Biology subjects

Farre, X.

Publications and source records attributed to Farre, X..

3 recordsLinked to original sources

bioRxiv2021

GCAT|Panel, a comprehensive structural variant haplotype map of the Iberian population from high-coverage whole-genome sequencing

The combined analysis of haplotype panels with phenotype clinical cohorts is a common approach to explore the genetic architecture of human diseases. However, genetic studies are mainly based on single nucleotide variants (SNVs) and small insertions and deletions (indels). Here, we contribute to fill this gap by generating a dense haplotype map focused on the identification, characterization and phasing of structural variants (SVs). By integrating multiple variant identification methods and Logistic Regression models, we present a catalogue of 35,431,441 variants, including 89,178 SVs ([≥]50bp), 30,325,064 SNVs and 5,017,199 indels, across 785 Illumina high coverage (30X) whole-genomes from the Iberian GCAT Cohort, containing 3.52M SNVs, 606,336 indels and 6,393 SVs in median per individual. The haplotype panel is able to impute up to 14,360,728 SNVs/indels and 23,179 SVs, showing a 2.7-fold increase for SVs compared with available genetic variation panels. The value of this panel for SVs analysis is shown through an imputed rare Alu element located in a new locus associated with mononeuritis of lower limb, a rare neuromuscular disease. This study represents the first deep characterization of genetic variation within the Iberian population and the first operational haplotype panel to systematically include the SVs into genome-wide genetic studies.

genomics↗

bioRxiv2021

Comparative analysis of mammal genomes unveils key genomic variability for human lifespan.

Mammals vary 100-fold in their maximum lifespan. This enormous variation is the result of the adaptations of each species to their own biological trade-offs and ecological conditions. Comparative genomics studies have demonstrated that the genomic factors underlying the lifespans of species and the longevity of individuals are shared across the tree of life. Here, we set out to compare protein-coding regions across the mammalian phylogeny, aiming to detect individual amino acid changes shared by the most long-lived mammal species and genes whose rates of protein evolution correlate with longevity. We discovered a total of 2,737 amino acid changes in 2,004 genes that distinguish long- and short-lived mammals, significantly more than expected by chance (p=0.003). The detected genes belong to pathways involved in regulating lifespan, such as inflammatory response and hemostasis. Among them, a total 1,157 amino acids, located in 996 different genes, showed a significant association with maximum lifespan in a phylogenetically controlled test. Interestingly, most of the detected amino acids positions do not vary in extant human populations (>81.2%) or have allele frequencies below 1% (99.78%), Consequently, almost none could have been detected by Genome-Wide Association Studies (GWAS). Additionally, we identified four more genes whose rate of protein evolution correlated with longevity in mammals. Crucially, SNPs located in the detected genes explain a larger fraction of human lifespan heritability than expected by chance, successfully demonstrating for the first time that comparative genomics can be used to enhance the interpretation of human GWAS. Finally, we show that the human longevity-associated proteins coded by the detected genes are significantly more stable than the orthologous proteins from short-lived mammals, strongly suggesting that general protein stability is linked to increased lifespan.

genomics↗

bioRxiv2020

Evolutionary phenome-genome analysis of cranial suture closure in mammals

Cranial sutures are growth and stress diffusion sites that connect the bones protecting the brain. The closure of cranial suture is a key feature of mammalian late development and evolution, which can also lead to head malformations when it occurs prematurely (craniosynostosis). To unveil the phenotypic and genetic causes of suture closure in evolution, we examined 48 mammalian species searching for (i) causal links between suture patency, brain size, and diet using phylogenetic path analysis; and (ii) instances of genome-phenome convergence amino acid substitutions. Here we show that brain size and the anteroposterior order of ossification of the skull are the two main causes of sutures patency in evolution. We also identified three novel candidate genes for suture closure in evolution (HRNR, KIAA1549, and TTN), which have never been reported in clinical studies of craniosynostosis. Our results suggest that different genetic pathways underlie cranial suture closure in evolution and disease.

evolutionary biology↗