Biology subjects

Lao, O.

Publications and source records attributed to Lao, O..

10 recordsLinked to original sources

bioRxiv2026

Beyond single-trait analysis: ancient genomes reveal coordinated evolution of dietary endophenotypes in Holocene Europe

Diet has been a major selective force throughout human evolution, yet dietary adaptation is often studied through individual loci rather than as interconnected systems of traits. Here, we integrated genome-wide association data for 58 diet-related phenotypes with genomes from 938 ancient Europeans spanning the last 10,000 years to reconstruct the evolution of dietary endophenotypes. We identified four major systems encompassing adiposity and metabolism, body composition, fatty-acid metabolism and food-related behaviours. Multiple endophenotypes showed significant temporal shifts during the Holocene departing from the expected under neutrality, including coordinated decreases in genetic architectures associated with adiposity, insulin regulation and lipid metabolism, alongside increases in traits related to docosahexaenoic acid metabolism. Moreover, these patterns showed marked geographic heterogeneity across Europe. Our results indicate that dietary adaptation proceeded through coordinated evolutionary changes across interconnected physiological systems, providing a systems-level perspective on how cultural and subsistence transitions reshaped human biology.

evolutionary biology↗

bioRxiv2026

Denisovan introgression left differential selection regimes in Humans and Neanderthals on the SLC30A9 gene

Signals of positive selection around the SLC30A9 gene have been reported in human populations outside Africa. Selection likely acted on a highly differentiated single-nucleotide polymorphism, rs1047626, leading to a non-synonymous substitution in the encoded zinc transporter. Because of the striking similarity between the putatively selected SLC30A9 haplotype observed in several current human populations and the Denisovan individual, previous work has proposed adaptive introgression. Yet alternative explanations, including ancient human variation, and the precise archaic source -Neanderthal or Denisovan- remained unresolved. Considering the potentially complex evolution of SLC30A9, we applied Approximate Bayesian Computation (ABC) algorithms coupled to machine learning to investigate the most plausible evolutionary origin of this substitution. After modelling different evolutionary scenarios with forward-in-time simulations, our results highlight that the most probable scenario is a Denisovan origin of the rs1047626 polymorphism. However, the allele likely introgressed into Neanderthals first and was then passed into non-African modern humans. Moreover, the derived allele frequency for rs1047626 across several African populations is consistent with back-to-Africa migrations. Finally, our ABC analyses indicate strong positive selection in East Asian populations and other out-of-Africa populations, whereas in Neanderthal populations, the selection coefficient was probably neutral or slightly deleterious.

evolutionary biology↗

bioRxiv2025

Performance of Sequential Markovian Coalescence Methods when Populations are Structured

Sequentially Markovian Coalescent (SMC) methods are widely used to reconstruct demographic histories from genomic data, yet their accuracy in the presence of population structure has not been systematically evaluated. Here we assessed the performance of two popular SMC based algorithms (PSMC and SMC++) in retrieving the inverse instantaneous coalescent rate (IICR) simulated under two structured equilibrium scenarios, namely the finite island (FIM) and the two-dimensional stepping-stone (2D-SST). Looking backward in time, the IICR of a couple of lineages collected in a deme is characterized by a short period of constant value (the scattering phase) followed by an increase over time (the transition phase) up to a plateau (the collecting phase). Both algorithms recovered the IICR at the collecting phase but significantly deviated from the values expected during the transition phase under specific parameters combination. Specifically, the total error increased with the number of demes and the abruptness of the transition phase, which in turn is related to the extent of between demes connectivity. Moreover, each algorithm displayed a specific bias, corresponding backward in time to an artificial expansion either at the beginning of the collecting phase (PSMC) or of the transition phase (SMC++). Our results demonstrate that the observed systematic biases carry information about metapopulation dynamics, rather than being simple artefacts. Moreover, combining the results obtained from the two algorithms will increase our understanding of the historical demography of the metapopulations and help to put forward specific evolutionary scenarios to be tested with model-based algorithms using SFS or LD statistics.

evolutionary biology↗

bioRxiv2025

Variability vs Phenotype: multimodal analysis of Dravet Syndrome Brain Organoids powered by Deep Learning

Brain organoids (BO) have risen as a reliable model for neurodelopmental disorders (ND), reproducing human brain development milestones. However, their significant intra- and inter-organoid variability compromises their use in advanced tasks such as drug testing. Overcoming experimental variability is crucial for models prone to variation, like unguided BO. BO modelling in Dravet Syndrome, a late-onset epileptic ND, represents a great challenge since BO variability accumulates with time, when phenotype shows in vitro. Leveraging deep learning, we developed ImPheNet, a predictive tool grounded in BO live imaging datasets. ImPheNet accurately classified phenotypes and assessed drug toxicity in BO derived from DS, revealing differences between genotypes and upon antiseizure drug exposure. These results are supported by transcriptomic and functional data, revealing an excitatory-inhibitory imbalance during the maturation of DS organoids. Altogether, our DL-predictive live imaging strategy, ImPheNet, emerges as a powerful tool enhancing BO research and advancing ND treatments.

developmental biology↗

bioRxiv2023

Modelling the demographic history of human North African genomes points to a recent soft split divergence between populations

BackgroundNorth African human populations present a complex demographic scenario. The presence of an autochthonous genetic component and population substructure, plus extensive gene flow from the Middle East, Europe, and sub-Saharan Africa, have shaped the genetic composition of its people through time. ResultsWe conducted a comprehensive analysis of 364 genomes to construct detailed demographic models for the North African region, encompassing its two primary ethnic groups, the Arab and Amazigh populations. This was achieved through the utilization of the Approximate Bayesian Computation with Deep Learning (ABC-DL) framework and a novel algorithm called Genetic Programming for Population Genetics (GP4PG). This innovative approach enabled us to effectively model intricate demographic scenarios, utilizing a subset of 16 whole-genomes at >30X coverage. The demographic model suggested by GP4PG exhibited a closer alignment with the observed data compared to the ABC-DL model. Both methods point to a back-to-Africa origin of North African individuals and a close relationship of North African with Eurasian populations. Results support different origins for Amazigh and Arab populations, with Amazigh populations originating back in Epipaleolithic times, as early as 22.3 Kya. GP4PG model supports Arabization as the main source of Middle Eastern ancestry in North Africa. The GP4PG model better explaining the observed data includes population substructure in surrounding populations (sub-Saharan Africa and Middle East) with continuous gene flow after the split between populations (migration decay). In contrast to what we observed in the ABC-DL, the best GP4PG model does not require pulses of admixture from surrounding populations into North Africa pointing to soft splits as drivers of divergence in North Africa. ConclusionsWe have built a demographic model on North Africa that points to a back-to-Africa expansion and a differential origin between Arab and Amazigh populations, emphasizing the complex demographic history at a population level.

genomics↗

bioRxiv2022

Ghost admixture in eastern gorillas

Archaic admixture has had a significant impact on human evolution with multiple events across different clades, including from extinct hominins such as Neanderthals and Denisovans into modern humans. Within the great apes archaic admixture has been identified in chimpanzees and bonobos, but the possibility of such events has not been explored in other species. Here, we address this question using high-coverage whole genome sequences from all four extant gorilla subspecies, including six newly sequenced eastern gorillas from previously unsampled geographic regions. Using Approximate Bayesian Computation (ABC) with neural networks to model the demographic history of gorillas, we find a signature of admixture from an archaic ghost lineage into the common ancestor of eastern gorillas, but not western gorillas. We infer that up to 3% of the genome of these individuals is introgressed from an archaic lineage that diverged more than 3 million years ago from the common ancestor of all extant gorillas. This introgression event took place before the split of mountain and eastern lowland gorillas, likely more than 40 thousand years ago, and may have influenced perception of bitter taste in eastern gorillas. When comparing the introgression landscapes of gorillas, humans and bonobos, we find a consistent depletion of introgressed fragments on the X chromosome across these species. However, depletion in protein-coding content is not detectable in eastern gorillas, possibly as a consequence of stronger genetic drift in this species.

evolutionary biology↗

bioRxiv2022

Sex-determining 3D regulatory hubs revealed by genome spatial auto-correlation analysis

Mammalian sex is determined by opposing networks of ovarian and testicular genes that are well characterized. However, its epigenetic regulation is still largely unknown, thus limiting our understanding of a fundamental process for species propagation. Here we explore the 3D chromatin landscape of sex determination in vivo, by profiling FACS-sorted embryonic mouse gonadal populations, prior and after sex determination, in both sexes. We integrate Hi-C with ChIP-seq experiments using METALoci, a novel genome spatial auto-correlation analysis that identifies 3D enhancer hubs across the genome. We uncover a prominent rewiring of chromatin interactions during sex determination, affecting the enhancer hubs of hundreds of genes that display temporal- and sex-specific expression. Moreover, the identification of the 3D enhancer hubs allows the reconstruction of regulatory networks, revealing key transcription factors involved in sex determination. By combining predictive approaches and validations in transgenic mice we identify a novel Fgf9 regulatory hub, deletion of which results in male-to-female sex reversal with the upregulation of ovarian-specific markers and the initiation of meiosis. Thus, spatial auto-correlation analysis is an effective strategy to identify regulatory networks associated to biological processes and to further characterize the functional role of the 3D genome.

developmental biology↗

bioRxiv2022

The power of geohistorical boundaries for modeling the genetic background of human populations: the case of the rural Catalan Pyrenees

The genetic variation of the European population at a macro-geographic scale follows genetic gradients which reflect main migration events. However, less is known about factors affecting mating choices at a micro-geographic scale. In this study we have analyzed 726,718 autosomal SNPs in 435 individuals from the Catalan Pyrenees covering around 200 km of a vast and abrupt region in the north of the Iberian Peninsula, for which we have information about the geographic origin of all grand-parents and parents. At a macro-geographic scale, our analyses recapitulate the genetic gradient observed in Spain. However, we also identified the presence of micro-population substructure among the sampled individuals. Such micro-population substructure does not correlate with geographic barriers such as the expected by the orography of the considered region, but by the bishoprics present in the covered geographic area. These results support that, on top of main human migrations, long ongoing socio-cultural factors have also shaped the genetic diversity observed at rural populations.

genetics↗

bioRxiv2022

Genotypic Sex Determination Systems could be Adaptations to Extreme Temperature Environments in Reptiles and to Endothermy in Mammals and Birds

In some vertebrates species, environmental temperatures (TSD) determine their sex determination. In others, it is controlled by genomic mechanisms (GSD). One hypothesis suggests that GSD systems could have evolved in ectothermic TSD species to escape the geographical limitation imposed by environmental temperatures. Recently, it has been found that TSD reptiles species tend to breed at warmer temperatures than GSD species, especially in habitat with four months of warm temperatures. Here we obtain the pivotal temperature (the one that generates equal ratios of male and females) in 53 reptiles species (from four orders: sphenodontia, crocodilia, testudines and squamata) and compare it with the environmental temperature in the nest during the breeding season in 100 TSD reptiles species and 78 GSD reptiles species. Our results show that GSD species statistically breed in temperatures that would cause a sex bias if they had TSD systems, whereas species with TSD breed in a similar range of temepratrues to the pivotal ones. Additionally, we also found that the body temperature of more than 1,200 endothermic species statistically exceeds the pivotal temperature suggesting that GSD is necessary for endotherms to avoid sex bias that could lead to extinction. Finally, we observed that one of the 100 most invasive species worldwide, Trachemys scripta elegans, a turtle species with TSD, has never been able to establish in countries with less than four months of warm temperatures, confirming a restriction in the geographic range in TSD species caused by extreme temperatures. Altogether, these results suggest that GSD could have evolved as an adaptation to avoid the biased sex ratios that extreme temperature may cause in species with a TSD system.

evolutionary biology↗

bioRxiv2020

A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer

Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To-date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. Here, we complemented a classical new PC GWAS (1D) with spatial autocorrelation analysis (2D) and Hi-C maps (3D) to gain additional insight into the inherited basis of PC. In-silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. We replicated 17/40 previous PC-GWAS hits and identified novel variants with potential biological functions. The spatial autocorrelation approach prioritized low MAF variants not detected by GWAS. These were further expanded via 3D interactions to 54 target regions with high functional relevance. This multi-step strategy, combined with an in-depth in-silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.

genetics↗