Dosage Sensitivity
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Over 17,000 protein coding genes have been scored according to their predicted probability of exhibiting haploinsufficiency. These predictions are generated using a classification model trained on two datasets:
- known haploinsufficient genes and
- genes disrupted by unambiguous loss-of-function variants in at least two apparently healthy individuals. The model uses sequence conservation, expression patterns and proximity within a gene network to known haploinsufficient genes as predictor variables. Missing predictor variables are imputed using other gene properties before prediction. Percentages refer to genome-wide percentiles of genes ranked according to their haploinsufficient score.
- High ranks (e.g. 0-10%) indicate a gene is more likely to exhibit haploinsufficiency, low ranks (e.g. 90-100%) indicate a gene is more likely to NOT exhibit haploinsufficiency.
- The manuscript describing the generation and validation of these haploinsufficiency predictions (Huang et al) is published in PLoS Genetics. Updated predictions of haploinsufficiency can be downloaded from our data download page. https://decipher.sanger.ac.uk/about#downloads/data
The Exome Aggregation Consortium (ExAC) has computed a score called pLI, which indicates the probability that a gene is intolerant to a Loss of Function (LoF) mutation. This analysis is based on high-quality exome sequence data for 60,706 individuals of diverse ethnicities.
The ExAC consortium used a selection-neutral, sequence-context-based mutational model to compare the observed number of rare variants per gene to an expected number, then quantified deviation from expectation with a Z score (method described in Samocha et al.). To reduce confounding by coding sequence length, for Protein Truncating Variants (PTV) an expectation-maximization algorithm using the observed and expected PTV counts within each gene was used to separate genes into three categories:
- Null, where observed ≈ expected (LoF variation is tolerated)
- Recessive, where observed ≤ 50% of expected (heterozygous LoFs are tolerated)
- Haploinsufficient, where observed < 10% of expected (heterozygous LoFs are not tolerated)
The pLI score is the probability that a given gene falls into the Haploinsufficient category, therefore is extremely intolerant of loss-of-function variation. Genes with high pLI scores (pLI ≥ 0.9) are extremely LoF intolerant, whereby genes with low pLI scores (pLI ≤ 0.1) are LoF tolerant.
The manuscript describing this dataset and analysis (Lek et al.) is published in Nature. http://exac.broadinstitute.org/
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