lof

Loss-of-function, abbreviated LoF, denotes genetic changes that reduce or abolish the normal function of a gene product. In diploid organisms, a single functional copy may be sufficient for normal phenotype in some genes, while others require both copies. LoF mutations are a broad category that can impact protein-coding sequences or gene expression.

LoF mutations include nonsense variants that create premature stop codons, frameshift insertions or deletions that disrupt the reading frame, essential splice-site mutations that alter mRNA splicing, start codon mutations, and large deletions that remove all or part of a gene. Regulatory changes that drastically reduce expression can also be classified as LoF.

LoF can cause disease when the affected gene is dosage-sensitive or when both copies are inactivated (recessive) or when a dominant-negative or haploinsufficient effect occurs. Some genes tolerate LoF in one allele without symptoms. In population genetics, many LoF variants are rare due to purifying selection, and the overall tolerance of a gene to LoF varies across the genome.

Detection relies on sequencing, annotation, and functional assays. Population-genomics resources such as gnomAD provide LoF annotations and tolerance scores (such as pLI and LOEUF) used to assess the likelihood that a gene is intolerant to loss of function.

LoF mutations underpin numerous disorders, including cystic fibrosis (CFTR LoF variants), and contribute to cancer susceptibility when tumor suppressor genes such as TP53 or BRCA1 are inactivated. In research, LoF alleles created by gene knockout or CRISPR screens reveal gene functions.

Understanding LoF helps in disease diagnosis, drug development, and functional genomics, but interpretation requires considering genetic background, tissue-specific expression, and potential redundancy.