Question

Explain why recessive pathogenic mutations often segregate at higher frequencies than dominant pathogenic mutations in human populations. (3 points)

Answer 1

In some cases, the consequences of the dominant pathogenic mutations for the cell or the organism may be too severe for the mutation ever to be transmitted to offspring. Certain constitutively activating heterozygous mutations of fibroblast growth factor receptor 3 (achondroplasia, thanatophoric dwarfism) (FGFR3) cause thanatophoric dysplasia, a serious bone disorder.Affected infants die at birth because they are unable to breathe, hence the frequency of the disorder is maintained by new mutations occuring in the germ line. Even more serious are specific activating mutations in the G protein-coupled receptor encoded by GNAS complex locus (GNAS). Germ - line mutations would be incompatible with fetal development;all mutations arise postzygotically and so exist as somatic mosaics.Here, the wild type cells may be viewed as rescuing the mutant cells from lethality. Affected individuals manifest McCune-Albright syndrome, which is associated with abnormalities of the bone, skin and endocrine systems. These abnormalities depend on the distribution of mutant cells in the body and so are extremely variable between patients.Post zygotic mutations occuring later in development contribute to the abnormalities in the control of cellular growth that lead to cancer.Frequently, the genes involved are also mutated in inherited disorders. For example, the forkhead transcription factor encoded by forkhead box O1a (rhabdomyosarcoma) (FOXO1A) located on the chromosome 13q, leads to alveolar rhabdomyosarcoma.