Biology subjects

Huang, E.

Publications and source records attributed to Huang, E..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Neoplastic immune mimicry is a generalizable phenomenon in breast cancer and epithelial CD69 enables early tumor progression

Dedifferentiation programs are commonly enacted during breast cancer progression to enhance tumor cell fitness. Increased cellular plasticity within the neoplastic compartment of tumors correlates with disease aggressiveness, often culminating in greater resistance to cytotoxic therapies or augmented metastatic potential. Here we report that subpopulations of dedifferentiated neoplastic breast epithelial cells express canonical leukocyte cell surface receptor proteins and have thus named this cellular program "immune mimicry." We document neoplastic cells engaging in immune mimicry within public human breast tumor single-cell RNA-seq datasets, histopathological breast tumor specimens, breast cancer cell lines, as well as in murine transgenic and cell line-derived mammary cancer models. Immune-mimicked neoplastic cells harbor hallmarks of dedifferentiation and are enriched in treatment-resistant and high-grade breast tumors. We corroborated these observations in aggressive breast cancer cell lines where anti-proliferative cytotoxic chemotherapies drove epithelial cells toward immune mimicry. Moreover, in subsequent proof-of-concept studies, we demonstrate that expression of the CD69 leukocyte activation protein by neoplastic cells confers a proliferative advantage that facilitates early tumor growth and therefore conclude that neoplastic breast epithelial cells upregulating leukocyte surface receptors potentiate malignancy. Moving forward, neoplastic immune mimicry should be evaluated for prognostic utility in additional breast cancer cohorts to determine its potential for patient stratification. Future research should evaluate correlates with distal metastases, progression-free survival, overall survival, and therapeutic response/resistance. Statement of SignificanceNeoplastic breast epithelial cells express surface receptors canonically attributed to leukocytes and are associated with therapy resistance and aggressive tumor behavior.

cancer biology↗

bioRxiv2024

Reconstructing the deep phylogeny of the MAPK signaling network: functional specialization via multi-tier coevolutionary expansion

The mitogen-activated protein kinase (MAPK) signaling network is a three-tier cascade that regulates key cellular responses in eukaryotes. However, the evolutionary origins of its complex interactions and functional diversity remain poorly understood. Here, we conducted a comprehensive phylogenetic analysis of MAPK components across Eukarya to delineate divergences of non-human orthologs of human paralogs along the human evolutionary backbone. We identified two major pulses of coevolutionary expansion: one predating the divergence of fungi and animals, and another predating the origin of animals. Our reconstruction also infers a polyphyletic origin for the atypical MAPKs. Integrating functional literature across eukaryotic taxa with our reconstructed trees reveals that the two clades of MAP3K, Sterile-like (STE) and tyrosine kinase-like (TKL), had distinct evolutionary trajectories and influences on downstream pathway diversification. STEs that function as MAP3Ks are conserved across extant eukaryotes. Despite the absence of TKL MAP3Ks in many early diverging eukaryotes, the expansion of TKL MAP3Ks aligns phylogenetically and functionally with that of the downstream MAP2Ks and MAPKs. We thus propose that the MAPK network originated as a STE-regulated pathway, and that subsequent radiations of the TKLs drove the diversification of downstream components and top-down finetuning of pathway specificity. We thus provide an evolutionary framework for generating novel hypotheses on the functional diversity of this key signaling network, including potential insights into the evolution of animal multicellularity. Our study demonstrates that phylogenetics can offer new perspectives towards understanding complex cellular physiology. SignificanceThe mitogen-activated protein kinase (MAPK) signaling network responds to various signals and regulates basic cell physiology including proliferation and apoptosis. This three-tier network is universal in eukaryotes, but there is great functional diversity among different homologs as well as different taxa. Here we compared amino acid sequences to reconstruct MAPK evolutionary history as a network. We found that the three levels expand in parallel, showcasing a special case of coevolution. Two distinct pulses of network expansion predate the origin of animals, indicating that the functional diversity of human MAPK network proteins originate from ancient evolutionary radiations. Together, our study provides a critical look at the deep history of this important network.

evolutionary biology↗

bioRxiv2024

GlycoRNA-L and glycoRNA-S mediate human monocyte adhesion via binding to Siglec-5

It was recently reported that RNAs can be glycosylated, and a majority of such glycosylated RNAs (referred to as glycoRNAs) are located on the outer cell surface. We here reported that there are two forms of glycoRNAs, named as glycoRNA-L and glycoRNA-S, robustly expressed in human monocytes. Both of glycoRNA-L and glycoRNA-S contributed to the interaction of human monocytes and endothelial cells via directly binding to Siglec-5. GlycoRNA-L predominantly expressed in most of tissues and cell lines. GlycoRNA-S only expressed in some cell lines and tissues. Siglec-5 preferentially binds to glycoRNA-L than glycoRNA-S. The composition of glycan chains in glycoRNA-L and glycoRNA-S is different. GlycoRNA-L contains more sialic acid, whereas glycoRNA-S contains more GlcNAc. Together, these results demonstrate that two forms of glycoRNAs exist, which may play significant role in controlling the interaction of human monocytes and endothelial cells and contribute to the pathogenesis of inflammatory diseases.

cell biology↗

bioRxiv2024

Data Independent Acquisition to Inform the Development of Targeted Proteomics Assays Using a Triple Quadrupole Mass Spectrometer

Mass spectrometry based targeted proteomics methods provide sensitive and high-throughput analysis of selected proteins. To develop a targeted bottom-up proteomics assay, peptides must be evaluated as proxies for the measurement of a protein or proteoform in a biological matrix. Candidate peptide selection typically relies on predetermined biochemical properties, data from semi-stochastic sampling, or by empirical measurements. These strategies require extensive testing and method refinement due to the difficulties associated with prediction of peptide response in the biological matrix of interest. Gas-phase fractionated (GPF) narrow window data-independent acquisition (DIA) aids in the development of reproducible selected reaction monitoring (SRM) assays by providing matrix-specific information on peptide detectability and quantification by mass spectrometry. To demonstrate the suitability of DIA data for selecting peptide targets, we reimplement a portion of an existing assay to measure 98 Alzheimers disease proteins in cerebrospinal fluid (CSF). Peptides were selected from GPF-DIA based on signal intensity and reproducibility. The resulting SRM assay exhibits similar quantitative precision to published data, despite the inclusion of different peptides between the assays. This workflow enables development of new assays without additional up-front data acquisition, demonstrated here through generation of a separate assay for an unrelated set of proteins in CSF from the same dataset.

biochemistry↗

bioRxiv2024

AmpliconSuite: an end-to-end workflow for analyzing focal amplifications in cancer genomes

Focal amplifications in the cancer genome, particularly extrachromosomal DNA (ecDNA) amplifications, are emerging as a pivotal event in cancer progression across diverse cancer contexts, presenting a paradigm shift in our understanding of tumor dynamics. Simultaneously, identification of the various modes of focal amplifications is bioinformatically challenging. We present AmpliconSuite, a collection of tools that enables robust identification of focal amplifications from whole-genome sequencing data. AmpliconSuite includes AmpliconSuite- pipeline; utilizing the AmpliconArchitect (AA) method, and AmpliconRepository.org; a community- editable website for the sharing of focal amplification calls. We also describe improvements made to AA since its initial release that improve its accuracy and speed. As a proof of principle, we utilized publicly available pan-cancer datasets encompassing 2,525 tumor samples hosted on AmpliconRepository.org to illustrate important properties of focal amplifications, showing ecDNA has higher copy number, and stronger oncogene enrichment, compared to other classes of focal amplifications. Finally, we illustrate how AmpliconSuite-pipeline enables delineation of the various mechanisms by which ecDNA forms.

bioinformatics↗

bioRxiv2024

A framework for quality control in quantitative proteomics

A thorough evaluation of the quality, reproducibility, and variability of bottom-up proteomics data is necessary at every stage of a workflow from planning to analysis. We share vignettes applying adaptable quality control (QC) measures to assess sample preparation, system function, and quantitative analysis. System suitability samples are repeatedly measured longitudinally with targeted methods, and we share examples where they are used on three instrument platforms to identify severe system failures and track function over months to years. Internal QCs incorporated at protein and peptide-level allow our team to assess sample preparation issues and to differentiate system failures from sample-specific issues. External QC samples prepared alongside our experimental samples are used to verify the consistency and quantitative potential of our results during batch correction and normalization before assessing biological phenotypes. We combine these controls with rapid analysis (Skyline), longitudinal QC metrics (AutoQC), and server-based data deposition (PanoramaWeb). We propose that this integrated approach to QC is a useful starting point for groups to facilitate rapid quality control assessment to ensure that valuable instrument time is used to collect the best quality data possible. Data are available on Panorama Public and on ProteomeXchange under the identifier PXD051318.

biochemistry↗

bioRxiv2023

Discovery of CMX990: A Potent SARS-CoV-2 3CL Protease Inhibitor Bearing a Novel Covalent Warhead

There remains a need to develop novel SARS-CoV-2 therapeutic options that improve upon existing therapies by increased robustness of response, fewer safety liabilities, and global-ready accessibility. Functionally critical viral main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target due to its homology within the coronaviral family, and lack thereof towards human proteases. In this disclosure, we outline the advent of a novel SARS-CoV-2 3CLpro inhibitor, CMX990, bearing an unprecedented trifluoromethoxymethyl ketone warhead. Compared with the marketed drug nirmatrelvir (combination with ritonavir = PaxlovidTM), CMX990 has distinctly differentiated potency ([~]5x more potent in primary cells) and human in vitro clearance (>4x better microsomal clearance and >10x better hepatocyte clearance), with good in vitro-in vivo correlation. Based on its compelling preclinical profile and projected once or twice a day dosing supporting unboosted oral therapy in humans, CMX990 advanced to a Phase 1 clinical trial as an oral drug candidate for SARS-CoV-2.

microbiology↗

bioRxiv2023

Hierarchical replay of multi-regional sequential spiking associated with working memory

How does millisecond-scale neural activity mediate behaviors over seconds? We recorded brain-wide activity in mice performing an olfactory working-memory task to decipher cross-region organization of activity. Spike-correlograms revealed millisecond within- and cross-region spike couplings, more prominent among neurons encoding similar memories. Spike coupling linked neurons into motifs of chains, single loops, and nested loops, especially among hippocampal and prefrontal-cortex neurons. Direction of spike coupling and activity chains was in line with that of memory-associated activity waves. Intriguingly, activity motifs were replayed before and after task performance, and during inter-trial intervals. Motifs were hierarchically organized, with progressively increasing time constants and the number of participating neurons. Thus, hierarchically organized and replayed cross-region spiking motifs are modulated on demand during delay period to mediate perceptual working memory. One Sentence SummaryNested activity motifs of chains, single loops, and nested loops, with progressively increasing time constants and number of participating neurons, are hierarchically organized and replayed to mediate perceptual working-memory maintenance.

neuroscience↗

bioRxiv2023

Membrane Bound O-Acyltransferase 7 (MBOAT7) Shapes Lysosomal Lipid Homeostasis and Function to Control Alcohol-Associated Liver Injury

Several recent genome-wide association studies (GWAS) have identified single nucleotide polymorphism (SNPs) near the gene encoding membrane-bound O-acyltransferase 7 (MBOAT7) that is associated with advanced liver diseases. In fact, a common MBOAT7 variant (rs641738), which is associated with reduced MBOAT7 expression, confers increased susceptibility to non-alcoholic fatty liver disease (NAFLD), alcohol-associated liver disease (ALD), and liver fibrosis in those chronically infected with hepatitis viruses B and C. The MBOAT7 gene encodes a lysophosphatidylinositol (LPI) acyltransferase enzyme that produces the most abundant form of phosphatidylinositol 38:4 (PI 18:0/20:4). Although these recent genetic studies clearly implicate MBOAT7 function in liver disease progression, the mechanism(s) by which MBOAT7-driven LPI acylation regulates liver disease is currently unknown. Previously we showed that antisense oligonucleotide (ASO)-mediated knockdown of Mboat7 promoted non-alcoholic fatty liver disease (NAFLD) in mice (Helsley et al., 2019). Here, we provide mechanistic insights into how MBOAT7 loss of function promotes alcohol-associated liver disease (ALD). In agreement with GWAS studies, we find that circulating levels of metabolic product of MBOAT7 (PI 38:4) are significantly reduced in heavy drinkers compared to age-matched healthy controls. Hepatocyte specific genetic deletion (Mboat7HSKO), but not myeloid-specific deletion (Mboat7MSKO), of Mboat7 in mice results in enhanced ethanol-induced hepatic steatosis and high concentrations of plasma alanine aminotransferase (ALT). Given MBOAT7 is a lipid metabolic enzyme, we performed comprehensive lipidomic profiling of the liver and identified a striking reorganization of the hepatic lipidome upon ethanol feeding in Mboat7HSKO mice. Specifically, we observed large increases in the levels of endosomal/lysosomal lipids including bis(monoacylglycero)phosphates (BMP) and phosphatidylglycerols (PGs) in ethanol-exposed Mboat7HSKO mice. In parallel, ethanol-fed Mboat7HSKO mice exhibited marked dysregulation of autophagic flux and lysosomal biogenesis when exposed to ethanol. This was associated with impaired transcription factor EB (TFEB)-mediated lysosomal biogenesis and accumulation of autophagosomes. Collectively, this works provides new molecular insights into how genetic variation in MBOAT7 impacts ALD progression in humans and mice. This work is the first to causally link MBOAT7 loss of function in hepatocytes, but not myeloid cells, to ethanol-induced liver injury via dysregulation of lysosomal biogenesis and autophagic flux.

cell biology↗

bioRxiv2023

Genomic context sensitizes regulatory elements to genetic disruption

Enhancer function is frequently investigated piecemeal using truncated reporter assays or single deletion analysis. Thus it remains unclear to what extent enhancer function at native loci relies on surrounding genomic context. Using the Big-IN technology for targeted integration of large DNAs, we analyzed the regulatory architecture of the murine Igf2/H19 locus, a paradigmatic model of enhancer selectivity. We assembled payloads containing a 157-kb functional Igf2/H19 locus and engineered mutations to genetically direct CTCF occupancy at the imprinting control region (ICR) that switches the target gene of the H19 enhancer cluster. Contrasting activity of payloads delivered at the endogenous Igf2/H19 locus or ectopically at Hprt revealed that the Igf2/H19 locus includes additional, previously unknown long-range regulatory elements. Exchanging components of the Igf2/H19 locus with the well-studied Sox2 locus showed that the H19 enhancer cluster functioned poorly out of context, and required its native surroundings to activate Sox2 expression. Conversely, the Sox2 locus control region (LCR) could activate both Igf2 and H19 outside its native context, but its activity was only partially modulated by CTCF occupancy at the ICR. Analysis of regulatory DNA actuation across different cell types revealed that, while the H19 enhancers are tightly coordinated within their native locus, the Sox2 LCR acts more independently. We show that these enhancer clusters typify broader classes of loci genome-wide. Our results show that unexpected dependencies may influence even the most studied functional elements, and our synthetic regulatory genomics approach permits large-scale manipulation of complete loci to investigate the relationship between locus architecture and function. HIGHLIGHTSO_LIComposite enhancer elements are subject to genomic context effects mapped to a specific architecture of their endogenous loci. C_LIO_LIIgf2/H19 expression is affected by long-range regulatory elements beyond the canonically defined locus, and the H19 enhancer cluster in particular relies on the surrounding context at its endogenous locus. C_LIO_LIThe Sox2 LCR functions as an autonomous enhancer without requiring additional surrounding context. C_LIO_LIThe influence of genomic context is buffered at intact loci, but manifests more strongly as key regulatory elements are deleted or repositioned. C_LI

genomics↗

bioRxiv2023

NMFClustering: Accessible NMF-based clustering utilizing GPU acceleration

SummaryNon-negative Matrix Factorization (NMF) is an algorithm that can reduce high dimensional datasets of tens of thousands of genes to a handful of metagenes which are biologically easier to interpret. Application of NMF on gene expression data has been limited by its computationally intensive nature, which hinders its use on large datasets such as single-cell RNA sequencing (scRNA-seq) count matrices. We have implemented NMF based clustering to run on high performance GPU compute nodes using CuPy, a GPU backed python library, and the Message Passing Interface (MPI). This reduces the computation time by up to three orders of magnitude and makes the NMF Clustering analysis of large RNA-Seq and scRNA-seq datasets practical. We have made the method freely available through the GenePattern gateway, which provides free public access to hundreds of tools for the analysis and visualization of multiple omic data types. Its web-based interface gives easy access to these tools and allows the creation of multi-step analysis pipelines on high performance computing (HPC) clusters that enable reproducible in silico research for non-programmers. Availability and ImplementationNMFClustering is freely available on the public GenePattern server at https://genepattern.ucsd.edu. Code for the NMFClustering is available under a BSD style license on github at https://github.com/genepattern/nmf-gpu. ContactTed Liefeld, jliefeld@cloud.ucsd.edu Supplementary InformationSupplementary data are available at Bioinformatics online and at https://datasets.genepattern.org/?prefix=data/test_data/NMFClustering/.

bioinformatics↗

bioRxiv2023

Mag-Net: Rapid enrichment of membrane-bound particles enables high coverage quantitative analysis of the plasma proteome

Membrane-bound particles in plasma are composed of exosomes, microvesicles, and apoptotic bodies and represent [~]1-2% of the total protein composition. Proteomic interrogation of this subset of plasma proteins augments the representation of tissue-specific proteins, representing a "liquid biopsy," while enabling the detection of proteins that would otherwise be beyond the dynamic range of liquid chromatography-tandem mass spectrometry of unfractionated plasma. We have developed an enrichment strategy (Mag-Net) using hyper-porous strong-anion exchange magnetic microparticles to sieve membrane-bound particles from plasma. The Mag-Net method is robust, reproducible, inexpensive, and requires <100 L plasma input. Coupled to a quantitative data-independent mass spectrometry analytical strategy, we demonstrate that we can collect results for >37,000 peptides from >4,000 plasma proteins with high precision. Using this analytical pipeline on a small cohort of patients with neurodegenerative disease and healthy age-matched controls, we discovered 204 proteins that differentiate (q-value < 0.05) patients with Alzheimers disease dementia (ADD) from those without ADD. Our method also discovered 310 proteins that were different between Parkinsons disease and those with either ADD or healthy cognitively normal individuals. Using machine learning we were able to distinguish between ADD and not ADD with a mean ROC AUC = 0.98 {+/-} 0.06.

biochemistry↗

bioRxiv2022

De novo design of high-affinity protein binders to bioactive helical peptides

Many peptide hormones form an alpha-helix upon binding their receptors1-4, and sensitive detection methods for them could contribute to better clinical management. De novo protein design can now generate binders with high affinity and specificity to structured proteins5,6. However, the design of interactions between proteins and short helical peptides is an unmet challenge. Here, we describe parametric generation and deep learning-based methods for designing proteins to address this challenge. We show that with the RFdiffusion generative model, picomolar affinity binders can be generated to helical peptide targets either by noising and then denoising lower affinity designs generated with other methods, or completely de novo starting from random noise distributions; to our knowledge these are the highest affinity designed binding proteins against any protein or small molecule target generated directly by computation without any experimental optimization. The RFdiffusion designs enable the enrichment of parathyroid hormone or other bioactive peptides in human plasma and subsequent detection by mass spectrometry, and bioluminescence-based protein biosensors. Capture reagents for bioactive helical peptides generated using the methods described here could aid in the improved diagnosis and therapeutic management of human diseases.7,8

bioengineering↗

bioRxiv2022

Mouse genomic rewriting and tailoring: synthetic Trp53 and humanized ACE2

Genetically Engineered Mouse Models (GEMMs) aid in understanding human pathologies and developing new therapeutics, yet recapitulating human diseases authentically in mice is challenging to design and execute. Advances in genomics have highlighted the importance of non-coding regulatory genome sequences controlling spatiotemporal gene expression patterns and splicing to human diseases. It is thus apparent that including regulatory genomic regions during the engineering of GEMMs is highly preferable for disease modeling, with the prerequisite of large-scale genome engineering ability. Existing genome engineering methods have limits on the size and efficiency of DNA delivery, hampering routine creation of highly informative GEMMs. Here, we describe mSwAP-In (mammalian Switching Antibiotic resistance markers Progressively for Integration), a method for efficient genome rewriting in mouse embryonic stem cells. We first demonstrated the use of mSwAP-In for iterative genome rewriting of up to 115 kb of the Trp53 locus, as well as for genomic humanization of up to 180 kb ACE2 locus in response to the COVID-19 pandemic. Second, we showed the hACE2 GEMM authentically recapitulated human ACE2 expression patterns and splicing, and importantly, presented milder symptoms without mortality when challenged with SARS-CoV-2 compared to the K18-ACE2 model, thus representing a more authentic model of infection.

genomics↗

bioRxiv2022

Dissection of a complex enhancer cluster at the Sox2 locus

Expression of Sox2 in mouse embryonic stem cells (mESCs) depends on a distal regulatory cluster of DNase I hypersensitive sites (DHSs), but their individual contributions and degree of independence remain a mystery. Here, we comprehensively analyze the regulatory architecture of Sox2 at its endogenous locus using Big-IN to scarlessly integrate DNA payloads ranging up to 143 kb. We analyzed 83 payloads incorporating deletions, rearrangements, and inversions affecting single or multiple DHSs, as well as surgical alterations to transcription factor (TF) recognition sequences. Multiple mESC clones were derived for each payload, sequence-verified, and analyzed to establish the necessity and sufficiency of genomic features for Sox2 expression. We found that two LCR DHSs comprising a handful of key TF recognition sequences were each sufficient to autonomously sustain significant expression in mESCs. However, three additional LCR DHSs were entirely context-dependent, in that they showed no activity alone but could dramatically augment activity of the core DHSs. Our synthetic regulatory genomics approach demonstrates that composite regulatory elements can be reduced to a tractable set of essential sequence features, and is readily scalable to investigate regulatory architecture at other key loci genome-wide.

genomics↗

bioRxiv2022

A novel cuproptosis-related long non-coding RNAs model that effectively predicts prognosis in hepatocellular carcinoma

BackgroundCuproptosis has recently been considered a novel form of programmed cell death. To date, factors crucial to the regulation of this process remain unelucidated. Here, we aimed to identify long-chain non-coding RNAs (lncRNAs) associated with cuproptosis in order to predict the prognosis of patients with hepatocellular carcinoma (HCC). MethodsUsing RNA sequence data from The Cancer Genome Atlas Live Hepatocellular Carcinoma (TCGA-LIHC), a co-expression network of cuproptosis-related mRNAs and lncRNAs was constructed. For HCC prognosis, we developed a cuproptosis-related lncRNA signature (CupRLSig) using univariate Cox, lasso, and multivariate Cox regression analyses. Kaplan-Meier analysis was used to compare overall survival among high- and low-risk groups stratified by median CupRLSig score. Furthermore, comparisons of functional annotation, immune infiltration, somatic mutation, TMB (tumor mutation burden), and pharmacologic options were made between high- and low-risk groups. ResultsOur prognostic risk model was constructed using the cuproptosis-related PICSAR, FOXD2-AS1, and AP001065.1 lncRNAs. The CupRLSig high-risk group was associated with poor overall survival (hazard ratio = 1.162, 95% CI = 1.063- 1.270; p < 0.001). Model accuracy was further supported by receiver operating characteristic and principal component analysis as well as internal validation cohorts. A prognostic nomogram developed considering CupRLSig data and a number of clinical characteristics were found to exhibit adequate performance in survival risk stratification. Mutation analysis revealed that high-risk combinations with high TMB carried worse prognoses. Finally, differences in immune checkpoint expression and responses to chemotherapy as well as in targeted therapy among CupRLSig stratified high- and low-risk groups were explored. ConclusionsThe lncRNA signature constructed in this study is valuable in prognostic estimation in the setting of HCC.

bioinformatics↗

bioRxiv2022

Visual Perception of 3D Space and Shape in Time - Part III: 2D Shape Recognition by Log-Scaling

Human vision has a remarkable ability to recognize complex 3D objects such as faces that appear with any size and 3D orientations at any 3D location. If we initially memorize a face only with a normalized size and viewed from directly head on, the direct comparison between the one-sized memory and a new incoming image would demand tremendous mental frame translations in 7D. How can we perform such a demanding task so promptly and reliably as we experience the objects in the world around us? Intriguingly, our primary visual cortex exhibits a 2D retinotopy with a log-polar coordinate system, where scaling up/down of shape is converted to linear frame translation. As a result, mental scaling can be performed by linearly translating the memory or the perceptual image until they overlap with each other. According to our new model of NHT (Neural Holography Tomography), alpha brainwaves traveling at a constant speed can conduct this linear translation. With this scheme, every scaling up/down by a factor of two should take the same amount of extra mental time to recognize a smaller/larger face. To test this hypothesis, we designed a reaction time (RT) experiment, where participants were first asked to memorize sets of unfamiliar faces with a given specific size (4{degrees} or 8{degrees}). Following the memorization phase, similar stimuli with a wide range of sizes (from 1{degrees} to 32{degrees}) were presented, and RTs were recorded. As predicted, the increase in RT was proportional to the scaling factor in the log scale. Furthermore, we observed that RTs were fastest for 8{degrees} faces even if the memorized face was 4{degrees}. This supports our hypothesis that we always memorize faces at the exact size of ~8 {degrees}. To our surprise, the increases in RT were also consistent with the mentally-estimated depth sensation, which indicates that the apparent size of the recognized face can create a proper depth sensation.

neuroscience↗

bioRxiv2021

The genetic basis of tail-loss evolution in humans and apes

The loss of the tail is one of the main anatomical evolutionary changes to have occurred along the lineage leading to humans and to the "anthropomorphous apes"1,2. This morphological reprogramming in the ancestral hominoids has been long considered to have accommodated a characteristic style of locomotion and contributed to the evolution of bipedalism in humans3-5. Yet, the precise genetic mechanism that facilitated tail-loss evolution in hominoids remains unknown. Primate genome sequencing projects have made possible the identification of causal links between genotypic and phenotypic changes6-8, and enable the search for hominoid-specific genetic elements controlling tail development9. Here, we present evidence that tail-loss evolution was mediated by the insertion of an individual Alu element into the genome of the hominoid ancestor. We demonstrate that this Alu element - inserted into an intron of the TBXT gene (also called T or Brachyury10-12) - pairs with a neighboring ancestral Alu element encoded in the reverse genomic orientation and leads to a hominoid-specific alternative splicing event. To study the effect of this splicing event, we generated a mouse model that mimics the expression of human TBXT products by expressing both full-length and exon-skipped isoforms of the mouse TBXT ortholog. We found that mice with this genotype exhibit the complete absence of a tail or a shortened tail, supporting the notion that the exon-skipped transcript is sufficient to induce a tail-loss phenotype, albeit with incomplete penetrance. We further noted that mice homozygous for the exon-skipped isoforms exhibited embryonic spinal cord malformations, resembling a neural tube defect condition, which affects [~]1/1000 human neonates13. We propose that selection for the loss of the tail along the hominoid lineage was associated with an adaptive cost of potential neural tube defects and that this ancient evolutionary trade-off may thus continue to affect human health today.

evolutionary biology↗