Biology subjects

Pairo-Castineira, E.

Publications and source records attributed to Pairo-Castineira, E..

6 recordsLinked to original sources

bioRxiv2022

Expanded Analysis of Pigmentation Genetics in UK Biobank

The genetics of pigmentation is an excellent model for understanding gene interactions in a trait almost entirely unaffected by environment. We have analysed pigmentation phenotypes in UK Biobank using DISSECT, a tool which enables genome-wide association studies (GWAS) whilst accounting for relatedness between individuals, and thus allows a much larger cohort to be studied. We have increased the number of candidate genes associated with red and blonde hair colour, basal skin colour and tanning response to UV radiation. As previously described, we find almost all red hair individuals have two variant MC1R alleles; exome sequence data expands the number of associated coding variants. Rare red-headed individuals with only a single MC1R variant are enriched for an associated eQTL at the ASIP gene. We find that females are most likely to self-report red or blonde hair, paler skin and less tanning ability than men, and that variants at KITLG, MC1R, OCA2 and IRF4 show significant sex differences in effect. After taking sex into account, pigmentation phenotypes are not correlated with sex hormone levels, except for tanning ability, which shows a positive correlation with testosterone in men. Across the UK there is a correlation between place of birth and hair colour; red hair being more common in the north and west, whilst blonde hair is more common in the east. Combining GWAS with transcriptome data to generate a transcriptome wide association study identifies candidate genes whose expression in skin or melanocytes shows association with pigmentation phenotypes. A comparison of candidates associated with different pigmentation phenotypes finds that candidates for blonde hair, but not skin colour, are enriched for skin and hair genes suggesting that it may be hair shape and structure that impacts hair colour, rather than the melanocyte/keratinocyte interaction.

genetics↗

bioRxiv2021

Investigating the genetic architecture of eye colour in a Canadian cohort

The main factors that determine eye colour are the amount of melanin concentrated in iris melanocytes, as well as the shape and distribution of melanosomes. Eye colour is highly variable in populations with European ancestry, in which eye colour categories cover a continuum of low to high quantities of melanin accumulated in the iris. A few polymorphisms in the HERC2/OCA2 locus in chromosome 15 have the largest effect on eye colour in these populations, although there is evidence of other variants in the locus and across the genome also influencing eye colour. To improve our understanding of the genetic loci determining eye colour, we performed a meta-analysis of genome-wide association studies in a Canadian cohort of European ancestry (N= 5,641) and investigated putative causal variants. Our fine-mapping results indicate that there are several candidate causal signals in the HERC2/OCA2 region, whereas other significant loci in the genome likely harbour a single causal signal (TYR, TYRP1, IRF4, SLC24A4). Furthermore, a short subset of the associated eye colour regions was colocalized with the gene expression or methylation profiles of cultured melanocytes (HERC2, OCA2), and transcriptome-wide association studies highlighted the expression of two genes associated with eye colour: SLC24A4 and OCA2. Finally, genetic correlations of eye and hair colour from the same cohort suggest high pleiotropy at the genome level, but locus-level evidence hints at several differences in the genetic architecture of both traits. Overall, we provide a better picture of how polymorphisms modulate eye colour variation, particularly in the HERC2/OCA2 locus, which may be a consequence of specific molecular processes in the iris melanocytes. Author SummaryEye colour differences among humans are the result of different amounts of melanin produced, as well as due to differences in the shape and distribution of the organelles in charge of producing melanin. Eye colour is a highly heritable trait, where several genes across the genome are involved in the process, but we currently do not fully understand which are the causal variants and how they modulate eye colour variation. By performing genome-wide association studies of eye colour across Canadian individuals of European ancestry, we identify several candidate causal signals in and near the gene OCA2, and one candidate signal in other genes, such as TYR, TYRP1, IRF4 and SLC24A4. Furthermore, we provide insights about how significant loci may modulate eye colour variation by testing for shared signals with polymorphisms associated with the expression of genes and DNA methylation. Overall, we provide a better picture of the genetic architecture of eye colour and the molecular mechanisms contributing to its variation.

genetics↗

bioRxiv2021

Endomembrane targeting of human OAS1 p46 augments antiviral activity

Many host RNA sensors are positioned in the cytosol to detect viral RNA during infection. However, most positive-strand RNA viruses replicate within a modified organelle co-opted from intracellular membranes of the endomembrane system, which shields viral products from host cell innate immune sensors. Targeting innate RNA sensors to the endomembrane system may enhance their ability to sense viral RNA generated by viruses that use these compartments for replication. Here, we reveal that an isoform of oligoadenylate synthetase 1, OAS1 p46, is prenylated and targeted to the endomembrane system. Membrane localization of OAS1 p46 confers enhanced access to viral replication sites and results in increased antiviral activity against a subset of RNA viruses including flavivirus, picornavirus, and SARS-CoV-2. Finally, our human genetic analysis shows that the OAS1 splice-site SNP responsible for production of the OAS1 p46 isoform strongly associates with COVID-19 severity. This study highlights the importance of endomembrane targeting for the antiviral specificity of OAS1 and suggests early control of SARS-CoV-2 replication through OAS1-p46 is an important determinant of COVID-19 severity.

immunology↗

bioRxiv2020

A comprehensive catalogue of regulatory variants in the cattle transcriptome

Characterization of genetic regulatory variants acting on the transcriptome of livestock is essential for interpreting the molecular mechanisms underlying traits of economic value and for increasing the rate of genetic gain through artificial selection. Here, we build a cattle Genotype-Tissue Expression atlas (cattle GTEx, http://cgtex.roslin.ed.ac.uk/) as part of the pilot phase of Farm animal GTEx (FarmGTEx) project for the research community based on publicly available 11,642 RNA-Seq datasets. We describe the landscape of the transcriptome across over 100 tissues and report hundreds of thousands of genetic associations with gene expression and alternative splicing for 24 major tissues. We evaluate the tissue-sharing patterns of these genetic regulatory effects, and functionally annotate them using multi-omics data. Finally, we link gene expression in different tissues to 43 economically important traits using both transcriptome-wide association study (TWAS) and colocalization analyses to decipher the molecular regulatory mechanisms underpinning such agronomic traits in cattle.

genomics↗

bioRxiv2018

Functionally Coherent Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling and Oncogenic Notch

BackgroundCell identity is governed by gene expression, regulated by Transcription Factor (TF) binding at cis-regulatory modules. Decoding the relationship TF binding patterns and the regulation of cognate target genes is nontrivial, remaining a fundamental limitation in understanding cell decision-making mechanisms. Identification of TF physical binding that is biologically neutral is a current challenge. We studied cell identity in the context of Epithelial to Mesenchymal Transition (EMT), a cell programme fundamental for normal embryonic development that contributes to tumour progression and fibrosis.\n\nResultsWe developed the NetNC software for discovery of functionally coherent TF targets. NetNC was applied to analyse gene regulation by the EMT TFs Snail, Twist in early embryogenesis and also to modENCODE HOT regions. Predicted neutral binding accounted for 50% to [≥]80% of candidate target genes assigned from significant binding peaks. Novel gene functions and network modules were identified, including regulation of chromatin organisation and crosstalk with notch signalling. Orthologues of predicted TF targets discriminated breast cancer molecular subtypes and NetNC analysis predicted new gene functions; for example, evidencing networks that reshape Waddingtons landscape during EMT-like phenotype switching. Predicted invasion roles for SNX29, ATG3, UNK and IRX4 were validated using a tractable cell model.\n\nConclusionsWe found extensive neutral TF binding across the nine datasets examined and showed that NetNC performs well in identifying functionally coherent targets. HOT regions had comparatively high functional coherence. Our results illuminate conserved molecular networks that regulate epithelial remodelling in development and disease, with potential implications for precision medicine.

systems biology↗

bioRxiv2018

The genetic architecture of hair colour in the UK population

We have extensively mapped the genes responsible for hair colour in the UK population. MC1R mutations are well established as the principal genetic cause of red hair colour, but with variable penetrance. We find variation at genes encoding its agonist (POMC), inverse agonist (ASIP) and other loci contribute to red hair and demonstrate epistasis between MC1R and some of these loci. Blonde hair is associated with over 200 loci, and we find a genetic continuum from black through dark and light brown to blonde. Many of the associated genes are involved in hair growth or texture, emphasising the cellular connections between keratinocytes and melanocytes in the determination of hair colour.

genetics↗