The pLI (probability of Loss-of-Function Intolerance) score is a metric that assesses how likely a gene is to be intolerant to loss-of-function (LoF) mutations, meaning mutations that disrupt or disable the gene's protein product.
Understanding pLI Scores
The pLI score, ranging from 0 to 1, quantifies the probability that a gene is haploinsufficient. This means that having only one functional copy of the gene (the other copy being inactivated by a LoF mutation) is detrimental to the organism. Genes with high pLI scores are therefore considered more essential and less likely to tolerate LoF mutations in the human population.
- pLI close to 1 (e.g., >0.9): Indicates a very high probability that the gene is LoF-intolerant. These genes are often essential for development or survival.
- pLI close to 0: Indicates a low probability of LoF intolerance, suggesting the gene can tolerate LoF mutations without significant consequences.
- Intermediate pLI values: Suggest some tolerance of LoF mutations, but the impact might depend on the specific mutation and individual.
How pLI Scores are Calculated
pLI scores are calculated using large-scale datasets, such as the Exome Aggregation Consortium (ExAC) and its successor, the Genome Aggregation Database (gnomAD). These databases contain genetic variation data from a large number of individuals.
The calculation considers:
- The observed number of LoF variants: The actual number of LoF variants observed in the population for a specific gene.
- The expected number of LoF variants: The number of LoF variants that would be expected to occur based on the gene's size and mutation rate, assuming it is not under selection.
A significant difference between the observed and expected number of LoF variants suggests selection against LoF mutations, indicating LoF intolerance. The pLI score quantifies this intolerance.
Significance of pLI Scores
pLI scores are important in several areas:
- Disease Gene Identification: Helps prioritize candidate genes in disease studies. Genes with high pLI scores are more likely to be involved in dominant genetic disorders because individuals are unlikely to tolerate having only one functional copy.
- Drug Target Selection: Useful in drug development to identify genes that are safe to target. Genes with low pLI scores might be better drug targets, as inhibiting their function is less likely to cause severe adverse effects.
- Understanding Gene Function: Provides insights into the functional importance of genes. High pLI scores suggest that a gene plays a crucial role in essential biological processes.
Example
Imagine a gene vital for early embryonic development. If a LoF mutation occurs in this gene, it could lead to severe developmental defects or even lethality. Because of this strong selection against LoF mutations, the observed number of LoF variants in the population will be much lower than expected. This gene would likely have a high pLI score, indicating its LoF intolerance.
In contrast, a gene involved in a non-essential function might tolerate LoF mutations without significant consequences. The observed number of LoF variants would be closer to the expected number, resulting in a low pLI score.
