Biology subjects

Villegas, V.

Publications and source records attributed to Villegas, V..

6 recordsLinked to original sources

bioRxiv2021

Disentangling signatures of selection before and after European colonization in Latin Americans

Throughout human evolutionary history, large-scale migrations have led to intermixing (i.e., admixture) between previously separated human groups. While classical and recent work have shown that studying admixture can yield novel historical insights, the extent to which this process contributed to adaptation remains underexplored. Here, we introduce a novel statistical model, specific to admixed populations, that identifies loci under selection while determining whether the selection likely occurred post-admixture or prior to admixture in one of the ancestral source populations. Through extensive simulations we show that this method is able to detect selection, even in recently formed admixed populations, and to accurately differentiate between selection occurring in the ancestral or admixed population. We apply this method to genome-wide SNP data of ~4,000 individuals in five admixed Latin American cohorts from Brazil, Chile, Colombia, Mexico and Peru. Our approach replicates previous reports of selection in the HLA region that are consistent with selection post-admixture. We also report novel signals of selection in genomic regions spanning 47 genes, reinforcing many of these signals with an alternative, commonly-used local-ancestry-inference approach. These signals include several genes involved in immunity, which may reflect responses to endemic pathogens of the Americas and to the challenge of infectious disease brought by European contact. In addition, some of the strongest signals inferred to be under selection in the Native American ancestral groups of modern Latin Americans overlap with genes implicated in energy metabolism phenotypes, plausibly reflecting adaptations to novel dietary sources available in the Americas.

genomics↗

bioRxiv2020

Prediction Of Eye, Hair And Skin Color In Admixed Populations Of Latin America

We report an evaluation of prediction accuracy for eye, hair and skin pigmentation based on genomic and phenotypic data for over 6,500 admixed Latin Americans (the CANDELA dataset). We examined the impact on prediction accuracy of three main factors: (i) The methods of prediction, including classical statistical methods and machine learning approaches, (ii) The inclusion of non-genetic predictors, continental genetic ancestry and pigmentation SNPs in the prediction models, and (iii) Compared two sets of pigmentation SNPs: the commonly-used HIrisPlex-S set (developed in Europeans) and novel SNP sets we defined here based on genome-wide association results in the CANDELA sample. We find that Random Forest or regression are globally the best performing methods. Although continental genetic ancestry has substantial power for prediction of pigmentation in Latin Americans, the inclusion of pigmentation SNPs increases prediction accuracy considerably, particularly for skin color. For hair and eye color, HIrisPlex-S has a similar performance to the CANDELA-specific prediction SNP sets. However, for skin pigmentation the performance of HIrisPlex-S is markedly lower than the SNP set defined here, including predictions in an independent dataset of Native American data. These results reflect the relatively high variation in hair and eye color among Europeans for whom HIrisPlex-S was developed, whereas their variation in skin pigmentation is comparatively lower. Furthermore, we show that the dataset used in the training of prediction models strongly impacts on the portability of these models across Europeans and Native Americans.

genetics↗

bioRxiv2019

Small molecule inhibitors of G9a reactivate the maternal PWS genes in Prader-Willi-Syndrome patient derived neural stem cells and differentiated neurons

Abstract/SummaryPatients with Prader-Willi-Syndrome (PWS) display intellectual impairment, hyperphagia, and various behavioral problems during childhood that converge on a neurologic deficit. The majority of PWS patients have genetic deletions of the paternal 15q11-q13 chromosomal region, with their maternal PWS locus intact but epigenetically silenced by hypermethylation and repressive histone modulation of the PWS imprinting center (PWS-IC). Inhibition of the euchromatin histone methyltransferase G9a by small molecules has been recently reported to reactivate PWS genes in patient fibroblasts and a mouse model. However, it is unknown if inhibition of G9a could have similar effect in human PWS neural cells, the cell types that have direct pathophysiological relevance to PWS. Here, we use neural progenitor cells (NPCs) and cortical excitatory neurons derived from a patient iPSC to model PWS, and quantitatively profile the expression of PWS genes using a NanoString panel. We demonstrated that the methylation of the PWS-IC is stable during neuronal lineage conversion, and that the maternal PWS genes remain silenced in PWS NPCs and neurons. Multiple small molecule inhibitors of G9a activate maternal PWS genes in a dose dependent manner in both NPCs and neurons. In addition, G9a inhibitors induce GNRH1 and HTR2C, two neuronal specific genes that contribute to PWS pathology in neurons. Interestingly, distinct from 5-Azacytidine, G9a inhibition does not induce methylation changes of the maternal PWS-IC, indicating that disruption of the histone repressive complex alone is sufficient to drive an open chromatin state at the PWS-IC that leads to partial reactivation of PWS genes. HighlightsO_LIModeling PWS disease in a dish using patient derived NPCs and neurons C_LIO_LIG9a inhibition activates maternal PWS genes in patient-derived neural cells C_LIO_LIG9a inhibition activates maternal SNORD116 and other PWS genes in patient-derived neurons C_LIO_LIInhibition of G9a induces PWS downstream genes GNRH1 and HTR2C in PWS neurons C_LI

cell biology↗

bioRxiv2019

Partial FMRP expression is sufficient to normalize neuronal hyperactivity in Fragile X neurons

Fragile X Syndrome (FXS) is the most common genetic form of intellectual disability caused by a CGG repeat expansion in the 5-UTR of the Fragile X mental retardation gene FMR1, triggering epigenetic silencing and the subsequent absence of the protein, FMRP. Reactivation of FMR1 represents an attractive therapeutic strategy targeting the genetic root cause of FXS. However, largely missing in the FXS field is an understanding of how much FMR1 reactivation is required to rescue FMRP-dependent mutant phenotypes. Here, we utilize FXS patient derived excitatory neurons to model FXS in vitro and confirm that the absence of FMRP leads to neuronal hyperactivity. We further determined the levels of FMRP and the percentage of FMRP positive cells necessary to correct this phenotype utilizing a mixed and mosaic neuronal culture system and a combination of CRISPR, antisense and expression technologies to titrate FMRP in FXS and WT neurons. Our data demonstrate that restoration of greater than 5% of overall FMRP expression levels or greater than 20% FMRP expressing neurons in a mosaic pattern is sufficient to normalize a FMRP-dependent, hyperactive phenotype in FXS iPSC-derived neurons.\n\nHighlightsO_LICRISPR gene editing to generate FMRP KO and CGG-deleted isogenic iPSCs\nC_LIO_LIMEA as an approach to identify FMR1 dependent phenotype in NGN2 neurons derived from FXS and FMRP KO iPSCs\nC_LIO_LICell mixing paradigm as mosaicism in a dish to rescue phenotype\nC_LIO_LIMinimal level of FMRP determined by FMR1 mRNA and targeted demethylation of CGG repeats to correct the hyperactive phenotype in FXS neurons\nC_LIO_LIASO titration-validated partial expression of FMRP is sufficient to normalize increased neuronal activity\nC_LI

neuroscience↗

bioRxiv2018

Latin Americans show wide-spread Converso ancestry and the imprint of local Native ancestry on physical appearance

Historical records and genetic analyses indicate that Latin Americans trace their ancestry mainly to the admixture of Native Americans, Europeans and Sub-Saharan Africans1. Using novel haplotype-based methods here we infer the sub-populations involved in admixture for over 6,500 Latin Americans and evaluate the impact of sub-continental ancestry on the physical appearance of these individuals. We find that pre-Columbian Native genetic structure is mirrored in Latin Americans and that sources of non-Native ancestry, and admixture timings, match documented migratory flows. We also detect South/East Mediterranean ancestry across Latin America, probably stemming from the clandestine colonial migration of Christian converts of non-European origin (Conversos). Furthermore, we find that Central Andean ancestry impacts on variation of facial features in Latin Americans, particularly nose morphology, possibly relating to environmental adaptation during the evolution of Native Americans.

genetics↗

bioRxiv2017

Mid-Infrared Spectroscopy Study of Effects of Neonicotinoids on Forager Honey Bee (Apis mellifera) Fat Bodies and Their Connection to Colony Collapse Disorder

This study investigated the negative effects of neonicotinoid pesticides on honey bees in environment surrounding areas of pesticide use. The aim of the experiment is to identify possible contributors to the sudden decrease in honey bee population over the past 60 years, a phenomenon known as Colony Collapse Disorder. Analysis was performed on three sets of bees: the control group which was not in contact with pesticides, the infected dead group which was a set of bees suspected to have died due to neonicotinoids, and the infected alive group which was suspected to be under the influence of neonicotinoids. After dissecting the bee samples and extracting their fat bodies, the chemical composition and protein structures of the samples were analyzed using Mid-Infrared Beamline at the Canadian Light Source. Results from the spectra of bee samples exposed to neonicotinoids demonstrated possible residual pesticide chemicals within fat bodies. Several spectral peaks were also correlated with a possible change in protein secondary structures from primarily {beta}-sheet to -helix within fat bodies of neonicotinoid-affected bees. It is likely that the pesticides caused the growth of additional -helical structures, which is consistent with consequences of the inhibition of nicotinic acetylcholine receptors (nAChRs) a current pathway of harm of Colony Collapse Disorder as identified in past literature.

pharmacology and toxicology↗