Possible scenarios for losing gene function. Start with two functional genes (deep blue and orange boxes) on the paternal and maternal chromosomes. The genic region is enlarged on the right. (A) A first mutation (black X) inactivates one of the active alleles, the paternal allele in this figure. (B) Double mutation: If a second mutation (black X) inactivates the maternal allele independently, the gene's function is completely lost. Additionally, loss of function can be achieved through LOH, and three major mechanisms for LOH are illustrated. (C) Deletion: The active allele is deleted by a chromosome loss (left) or a deletion of a chromosomal region (right). (D) Uniparental disomy (UPD): UPD creates a homozygote of the inactivated allele when only a chromosome (either the whole chromosome [left] or chromosome arm [right]) is inherited and doubled. (E) Gene conversion: Gene conversion transfers the first inactivating mutation to the active copy (red X), resulting in a homozygote for the inactivating mutation.
