Biology subjects

Moreno, C.

Publications and source records attributed to Moreno, C..

18 recordsLinked to original sources

bioRxiv2026

Direct detection of electrogenic polyamine transport

Polyamines are cationic metabolites that support critical cellular processes including transcription, translation, and cell proliferation. Although polyamine synthesis and transport are emerging therapeutic targets in human disease, the polyamine transport system remains poorly understood. ATP13A2-4 were recently identified as endolysosomal polyamine exporters, transporting putrescine (PUT), spermidine (SPD), and spermine (SPM) from the vesicular lumen to the cytosol. Despite interest in pharmacologically targeting these transporters, existing assays of transporter function rely on indirect or endpoint measures that cannot resolve transport as it occurs. Here, we report the first voltage-clamp recordings of polyamine transporter activity, directly detecting ATP13A2- and ATP13A3-mediated charge movement across cell membranes. When expressed in Xenopus oocytes, these transporters localized to the plasma membrane, enabling electrophysiological measurements. Polyamines induced inward currents dependent on transporter catalytic activity, and their dose-dependence correlated with ATPase assays. ATP13A2 currents were largest in response to SPM, whereas ATP13A3 currents were largest with PUT, consistent with their established substrate preferences. Polyamine-induced currents were blocked by the polyamine transport inhibitor AMXT-1501. These findings establish ATP13A2 and ATP13A3 as electrogenic polyamine pumps and demonstrate the utility of two-electrode voltage clamp as a label-free, transporter-resolved assay to complement other approaches in polyamine transporter-targeted drug discovery.

biophysics↗

bioRxiv2026

Proteolytic control of the SARS-CoV-2 furin cleavage site defines the phenotypic evolution from the pandemic to endemic state

The successive emergence of SARS-CoV-2 variants with altered tissue tropism has progressively decoupled transmissibility from lower respiratory tract pathogenicity. Omicron lineages transmit exceptionally well whilst limiting severe lung disease. Here, we demonstrate that this phenotype has evolved through two temporally distinct tissue-specific proteolytic controls at the Spike (S) furin cleavage site (FCS). At the virion level, cell-type-dependent furin-mediated FCS hyper-cleavage depletes S in lung but not nasal epithelial cells. At the infected cell membrane during cell-cell spread, TMPRSS2 mediates S FCS cleavage but is negatively regulated in the presence of ACE2. Tissue-specific solute carriers SLC6A19 and SLC6A20 sequester ACE2, thereby relieving inhibition of TMPRSS2 and enabling S FCS cleavage during cell-cell spread. Critically, whilst all SARS-CoV-2 lineages benefit from this latter pathway, Omicron variants have evolved exclusive dependence on it, a strategic consolidation that focuses S proteolytic activation to TMPRSS2 alone. The combined outcomes of S protein regulation across viral and cell membranes reveal how tissue-specific proteolytic optimisation drives Omicron's transmission fitness advantage in the upper respiratory tract but at the cost of heavy attenuation in the lower respiratory tract.

microbiology↗

bioRxiv2026

Visual deprivation in adulthood engages presynaptic plasticity of thalamocortical synapses

Synaptic plasticity between neurons in first order thalamus and layer 4 cortex is greatest during an early postnatal critical period and was thought to decrease irreversibly with age. However, here we show that robust and reversible plasticity can be induced in adult mice at synapses between dLGN axons and visual cortex layer 4 neurons by prolonged dark exposure (DE) and light reintroduction (LRx). Unexpectedly, the experience-dependent change in synaptic strength was mediated by a change in presynaptic structure, organization and function. DE/LRx declusters/clusters synaptic vesicles and reorganizes presynaptic molecular geometry. Furthermore, DE/LRx decreases/increases visually-evoked and spontaneous calcium signaling and neurotransmitter release probability in dLGN axonal boutons. The presynaptic plasticity mechanism described here has a high threshold for engagement which would allow maintenance of synapse stability across a wide activity range, and reactivation of thalamocortical plasticity in extraordinary conditions.

neuroscience↗

bioRxiv2026

Enkephalin constrains fear learning via volume transmission to the lateral amygdala

Fear learning involves the formation of associations between cues and aversive outcomes, a process that must be tightly regulated to prevent excessive or generalised fear. Dopamine release in the lateral amygdala (LA) drives fear acquisition, whereas endogenous opioids constrain it. However, whether opioids are dynamically released within the amygdala circuits during learning, and how they exert this control remain unclear. Here we show that met-enkephalin is locally released within the amygdala during auditory fear conditioning, with signals shifting from the aversive outcome to its predictive cue as learning progresses. The amygdalo-striatal transition zone (ASt), is the principal source of this enkephalin, released from medium spiny neurons receiving strong auditory thalamic input. This enkephalin spreads from the ASt to the LA via volume transmission. Selective knockdown in the ASt abolished opioid signals and enhanced fear learning, demonstrating that this diffuse signal constrains fear memory formation. We further show that enkephalin suppresses dopamine release in both the ASt and LA via {micro}-opioid receptors, identifying the ASt as a neuromodulator hub coordinating opioid and dopaminergic signalling across amygdala fear circuits. Although demonstrated here for auditory fear learning, the ASt receives multimodal sensory input, suggesting a broader mechanism through which sensory experience recruits enkephalin release to gate associative learning

neuroscience↗

bioRxiv2026

A decrease in specific health-associated commensals is linked to progressive periodontal tissue destruction independent of dysbiotic community profiles

Periodontitis is a chronic inflammatory disease associated with dysbiotic microbial communities that leads to destruction of the tooth-supporting tissues. The transition from host-microbial periodontal homeostasis to disease remains poorly understood. The murine ligature-induced periodontitis model was employed to characterize the temporal dynamics of the subgingival microbiome and host tissue features. Ligatures were placed in C57BL/6N mice, and collected on days 0, 1, 3, 5, and 7 post-induction. Bacterial load, alveolar bone loss, immune cells (CD45), cells with osteoclastogenic potential (TRAP) and collagen destruction were analyzed. Additionally, the V4 region of the 16S rRNA gene was sequenced for ecological analyses, including co-occurrence networks and functional prediction. Spatial distribution of the most abundant species was visualized using CLASI-FISH microscopy. Finally, association models were performed to link bacterial abundances with time and tissue parameters. The most substantial microbial shift occurred on day 1, and a dysbiotic community was established by day 3. CD45 cell infiltration increased as early as day 1, preceding the rise in TRAP cells on day 3 and the onset of tissue destruction on day 5. By day 7, predicted bacterial functions included protein export, lipid and galactose metabolism. Health-associated taxa were identified, and their abundance correlated positively with collagen integrity and negatively with immune cell infiltration and bacterial load, highlighting their role in homeostasis. These findings provide a high-resolution temporal map of microbiome-host interactions during experimental periodontitis establishment and identify specific microbial and cellular windows for potential therapeutic intervention.

microbiology↗

bioRxiv2026

Enhanced Ba2+-sensitive inward rectifying potassium conductance reduces intrinsic excitability of layer 2/3 pyramidal neurons in the primary auditory cortex of Fmr1 knockout mice

Fragile X syndrome (FXS) is frequently associated with auditory hypersensitivity and altered cortical processing, yet the intrinsic ionic mechanisms shaping auditory cortex excitability remain incompletely defined. Here, we tested whether subthreshold conductances contribute to compensatory changes in intrinsic excitability in layer 2/3 (L2/3) pyramidal neurons of the primary auditory cortex (AC) in Fmr1 knockout (Fmr1-KO) mice. We performed wholecell patchclamp recordings in acute slices from juvenile mice (P28-P42) and quantified passive properties, firing output, synaptic potentials, and subthreshold currents under pharmacological isolation. Compared with wild type (WT), Fmr1-KO L2/3 neurons displayed a more hyperpolarized resting membrane potential, reduced input resistance, elevated rheobase, prolonged firstspike latency, and reduced firing across depolarizing steps, consistent with a hypoexcitable state. Bath application of BaCl2 (60 M) depolarized the membrane, increased input resistance, and restored firing output and rheobase toward WT levels, indicating that a Ba2+-sensitive potassium conductance strongly constrains excitability in Fmr1-KO neurons. Voltageclamp recordings revealed a larger Ba2+-sensitive inwardly rectifying (Kir-like) current in Fmr1-KO neurons, supporting increased functional Ba2+-sensitive inwardly rectifying conductance. In contrast, blocking Ih with ZD7288 (10 M) produced modest changes in passive properties but induced genotype dependent effects on excitability and enhanced synaptic activity and EPSP summation preferentially in Fmr1-KO neurons, consistent with a role for Ih in input filtering rather than setting basal conductance. Together, these findings identify enhanced Ba2+-sensitive potassium conductance as a primary determinant of the Fmr1-KO subthreshold conductance state in AC L2/3 pyramidal neurons, suggesting an intrinsic homeostatic mechanism that stabilizes output in the presence of elevated excitatory drive.

neuroscience↗

bioRxiv2026

Subthreshold Kir and Ih currents modulate excitability of Layer 1 VIP interneurons in the medial prefrontal cortex

Cortical layer 1 (L1) is a key site for integrating top-down and bottom-up information and is populated by inhibitory interneurons, including vasoactive intestinal peptide (VIP)-expressing cells. These interneurons regulate information flow across the cortical column by disinhibiting pyramidal neurons, yet the subthreshold ionic mechanisms that shape their excitability in the medial prefrontal cortex (mPFC) remain poorly understood. Here, we characterize the electrophysiological properties of L1b VIP interneurons in mouse mPFC, focusing on the role of the hyperpolarization-activated cation current (Ih) and inward-rectifying potassium current (Kir). Using whole-cell recordings in acute slices, we find that L1b VIP interneurons exhibit constitutively active Ih and Kir conductances. Inhibition of Ih with ZD-7288 hyperpolarized the resting membrane potential (RMP), increased input resistance (Rin), and prolonged action potential (AP) duration without altering rheobase or firing frequency, while increasing EPSP-spike coupling probability. Blocking Kir with BaCl2 depolarized the RMP, increased Rin and membrane time constant, reduced rheobase, increased firing frequency, and similarly enhanced EPSP-spike probability and AP duration. Voltage-clamp experiments confirmed the presence of ZD-7288-sensitive Ih and BaCl2-sensitive Kir currents of small amplitude but operating on a high-resistance membrane, consistent with a strong impact on excitability. In contrast, neither Ih nor Kir inhibition affected the amplitude or frequency of spontaneous or miniature EPSCs, indicating that these currents do not measurably alter basal excitatory synaptic transmission. Immunofluorescence revealed weak somatic HCN1 and no detectable HCN2 expression in L1b VIP interneurons. Notably, Kir inhibition unmasked an Ih-dependent voltage sag during hyperpolarizing steps, suggesting that constitutive Kir activity normally masks Ih recruitment at subthreshold potentials. Together, these results indicate that Ih and Kir are active near RMP in L1b VIP interneurons and jointly regulate their passive properties, intrinsic excitability, and EPSP-spike coupling, therefore shaping how L1 VIP cells filter incoming signals and influence information flow within the prefrontal cortical column.

neuroscience↗

bioRxiv2024

Adult visual deprivation engages associative, presynaptic plasticity of thalamic input to cortex

Age constrains plasticity at inputs from first order thalamic nuclei to the cortex, endowing stability to ascending, feed-forward projections. However, here we show that prolonged visual deprivation can induce robust and reversible plasticity at thalamocortical synapses in layer 4 pyramidal neurons in the adult mouse primary visual cortex. The plasticity engaged by prolonged visual deprivation is non-homeostatic and mediated by changes in presynaptic function.

neuroscience↗

bioRxiv2024

Divergence and parallelism in two tropical drosophilids simultaneously invading a desert environment

Invasive species have once been called a grand experiment in evolution but natural replicates of such experiments are often scarce. In particular, whether the rapid adaptation to the new environment involves genetic predisposition in the ancestral range or mainly occurs via post-introductory selection on a genetically variable propagule remains unknown. Here, we investigate the parallel adaptation of two drosophilid species of the genus Zaprionus, Z. indianus (the African fig fly) and Z. tuberculatus, to contrasting agrarian and desert environments following their introduction in Egypt during the last four decades. Field collection unraveled distinct spatial distribution of the two species. Population genomics analyses showed correlated differentiation levels at orthologous genes before and after introduction in both species. Nonetheless, phenotypic analyses revealed distinct fruit preference and desiccation resistance between both species as well as between introduced and native Z. tuberculatus populations. Hence, despite signals of genomic parallelism, ecological divergence between the two species likely facilitates their co-existence in the introduced regions. Our results provide a significant step towards understanding the mechanisms underlying the simultaneous invasive success of both species, which have also recently invaded the Americas and Europe, and of which one at least is a notorious pest.

evolutionary biology↗

bioRxiv2024

Duodenal organoids from metabolic dysfunction-associated steatohepatitis patients exhibit altered digestive homeostasis

Background and AimsMetabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Though MASH is closely tied to metabolic risk factors, the underlying pathogenic mechanisms remain scarcely understood. Recent research underscores the importance of the gut-liver axis in its pathogenesis, an aspect less explored in human studies. Here, we investigated whether the duodenal epithelium of MASH patients, could exhibit intrinsic dysfunctions. MethodsDuodenal epithelial organoids were generated from 16 MASH patients and 14 healthy controls. Biopsies and patient-derived organoid transcriptomes were then analyzed to evaluate if specific intestinal pathways were differentially modulated in MASH subjects. Functional assays were performed to assess the duodenal epithelial digestive potential and barrier functionality. ResultsOrganoid formation efficiency was similar between control-derived epithelial organoids (CDEOs) and MASH-derived epithelial organoids (MDEOs) (71% and 69%, respectively). Despite global heterogeneity in growth patterns, MDEOs frequently exhibited cystic spheroid morphology. MDEOs displayed altered digestive homeostasis associated with reduced mature absorptive cell fate, but they retained their lipid metabolic capacity, possibly mediated by lipid oxidation in stem/progenitor cells. Additionally, MDEOs misexpressed components of tight and adherens junctions and desmosomes compared to controls. However, MDEOs maintained pore and leak pathway integrity, indicating that the duodenal epithelial barrier remained functionally preserved under tested conditions. ConclusionsThis study provides evidence that the duodenal epithelium of MASH patients exhibits significant alterations in its digestive and barrier functions. This study sheds light on the intricate dynamics of duodenal epithelial alterations in MASH, highlighting potential therapeutic avenues for restoring intestinal homeostasis.

cell biology↗

bioRxiv2022

iPSC-Derived PSEN2 (N141I) Astrocytes and Microglia Exhibit a Primed Inflammatory Phenotype

BackgroundWidescale evidence points to the involvement of glia and immune pathways in the progression of Alzheimers disease (AD). AD-associated iPSC-derived glial cells show a diverse range of AD-related phenotypic states encompassing cytokine/chemokine release, phagocytosis and morphological profiles, but to date studies are limited to cells derived from PSEN1, APOE and APP mutations or sporadic patients. The aim of the current study was to successfully differentiate iPSC-derived microglia and astrocytes from patients harbouring an AD-causative PSEN2 (N141I) mutation and characterise the inflammatory and morphological profile of these cells. MethodsiPSCs from three healthy control individuals and three familial AD patients harbouring a heterozygous PSEN2 (N141I) mutation were used to derive astrocytes and microglia-like cells and cell identity and morphology were characterised through immunofluorescent microscopy. Cellular characterisation involved the stimulation of these cells by LPS and A{beta}42 and analysis of cytokine/chemokine release was conducted through ELISAs and multi-cytokine arrays. The phagocytic capacity of these cells was then indexed by the uptake of fluorescently labelled fibrillar A{beta}42. ResultsAD-derived astrocytes and microglia-like cells exhibited an atrophied and less complex morphological appearance than healthy controls. AD-derived astrocytes showed increased basal expression of GFAP, S100{beta} and increased secretion and phagocytosis of A{beta}42 while AD-derived microglia-like cells showed decreased IL-8 secretion compared to healthy controls. Upon immunological challenge AD-derived astrocytes and microglia-like cells show exaggerated secretion of the pro-inflammatory IL-6, CXCL1, ICAM-1 and IL-8 from astrocytes and IL-18 and MIF from microglia. ConclusionOur study showed, for the first time, the differentiation and characterisation of iPSC-derived astrocytes and microglia-like cells harbouring a PSEN2 (N141I) mutation. PSEN2 (N141I)-mutant astrocytes and microglia-like cells presented with a primed phenotype characterised by reduced morphological complexity, exaggerated pro-inflammatory cytokine secretion and altered A{beta}42 production and phagocytosis.

neuroscience↗

bioRxiv2022

Nuanced role for dendritic cell intrinsic IRE1 RNase in the regulation of antitumor adaptive immunity.

The IRE1/XBPls axis of the unfolded protein response (UPR) plays divergent roles in dendritic cell (DC) biology in steady state versus tumor contexts. Whereas tumor associated DCs show dysfunctional IRE1/XBP1s activation that curtails their function, the homeostasis of conventional type 1 DCs (cDC1) in tissues requires intact IRE1 RNase activity. Considering that cDC1s are key orchestrators of antitumor immunity, it is relevant to understand the functional versus dysfunctional roles of IRE1/XBP1s in tumor DC subtypes. Here, we show that cDC1s constitutively activate IRE1 RNase within subcutaneous B16 melanoma and MC38 adenocarcinoma tumor models. Mice lacking XBP1s in DCs display increased melanoma tumor growth, reduced T cell effector responses and accumulation of terminal exhausted CD8+ T cells. Transcriptomic studies revealed that XBP1 deficiency in tumor cDCls decreased expression of mRNAs encoding XBPls and regulated IRE1 dependent decay (RIDD) targets. Finally, we find that the dysregulated melanoma growth and impaired T cell immunity noticed in XBP1 deficient mice are attributed to RIDD induction in DCs. This work indicates that IREl RNase activity in melanoma/MC38-associated DCs fine tunes aspects of antitumor immunity independently of XBP1s, revealing a differential role for the UPR axis that depends on the DC subtype and cancer model.

immunology↗

bioRxiv2020

Characterization of cell-cell communication in COVID-19 patients

COVID-19 patients display a wide range of disease severity, ranging from asymptomatic to critical symptoms with high mortality risk. Our ability to understand the interaction of SARS-CoV-2 infected cells within the lung, and of protective or dysfunctional immune responses to the virus, is critical to effectively treat these patients. Currently, our understanding of cell-cell interactions across different disease states, and how such interactions may drive pathogenic outcomes, is incomplete. Here, we developed a generalizable workflow for identifying cells that are differentially interacting across COVID-19 patients with distinct disease outcomes and use it to examine five public single-cell RNA-seq datasets with a total of 85 individual samples. By characterizing the cell-cell interaction patterns across epithelial and immune cells in lung tissues for patients with varying disease severity, we illustrate diverse communication patterns across individuals, and discover heterogeneous communication patterns among moderate and severe patients. We further illustrate patterns derived from cell-cell interactions are potential signatures for discriminating between moderate and severe patients.

systems biology↗

bioRxiv2020

Sodium Diethyldithiocarbamate antiparasitic activity against different Trypanosoma cruzi strains: Insights of its biological activity

BackgroundChagas disease is caused by the protozoan Trypanosoma cruzi, a neglected tropical disease that affects thousands of people, mainly in Latin America. The drugs currently used in therapy are toxic and have therapeutic limitations during treatment. In addition, the genetic diversity of T. cruzi represents an important variable and challenge with regard to the pathogenesis of the infection, the epidemiological profile of the cases, and the therapeutic control of the infection. Sodium diethyldithiocarbamate (DETC) is a compound of high pharmacological versatility acting as metal chelators and producing reactive oxygen species. Thus, the objective of this work is to characterize the antiparasitic action of DETC against different strains and evolutionary forms of T. cruzi, as well as the characterization of the mechanism of antiparasitic action. Methodology/Principal findingsThe different strains and evolutionary forms of T. cruzi were grown in LIT medium. To evaluate the antiparasitic activity of DETC, the evolutionary forms epimastigote and trypomastigote of T. cruzi were used by resazurin reduction methods and by counting under optical microscopy. Different response patterns were obtained between the strains and an IC50 of DETC ranging from 9.44 {+/-} 3,181{micro}M to 60.49 {+/-} 7.62 {micro}M. Cell cytotoxicity against cell lines 3T3 and RAW and evaluated by MTT, demonstrated that DETC in high concentration (2222 {micro}M) reduces around 60% the cell capacity of MTT reduction. The antiparasitic activity of DETC has been demonstrated through damage caused in the mitochondria of T. cruzi, a reduction of up to 80% in the mitochondrial potential of the parasites, as well as through damage caused in the membrane of the parasite. ConclusionIn this study we can conclude that DETC has antiparasitic activity against different genotypes and evolutionary forms of T. cruzi, representing a promising molecule as a drug for the treatment of Chagas disease.

pharmacology and toxicology↗

bioRxiv2020

Episignatures stratifying ADNP syndrome show modest correlation with phenotype

ADNP syndrome, also known as Helsmoortel-van Der Aa syndrome, is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. ADNP syndrome is caused by mutations in the activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with ADNP syndrome, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with ADNP syndrome into two groups, based on the location of the mutations. Here, we conducted an independent study on 24 individuals with ADNP syndrome and replicated the existence of the two, mutation-dependent ADNP episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of ADNP syndrome. We found limited phenotypic differences between the two ADNP groups, and no evidence that individuals with more widespread methylation changes are more severely affected. Also, in spite of the methylation changes, we observed no profound alterations in the blood transcriptome of individuals with ADNP syndrome. Our data warrant caution in harnessing methylation signatures in ADNP syndrome as a tool for clinical stratification, at least with regards to behavioral phenotypes.

developmental biology↗

bioRxiv2019

A toolbox of nanobodies developed and validated for diverse neuroscience research applications

Nanobodies (nAbs) are small, minimal antibodies that have distinct attributes that make them uniquely suited for certain biomedical research, diagnostic and therapeutic applications. Prominent uses include as intracellular antibodies or intrabodies to bind and deliver cargo to specific proteins and/or subcellular sites within cells, and as nanoscale immunolabels for enhanced tissue penetration and improved spatial imaging resolution. Here, we report the generation and validation of nAbs against a set of proteins prominently expressed at specific subcellular sites in brain neurons. We describe a novel hierarchical validation pipeline to systematically evaluate nAbs isolated by phage display for effective and specific use as intrabodies and immunolabels in mammalian cells including brain neurons. These nAbs form part of a robust toolbox for targeting proteins with distinct and highly spatially-restricted subcellular localization in mammalian brain neurons, allowing for visualization and/or modulation of structure and function at those sites.

neuroscience↗

bioRxiv2017

The Relationship Between Cancer Progression And Social Environment In Drosophila

The influence of oncogenic phenomena on the ecology and evolution of animal species is fast becoming an important research topic. Similar to host-pathogen interactions, cancer negatively affects host fitness, which should lead to the selection of host control mechanisms, including behavioral traits that best minimize the proliferation of malignant cells. Social behavior is one such trait, which is suggested to influence cancer progression. While the ecological benefits of sociality in gregarious species are widely acknowledged, only limited data are available on the role of the social environment on cancer progression. Here, we exposed adult Drosophila, with colorectal-like tumors, to different social environments. First, we show that cancerous flies kept in complete isolation exhibit increased tumor progression. Yet, more surprisingly, we find that cancerous flies, kept in groups with other noncancerous individuals, also develop tumors at a faster rate compared to those kept with other cancerous conspecifics, suggesting a strong impact of social group composition on cancer growth. Finally, we show that flies can discriminate between individuals at different stages of tumor growth and selectively choose their social environment accordingly. Control flies actively avoid flies with cancer but only at the later stages of tumor development, whereas cancerous flies display strong social interactions with cancerous flies in the early stages of tumor growth. Our study demonstrates the reciprocal links between cancer and social interactions, as well as highlighting how sociality impacts health and fitness in animals and its potential implications for disease ecology and ecosystem dynamics.

animal behavior and cognition↗

bioRxiv2017

Insights into the genetic determinism andevolution of recombination rates fromcombining multiple genome-wide datasets inSheep

Recombination is a complex biological process that results from a cascade of multiple events during meiosis. Understanding the genetic determinism of recombination can help to understand if and how these events are interacting. To tackle this question, we studied the patterns of recombination in sheep, using multiple approaches and datasets. We constructed male recombination maps in a dairy breed from the south of France (the Lacaune breed) at a fine scale by combining meiotic recombination rates from a large pedigree genotyped with a 50K SNP array and historical recombination rates from a sample of unrelated individuals genotyped with a 600K SNP array. This analysis revealed recombination patterns in sheep similar to other mammals but also genome regions that have likely been affected by directional and diversifying selection. We estimated the average recombination rate of Lacaune sheep at 1.5 cM/Mb, identified about 50,000 crossover hotspots on the genome and found a high correlation between historical and meiotic recombination rate estimates. A genome-wide association study revealed two major loci affecting inter-individual variation in recombination rate in Lacaune, including the RNF212 and HEI10 genes and possibly 2 other loci of smaller effects including the KCNJ15 and FSHR genes. Finally, we compared our results to those obtained previously in a distantly related population of domestic sheep, the Soay. This comparison revealed that Soay and Lacaune males have a very similar distribution of recombination along the genome and that the two datasets can be combined to create more precise male meiotic recombination maps in sheep. Despite their similar recombination maps, we show that Soay and Lacaune males exhibit different heritabilities and QTL effects for inter-individual variation in genome-wide recombination rates.

genetics↗