disorder with a wide range of severe symptoms including bone marrow failure and predisposition to cancer. CRISPR-Cas genome editing manipulates genotypes by harnessing DNA repair and has been proposed as a potential cure for FA. But FA is caused by deficiencies in DNA repair itself, preventing the use of editing strategies such as homology directed repair. Recently developed base editing (BE) systems do not rely on double stranded DNA breaks and might be used to target mutations in FA genes, but this remains to be tested. Here we develop a proof of concept therapeutic base editing strategy to address two of the most prevalent FANCA mutations in patient hematopoietic stem and progenitor cells. We find that optimizing adenine base editor construct, vector type, guide RNA format, and delivery conditions leads to very effective genetic modification in multiple FA patient backgrounds. Optimized base editing restored FANCA expression, molecular function of the FA pathway, and phenotypic resistance to crosslinking agents. ABE8e mediated editing in primary hematopoietic stem and progenitor cells from FA patients was both genotypically effective and restored FA pathway function, indicating the potential of base editing strategies for future clinical application in FA.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1038/s41467-022-34479-z

Sirtuin-1 sensitive lysine-136 acetylation drives phase separation and pathological aggregation of TDP-43

NOMIS Researcher(s)

Published in

December 1, 2022

Trans-activation response DNA-binding protein of 43 kDa (TDP-43) regulates RNA processing and forms neuropathological aggregates in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Investigating TDP-43 post-translational modifications, we discovered that K84 acetylation reduced nuclear import whereas K136 acetylation impaired RNA binding and splicing capabilities of TDP-43. Such failure of RNA interaction triggered TDP-43 phase separation mediated by the C-terminal low complexity domain, leading to the formation of insoluble aggregates with pathologically phosphorylated and ubiquitinated TDP-43. Introduction of acetyl-lysine at the identified sites via amber suppression confirmed the results from site-directed mutagenesis. K84-acetylated TDP-43 showed cytoplasmic mislocalization, and the aggregation propensity of K136-acetylated TDP-43 was confirmed. We generated antibodies selective for TDP-43 acetylated at these lysines, and found that sirtuin-1 can potently deacetylate K136-acetylated TDP-43 and reduce its aggregation propensity. Thus, distinct lysine acetylations modulate nuclear import, RNA binding and phase separation of TDP-43, suggesting regulatory mechanisms for TDP-43 pathogenesis.

Research field(s)
Health Sciences, Biomedical Research, Biochemistry & Molecular Biology

DOI
10.1038/s41467-022-28822-7

Improved gRNA secondary structures allow editing of target sites resistant to CRISPR-Cas9 cleavage

NOMIS Researcher(s)

Published in

December 1, 2022

The first step in CRISPR-Cas9-mediated genome editing is the cleavage of target DNA sequences that are complementary to so-called spacer sequences in CRISPR guide RNAs (gRNAs). However, some DNA sequences are refractory to CRISPR-Cas9 cleavage, which is at least in part due to gRNA misfolding. To overcome this problem, we have engineered gRNAs with highly stable hairpins in their constant parts and further enhanced their stability by chemical modifications. The ‘Genome-editing Optimized Locked Design’ (GOLD)-gRNA increases genome editing efficiency up to around 1000-fold (from 0.08 to 80.5%) with a mean increase across different other targets of 7.4-fold. We anticipate that this improved gRNA will allow efficient editing regardless of spacer sequence composition and will be especially useful if a desired genomic site is difficult to edit.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1038/s41467-022-28137-7

The broader sense of nonsense

NOMIS Researcher(s)

Published in

November 1, 2022

The term ‘nonsense-mediated mRNA decay’ (NMD) was initially coined to describe the translation-dependent degradation of mRNAs harboring premature termination codons (PTCs), but it is meanwhile known that NMD also targets many canonical mRNAs with numerous biological implications. The molecular mechanisms determining on which RNAs NMD ensues are only partially understood. Considering the broad range of NMD-sensitive RNAs and the variable degrees of their degradation, we highlight here the hallmarks of mammalian NMD and point out open questions. We review the links between NMD and disease by summarizing the role of NMD in cancer, neurodegeneration, and viral infections. Finally, we describe strategies to modulate NMD activity and specificity as potential therapeutic approaches for various diseases.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1016/j.tibs.2022.06.003

Synaptogenic activity of the axon guidance molecule Robo2 underlies hippocampal circuit function

NOMIS Researcher(s)

Published in

October 19, 2022

Synaptic connectivity within adult circuits exhibits a remarkable degree of cellular and subcellular specificity. We report that the axon guidance receptor Robo2 plays a role in establishing synaptic specificity in hippocampal CA1. In vivo, Robo2 is present and required postsynaptically in CA1 pyramidal neurons (PNs) for the formation of excitatory (E) but not inhibitory (I) synapses, specifically in proximal but not distal dendritic compartments. In vitro approaches show that the synaptogenic activity of Robo2 involves a trans-synaptic interaction with presynaptic Neurexins, as well as binding to its canonical extracellular ligand Slit. In vivo 2-photon Ca2+ imaging of CA1 PNs during spatial navigation in awake behaving mice shows that preventing Robo2-dependent excitatory synapse formation cell autonomously during development alters place cell properties of adult CA1 PNs. Our results identify a trans-synaptic complex linking the establishment of synaptic specificity to circuit function.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1016/j.celrep.2021.109828

Chronic Leptin Deficiency Improves Tolerance of Physiological Damage and Host-Pathogen Cooperation during Yersinia pseudotuberculosis Infection

NOMIS Researcher(s)

Published in

September 1, 2022

To combat infections, hosts employ a combination of antagonistic and cooperative defense strategies. The former refers to pathogen killing mediated by resistance mechanisms, while the latter refers to physiological defense mechanisms that promote host health during infection independent of pathogen killing, leading to an apparent cooperation between the host and the pathogen. Previous work has shown that Leptin, a pleiotropic hormone that plays a central role in regulating appetite and energy metabolism, is indispensable for resistance mechanisms, while a role for Leptin signaling in cooperative host-pathogen interactions remains unknown. Using a mouse model of Yersinia pseudotuberculosis (Yptb) infection, an emerging pathogen that causes fever, diarrhea, and mesenteric lymphadenitis in humans, we found that the physiological effects of chronic Leptin-signaling deficiency conferred protection from Yptb infection due to increased host-pathogen cooperation rather than greater resistance defenses. The protection against Yptb infection was independent of differences in food consumption, lipolysis, or fat mass. Instead, we found that the chronic absence of Leptin signaling protects from a shift to lipid utilization during infection that contributes to Yptb lethality. Furthermore, we found that the survival advantage conferred by Leptin deficiency was associated with increased liver and kidney damage. Our work reveals an additional level of complexity for the role of Leptin in infection defense and demonstrates that in some contexts, in addition to tolerating the pathogen, tolerating organ damage is more beneficial for survival than preventing the damage.

Research field(s)
Health Sciences, Biomedical Research, Microbiology

DOI
10.1128/iai.00242-22

Dyslexia associated gene KIAA0319 regulates cell cycle during human neuroepithelial cell development

NOMIS Researcher(s)

Published in

August 9, 2022

Dyslexia, also known as reading disability, is defined as difficulty processing written language in individuals with normal intellectual capacity and educational opportunity. The prevalence of dyslexia is between 5 and 17%, and the heritability ranges from 44 to 75%. Genetic linkage analysis and association studies have identified several genes and regulatory elements linked to dyslexia and reading ability. However, their functions and molecular mechanisms are not well understood. Prominent among these is KIAA0319, encoded in the DYX2 locus of human chromosome 6p22. The association of KIAA0319 with reading performance has been replicated in independent studies and different languages. Rodent models suggest that kiaa0319 is involved in neuronal migration, but its role throughout the cortical development is largely unknown. In order to define the function of KIAA0319 in human cortical development, we applied the neural developmental model of a human embryonic stem cell. We knocked down KIAA0319 expression in hESCs and performed the cortical neuroectodermal differentiation. We found that neuroepithelial cell differentiation is one of the first stages of hESC differentiation that are affected by KIAA0319 knocked down could affect radial migration and thus differentiation into diverse neural populations at the cortical layers.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.3389/fcell.2022.967147

A conformational switch controlling the toxicity of the prion protein

NOMIS Researcher(s)

Published in

August 1, 2022

Prion infections cause conformational changes of the cellular prion protein (PrPC) and lead to progressive neurological impairment. Here we show that toxic, prion-mimetic ligands induce an intramolecular R208-H140 hydrogen bond (‘H-latch’), altering the flexibility of the α2–α3 and β2–α2 loops of PrPC. Expression of a PrP2Cys mutant mimicking the H-latch was constitutively toxic, whereas a PrPR207A mutant unable to form the H-latch conferred resistance to prion infection. High-affinity ligands that prevented H-latch induction repressed prion-related neurodegeneration in organotypic cerebellar cultures. We then selected phage-displayed ligands binding wild-type PrPC, but not PrP2Cys. These binders depopulated H-latched conformers and conferred protection against prion toxicity. Finally, brain-specific expression of an antibody rationally designed to prevent H-latch formation prolonged the life of prion-infected mice despite unhampered prion propagation, confirming that the H-latch is an important reporter of prion neurotoxicity.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1038/s41594-022-00814-7

COVID-19 and seasonal flu vaccination hesitancy: Links to personality and general intelligence in a large, UK cohort

NOMIS Researcher(s)

Published in

July 30, 2022

Vaccines are a powerful and relatively safe tool to protect against a range of serious diseases. Nonetheless, a sizeable minority of people express ‘vaccination hesitancy’. Accordingly, understanding the bases of this hesitancy represents a significant public health opportunity. In the present study we sought to examine the role of Big Five personality traits and general intelligence as predictors of vaccination hesitancy across two vaccination types in a large (N = 9667) sample of UK adults drawn from the Understanding Society longitudinal household study. We found that lower levels of general intelligence were associated with COVID-19 and seasonal flu vaccination hesitancy, and lower levels of neuroticism was associated with COVID-19 vaccination hesitancy. Although the self-reported reasons for being vaccine hesitant indicated a range of factors were important to people, lower general intelligence was associated with virtually all of these reasons. In contrast, Big Five personality traits showed more nuanced patterns of association.

Research field(s)
Health Sciences, Biomedical Research, Virology

DOI
10.1016/j.vaccine.2022.05.062

Longer metaphase and fewer chromosome segregation errors in modern human than Neanderthal brain development

NOMIS Researcher(s)

Published in

July 29, 2022

Since the ancestors of modern humans separated from those of Neanderthals, around 100 amino acid substitutions spread to essentially all modern humans. The biological significance of these changes is largely unknown. Here, we examine all six such amino acid substitutions in three proteins known to have key roles in kinetochore function and chromosome segregation and to be highly expressed in the stem cells of the developing neocortex. When we introduce these modern human-specific substitutions in mice, three substitutions in two of these proteins, KIF18a and KNL1, cause metaphase prolongation and fewer chromosome segregation errors in apical progenitors of the developing neocortex. Conversely, the ancestral substitutions cause shorter metaphase length and more chromosome segregation errors in human brain organoids, similar to what we find in chimpanzee organoids. These results imply that the fidelity of chromosome segregation during neocortex development improved in modern humans after their divergence from Neanderthals.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1126/sciadv.abn7702

The evolutionary history of human spindle genes includes back-and-forth gene flow with Neandertals

NOMIS Researcher(s)

Published in

July 1, 2022

Proteins associated with the spindle apparatus, a cytoskeletal structure that ensures the proper segregation of chromosomes during cell division, experienced an unusual number of amino acid substitutions in modern humans after the split from the ancestors of Neandertals and Denisovans. Here, we analyze the history of these substitutions and show that some of the genes in which they occur may have been targets of positive selection. We also find that the two changes in the kinetochore scaffold 1 (KNL1) protein, previously believed to be specific to modern humans, were present in some Neandertals. We show that the KNL1 gene of these Neandertals shared a common ancestor with present-day Africans about 200,000 years ago due to gene flow from the ancestors (or relatives) of modern humans into Neandertals. Subsequently, some non-Africans inherited this modern human-like gene variant from Neandertals, but none inherited the ancestral gene variants. These results add to the growing evidence of early contacts between modern humans and archaic groups in Eurasia and illustrate the intricate relationships among these groups.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.7554/elife.75464

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