Biology subjects

Carracedo, A.

Publications and source records attributed to Carracedo, A..

23 records · Page 2Linked to original sources

bioRxiv2019

Reshaping the Hexagone: the genetic landscape of modern France

Unlike other European countries, the human population genetics and demographic history of Metropolitan France is surprisingly understudied. In this work, we combined newly genotyped samples from various zones in France with publicly available data and applied both allele frequency and haplotype-based methods in order to describe the internal structure of this country, by using genome-wide single nucleotide polymorphism (SNP) array genotypes. We found out that French Basques are genetically distinct from all other populations in the Hexagone and that the populations from southwest France (namely the Gascony region) share a large proportion of their ancestry with Basques. Otherwise, the genetic makeup of the French population is relatively homogeneous and mostly related to Southern and Central European groups. However, a fine-grained, haplotype-based analysis revealed that Bretons slightly separated from the rest of the groups, due mostly to gene flow from the British Isles in a time frame that coincides both historically attested Celtic population movements to this area between the 3th and the 9th centuries CE, but also with a more ancient genetic continuity between Brittany and the British Isles related to the shared drift with hunter-gatherer populations. Haplotype-based methods also unveiled subtle internal structures and connections with the surrounding modern populations, particularly in the periphery of the Hexagone.

genetics↗

bioRxiv2018

Novel genes for autism implicate both excitatory and inhibitory cell lineages in risk

We present the largest exome sequencing study to date focused on rare variation in autism spectrum disorder (ASD) (n=35,584). Integrating de novo and case-control variation with an enhanced Bayesian framework incorporating evolutionary constraint against mutation, we implicate 99 genes in ASD risk at a false discovery rate (FDR) [≤] 0.1. Of these 99 risk genes, 46 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 50 show higher frequencies in individuals ascertained for ASD, and comparing ASD cases with disruptive mutations in the two groups shows differences in phenotypic presentation. Expressed early in brain development, most of the risk genes have roles in neuronal communication or regulation of gene expression, and 12 fall within recurrent copy number variant loci. In human cortex single-cell gene expression data, expression of the 99 risk genes is also enriched in both excitatory and inhibitory neuronal lineages, implying that disruption of these genes alters the development of both neuron types. Together, these insights broaden our understanding of the neurobiology of ASD.

genetics↗

bioRxiv2018

Integrative analysis of transcriptomic and clinical data uncovers the tumor suppressive activity of MITF in prostate cancer.

The dysregulation of gene expression is an enabling hallmark of cancer. Computational analysis of transcriptomics data from human cancer specimens, complemented with exhaustive clinical annotation, provides an opportunity to identify core regulators of the tumorigenic process. Here we exploit well-annotated clinical datasets of prostate cancer for the discovery of transcriptional regulators relevant to prostate cancer. Following this rationale, we identify Microphthalmia-associated transcription factor (MITF) as a prostate tumor suppressor among a subset of transcription factors. Importantly, we further interrogate transcriptomics and clinical data to refine MITF perturbation-based empirical assays and unveil Crystallin Alpha B (CRYAB) as an unprecedented direct target of the transcription factor that is, at least in part, responsible for its tumor suppressive activity in prostate cancer. This evidence was supported by the enhanced prognostic potential of a signature based on the concomitant alteration of MITF and CRYAB in prostate cancer patients. In sum, our study provides proof-of-concept evidence of the potential of the bioinformatics screen of publicly available cancer patient databases as discovery platforms, and demonstrates that the MITF-CRYAB axis controls prostate cancer biology.

cancer biology↗

bioRxiv2018

Genetic analysis of Sephardic ancestry in the Iberian Peninsula

The Sephardim are a major Jewish ethnic division whose origins can be traced back to the Iberian Peninsula. We used genome-wide SNP data to investigate the degree of Sephardic admixture in seven populations from the Iberian Peninsula and surrounding regions in the aftermath of their religious persecution starting in the late 14th century. To this end, we used Eastern Mediterranean (from South Italy, Greece and Israel) and North African (Tunisian and Moroccan) populations as proxies for the major ancestral components found in the target populations and carried out unlinked- and linked-marker analyses on the available genetic data. We report evidence of Sephardic ancestry in some of our Iberian samples, as well as in North Italy and Tunisia. We find the Sephardic admixture to be more recent relative to the Berber admixture following an out-of-Iberia geographic dispersal, suggesting Sephardic gene flow from Spain outwards. We also report some of the challenges in assigning Sephardic ancestry to potentially admixed individuals due to the lack of a clear genetic signature.

genomics↗

bioRxiv2018

Patterns of genetic differentiation and the footprints of historical migrations in the Iberian Peninsula

Genetic differences within or between human populations (population structure) has been studied using a variety of approaches over many years. Recently there has been an increasing focus on studying genetic differentiation at fine geographic scales, such as within countries. Identifying such structure allows the study of recent population history, and identifies the potential for confounding in association studies, particularly when testing rare, often recently arisen variants. The Iberian Peninsula is linguistically diverse, has a complex demographic history, and is unique among European regions in having a centuries-long period of Muslim rule. Previous genetic studies of Spain have examined either a small fraction of the genome or only a few Spanish regions. Thus, the overall pattern of fine-scale population structure within Spain remains uncharacterised. Here we analyse genome-wide genotyping array data for 1,413 Spanish individuals sampled from all regions of Spain. We identify extensive fine-scale structure, down to unprecedented scales, smaller than 10 Km in some places. We observe a major axis of genetic differentiation that runs from east to west of the peninsula. In contrast, we observe remarkable genetic similarity in the north-south direction, and evidence of historical north-south population movement. Finally, without making particular prior assumptions about source populations, we show that modern Spanish people have regionally varying fractions of ancestry from a group most similar to modern north Moroccans. The north African ancestry results from an admixture event, which we date to 860 - 1120 CE, corresponding to the early half of Muslim rule. Our results indicate that it is possible to discern clear genetic impacts of the Muslim conquest and population movements associated with the subsequent Reconquista.

genomics↗