Mastodawn

La structure des réseaux de régulation explique l'évolution et l'héritabilité des phénotypes complexes

De nombreux phénotypes humains sont polygéniques, déterminés par plusieurs gènes et éléments régulateurs : la taille à l’âge adulte, le métabolisme, l’immunité, la prédisposition génétique à de nombreuses maladies, y compris des cancers et des maladies auto-immunes, des troubles psychiatriques et des maladies neurodégénératives. Ces gènes sont souvent pléiotropes, déterminant simultanément différents phénotypes. Cela s’explique par le grand nombre d’interactions au niveau moléculaire dans chaque cellule, où des réseaux complexes régulent finement l’expression des gènes. Étant donné l’intrication des bases génétiques des différents phénotypes complexes, nous nous sommes demandé comment un phénotype complexe peut évoluer en réponse aux contraintes environnementales, sans altérer les autres phénotypes.

En savoir plus ➡️ https://moulon.inrae.fr/news/2025/10/la-structure-des-r%C3%A9seaux-de-regulation-explique-l%C3%A9volution-et-lh%C3%A9ritabilit%C3%A9-des-ph%C3%A9notypes-complexes/

#ideev #gqelemoulon #maudfagny @hal_fr @officialSMBE #mbe #phenotype #regulation #polygenic @inrae_france

Giuseppe Michieli Jul 7, 2024

#Aminoacid #mutations #PB1-V719M and #PA-N444D combined with #PB2-627K contribute to the #pathogenicity of #H7N9 in #mice, Vet Res.: https://veterinaryresearch.biomedcentral.com/articles/10.1186/s13567-024-01342-6

Overall, this study revealed that #virulence in H7N9 is a #polygenic trait and identified novel virulence-related residues (PB2-627K combined with PB1-719M and/or PA-444D) in viral ribonucleoprotein (vRNP) complexes.

Amino acid mutations PB1-V719M and PA-N444D combined with PB2-627K contribute to the pathogenicity of H7N9 in mice - Veterinary Research

H7N9 subtype avian influenza viruses (AIVs) cause 1567 human infections and have high mortality, posing a significant threat to public health. Previously, we reported that two avian-derived H7N9 isolates (A/chicken/Eastern China/JTC4/2013 and A/chicken/Eastern China/JTC11/2013) exhibit different pathogenicities in mice. To understand the genetic basis for the differences in virulence, we constructed a series of mutant viruses based on reverse genetics. We found that the PB2-E627K mutation alone was not sufficient to increase the virulence of H7N9 in mice, despite its ability to enhance polymerase activity in mammalian cells. However, combinations with PB1-V719M and/or PA-N444D mutations significantly enhanced H7N9 virulence. Additionally, these combined mutations augmented polymerase activity, thereby intensifying virus replication, inflammatory cytokine expression, and lung injury, ultimately increasing pathogenicity in mice. Overall, this study revealed that virulence in H7N9 is a polygenic trait and identified novel virulence-related residues (PB2-627K combined with PB1-719M and/or PA-444D) in viral ribonucleoprotein (vRNP) complexes. These findings provide new insights into the molecular mechanisms underlying AIV pathogenesis in mammals, with implications for pandemic preparedness and intervention strategies.

BioMed Central

Daniel E. Weeks May 2, 2024

STATGEN 2024 talk
Polygenic risk score analysis for multiethnic populations
Chris Amos

Polygenic Risk Scores (PRS)
* Inform re biological processes
* Identify some at higher risk
* Might motivate behavioral change

PRS could inform when to start screening.

"measles plot instead of a manhattan plot" - has excessive false positives all over the genome.

Lung cancer risk snp also is related to response to smoking cessation

#STATGEN2024 #Polygenic #StatisticalGenetics #Genetics #PRS

MPI for Empirical Aesthetics Mar 26, 2024

#Beethoven's #musicality put to the test: An international #research team incl. @mpi_nl and @MPI_ae set out to analyze the composer’s #genetic predisposition by calculating his #polygenic score for #beat synchronization ability. Out now in @CurrentBiology: https://doi.org/10.1016/j.cub.2024.01.025

Scientific Frontline Mar 19, 2024

Researchers have developed statistical tools called #polygenic risk scores (PRSs) that can estimate individuals’ risk for certain diseases with strong #genetic components, such as #heart disease or #diabetes.
#Genetics #sflorg
https://www.sflorg.com/2024/03/gen03192401.html

Researchers roll out a more accurate way to estimate genetic risks of disease

Two new approaches for generating polygenic scores demonstrate that compiled data improves score accuracy.

Luke Pembleton Dec 21, 2023

This festive season 🎄 give the gift 🎁 of a #Bayesian model to a friend still trying to run a frequentist linkage mapping approach looking for significant associations 🧬🖥️

#genomics #QuantitativeGenetics #polygenic #omnigenic

Daniel E. Weeks Nov 17, 2023

"Polygenic risk scores performed poorly in population screening, individual risk prediction, and population risk stratification. Strong claims about the effect of polygenic risk scores on healthcare seem to be disproportionate to their performance."

Hingorani et al. Performance of polygenic risk scores in screening, prediction, and risk stratification: secondary analysis of data in the Polygenic Score Catalog. BMJ Medicine. 2023 Oct 1;2(1). DOI: https://doi.org/10.1136/bmjmed-2023-000554
#genetics #polygenic

Performance of polygenic risk scores in screening, prediction, and risk stratification: secondary analysis of data in the Polygenic Score Catalog

Objective To clarify the performance of polygenic risk scores in population screening, individual risk prediction, and population risk stratification. Design Secondary analysis of data in the Polygenic Score Catalog. Setting Polygenic Score Catalog, April 2022. Secondary analysis of 3915 performance metric estimates for 926 polygenic risk scores for 310 diseases to generate estimates of performance in population screening, individual risk, and population risk stratification. Participants Individuals contributing to the published studies in the Polygenic Score Catalog. Main outcome measures Detection rate for a 5% false positive rate (DR5) and the population odds of becoming affected given a positive result; individual odds of becoming affected for a person with a particular polygenic score; and odds of becoming affected for groups of individuals in different portions of a polygenic risk score distribution. Coronary artery disease and breast cancer were used as illustrative examples. Results For performance in population screening, median DR5 for all polygenic risk scores and all diseases studied was 11% (interquartile range 8-18%). Median DR5 was 12% (9-19%) for polygenic risk scores for coronary artery disease and 10% (9-12%) for breast cancer. The population odds of becoming affected given a positive results were 1:8 for coronary artery disease and 1:21 for breast cancer, with background 10 year odds of 1:19 and 1:41, respectively, which are typical for these diseases at age 50. For individual risk prediction, the corresponding 10 year odds of becoming affected for individuals aged 50 with a polygenic risk score at the 2.5th, 25th, 75th, and 97.5th centiles were 1:54, 1:29, 1:15, and 1:8 for coronary artery disease and 1:91, 1:56, 1:34, and 1:21 for breast cancer. In terms of population risk stratification, at age 50, the risk of coronary artery disease was divided into five groups, with 10 year odds of 1:41 and 1:11 for the lowest and highest quintile groups, respectively. The 10 year odds was 1:7 for the upper 2.5% of the polygenic risk score distribution for coronary artery disease, a group that contributed 7% of cases. The corresponding estimates for breast cancer were 1:72 and 1:26 for the lowest and highest quintile groups, and 1:19 for the upper 2.5% of the distribution, which contributed 6% of cases. Conclusion Polygenic risk scores performed poorly in population screening, individual risk prediction, and population risk stratification. Strong claims about the effect of polygenic risk scores on healthcare seem to be disproportionate to their performance. Data are available in a public, open access repository. Data are available on the Polygenic Score Catalog website.

BMJ Medicine

Nicolas Bierne Oct 25, 2023

A polygenic explanation for Haldane’s rule in butterflies
Xiong et al. (Jim Mallet's team)
#PopGen #Hybridization #Polygenic

"numerous small-effect factors on a single chromosome can appear as spurious large-effect loci. This mapping artifact persists even for large samples and dense markers and may cause underreporting of polygenicity from genetic crosses."

https://doi.org/10.1073/pnas.2300959120

Flávia E. Rius Jul 27, 2023

If you want to learn more about

- complex traits;
- #GWAS;
- #polygenic scores,

I have created a playlist in youtube with some great lectures and discussions from Broad Institute's Medical Population Genetics department.

Check it out: https://youtube.com/playlist?list=PLSTeUJbSJXfnUjstgtx2cTKWsCBJpnvGy

Polygenic Scores

Videos explaining important concepts and ways of analyzing and interpreting polygenic scores.

YouTube

American Naturaliﬆ Jul 6, 2023

Cryptic #sexChromosome was found after removing a master sex-determining #chromosome. This result suggests that #polygenic #sexDetermination system may be more prevalent than previously thought.

Open access article by Kitano et al. now available ahead of print!

https://www.journals.uchicago.edu/doi/10.1086/724840