Biology subjects

Humbert, C.

Publications and source records attributed to Humbert, C..

4 recordsLinked to original sources

bioRxiv2026

Rethinking human AMY1 copy number evolution in light of demographic history

Dietary change is often invoked as a major selective force in recent human evolution, with increased copy number of the salivary amylase gene (AMY1) widely cited as an adaptation to starch-rich agricultural diets. However, most evidence for this model comes from limited geographical sampling and analyses that do not fully account for shared ancestry. Here we combine newly generated droplet digital PCR estimates from 390 individuals representing 30 Sub-Saharan African populations with published copy number data from up to 1,307 individuals worldwide and re-evaluate AMY1 evolution using ancestry-aware and phylogenetically informed models. Across Africa, AMY1 copy number shows no consistent association with agriculture once population structure is accounted for. At a global scale, differences between agriculturalists and non-agriculturalists are substantially smaller than previously reported and are largely explained by shared ancestry rather than diet. Phylogenetic analyses further reveal baseline differences in AMY1 copy number between Sub-Saharan and non-Sub-Saharan populations, pointing to deep demographic processes shaping present-day variation. These results challenge the long-standing "agriculture hypothesis" and identify demographic history, rather than subsistence strategy, as the primary driver of AMY1 CN evolution worldwide.

evolutionary biology↗

bioRxiv2025

Bi-allelic mutations in KCTD11 cause a new form of autosomal recessive intermediate Charcot-Marie-Tooth disease

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disorder, characterized by progressive, length-dependent degeneration of peripheral nerves, resulting in distal muscle atrophy and weakness, foot and hand deformities, and sensory deficits. The disease is clinically and genetically heterogeneous, with over 125 disease-causing genes identified to date. Here, genetic studies in ten patients from 5 unrelated families of diverse ethnic background, led to the identification of KCTD11 as a novel CMT gene, responsible for a new autosomal recessive intermediate CMT subtype, RI-CMTE. The variants identified are loss of function. KCTD11 encodes KCTD11/REN, a protein of yet unknown function in the Peripheral Nervous System, known to regulate HDAC1, {beta}-catenin, and mTORC1, key regulators of myelination and neuronal differentiation in the PNS. To explore KCTD11s role in the PNS, we used a constitutive Kctd11-/- mouse model and the derived in vitro myelin model of sensory neuron and Schwann cell co-culture (DRGN/SC), to mimic the loss-of-function induced by patient mutations. We first demonstrate that the loss of KCTD11 is due to enhanced degradation of the mutated protein via autophagy. Both in vitro and in vivo, we demonstrate abnormal myelination in vivo and altered myelination dynamics in vitro. These defects were associated with dysregulation of the expression of key transcription factors in Schwann cells, such as Egr2 and Sox10, along with other myelin-related genes, as revealed by mRNA-sequencing data. Regarding pathophysiological mechanisms, we identified dysregulation of HDAC1 expression, as well as alterations in the Wnt/{beta}-catenin, Sonic Hedgehog and Hippo/YAP signaling pathways. The deregulation of these pathways seem to converge to altered autophagy and altered balance between proliferation, differentiation and apoptosis, at least in Schwann cells. These mechanisms remain to be explored in axons from PNS neurons. Altogether, our results identify KCTD11 as a novel gene defective in autosomal recessive intermediate RI-CMTE and highlight the key role of KCTD11 in maintaining myelin homeostasis through regulation of HDAC1 and phosphorylated {beta}-catenin levels, thereby preventing late-onset myelin abnormalities and degradation.

genetics↗

bioRxiv2024

Multi-modal refinement of the human heart atlas during the first gestational trimester

1.Forty first-trimester human hearts were studied to lay groundwork for further studies of principles underlying congenital heart defects. We first sampled 49,227 cardiac nuclei from three fetuses at 8.6, 9.0, and 10.7 post-conceptional weeks (pcw) for single-nucleus RNA sequencing, enabling distinction of six classes comprising 21 cell types. Improved resolution led to identification of novel cardiomyocytes and minority autonomic and lymphatic endothelial transcriptomes, among others. After integration with 5-7 pcw heart single-cell RNAseq, we identified a human cardiomyofibroblast progenitor preceding diversification of cardiomyocyte and stromal lineages. Analysis of six Visium sections from two additional hearts was aided by deconvolution, and key spatial markers validated on sectioned and whole hearts in two- and three-dimensional space and over time. Altogether, anatomical-positional features including innervation, conduction and subdomains of the atrioventricular septum translate latent molecular identity into specialized cardiac functions. This atlas adds unprecedented spatial and temporal resolution to the characterization of human-specific aspects of early heart formation.

developmental biology↗

bioRxiv2024

Altered NRG1/ErbB4 signaling and cholesterol metabolism dysregulation are key pathomechanisms in VRK1-related motor neuropathies and motor neuron diseases

Hereditary Motor and Sensory Neuropathy (HMSN), or Charcot-Marie-Tooth disease (CMT), are the most common group of Inherited peripheral neuropathies (IPN), characterized by a strong clinical and genetic heterogeneity. Among them, distal Hereditary Motor Neuropathy (dHMN), also known as neuronopathy, is a subgroup, where only motor nerves are affected. This subgroup is also genetically heterogeneous, with 25 genes described to date, of which VRK1, that we have recently described as responsible for dHMN, associated to upper motor neuron signs. There are now more than thirty mutations in VRK1, which cause a range of neurological diseases affecting motor neurons (mainly lower, but also upper) or their axons in the peripheral nervous system, that we design as VRK1-related motor neuron diseases. In two previous studies, we have demonstrated that dHMN due to VRK1 mutations lead to reduced levels of VRK1 in the nucleus, and that this depletion alters the dynamics of coilin, a phosphorylation target of VRK1. hiPSC-derived Motor Neurons (hiPSC-MN) from these patients, display Cajal Bodies (CBs) disassembly and defects in neurite outgrowth and branching, altered Action Potential (AP) waveform and decreased Axonal Initial Segment (AIS) length. In this study, we have further studied the link between the loss of VRK1 function and the defects observed in hiPSC-MNs, by realizing bulk mRNA-Seq sequencing in this in vitro model of the disease. Our results evidenced altered NRG1/ERBB4 signaling, leading to cholesterol metabolism dysregulation and deregulation of genes encoding the glutamate receptors AMPAR and NMDAR, which role in the Axonal Initial Segment and abnormal AP initiation in hiPSC-MNs remains to be investigated.

genetics↗