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Published on: August 15, 2019
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No preferential mode of inheritance for highly constrained genes
Alexandre Fabre1,2, Julien Mancini3,4
1Aix Marseille Univ, INSERM, MMG, Marseille, France.
Intractable & Rare Diseases Research
|March 9, 2022
Summary
Highly genetically constrained genes show increased association with Mendelian diseases and distinct intragenic constraint patterns. This study reveals that high genetic constraint is linked to specific intragenic scores, not a particular inheritance mode.
Area of Science:
- Genetics
- Genomic Medicine
Background:
- Genetic constraint metrics, like gnomAD's probability of being loss-of-function (LoF) intolerant (pLI), are crucial for prioritizing candidate genes.
- However, the inheritance patterns of highly constrained genes have not been specifically investigated.
Purpose of the Study:
- To compare genes with the highest pLI score (pLI1 group) against a random gene set.
- To analyze differences in genetic constraint metrics, Mendelian disease associations, and modes of inheritance.
Main Methods:
- Compared 605 pLI1 genes with 635 random gnomAD genes.
- Assessed genetic constraint metrics, Mendelian disease associations, and modes of inheritance.
- Evaluated intragenic constraint scores: percentage of constraint coding regions (CCR) and gene variation intolerance rank (GeVIR).
Main Results:
- Genes with pLI=1 showed a significantly higher association with Mendelian diseases (35.9%) compared to random genes (19.5%).
- The distribution of inheritance modes differed significantly between the pLI1 and random groups (p < 0.0001).
- The pLI1 group exhibited higher percentages of CCRs in the 99th percentile and lower GeVIR scores, indicating greater intragenic constraint.
Conclusions:
- High genetic constraint is strongly associated with increased Mendelian disease links and specific intragenic constraint scores.
- Genetic constraint does not appear tied to a single mode of inheritance, with some highly constrained genes exhibiting multiple inheritance patterns.
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