The currently accepted hypothesis is that these mutations were originally neutral, meaning that deletion of the vitamin C production pathway had no selective advantage or disadvantage.
Although this pattern cannot be used to determine if the mutations were originally fixed by natural selection, conservation after an ancient diversification indicates a long period of stasis, consistent with purifying selection on adaptive, alternative amino acid states.
Col4a1 and Col4a2 mutations were originally identified because of severe, highly penetrant cataracts and ocular ASD.
These mutations were originally identified and characterised as fly and mouse embryonic lethal mutations that cause early cardiac failure (Schott et al., 1998).
Muscle from transgenic Drosophila larvae was compared with skeletal muscle biopsies from the patients in whom the LMNA mutations were originally identified (Table 1).
KRAS mutations were originally detected in lung cancer (Rodenhuis et al, 1987) and since then have been assessed as a potential marker of survival in colorectal, ovarian and pancreatic cancers.
Considering only changes at canonical splice sites, ∼15% of mutations were originally estimated to induce aberrant splicing (1) and similar frequencies are recorded in human disease databases [for example, 12% in cystic fibrosis (CF) and 10% in coagulation FIX FIXX) deficiency (Haemophilia B)].
LRRK2 mutations were originally identified as the causative factor in dominantly inherited forms of PD linked to the PARK8 locus (Paisán-Ruíz et al., 2004; Zimprich et al., 2004) and, more recently, sequence variation at the LRRK2 locus has been associated with an increased risk of developing sporadic PD in genome-wide association studies (Satake et al., 2009; Simón-Sánchez et al., 2009).
ABCA4 mutations were originally discovered in patients with autosomal recessive Stargardt disease (SD) but shortly thereafter were also found to cause cone dystrophy, cone-rod dystrophy (CRD) and retinitis pigmentosa (RP), suggesting that a predictable relationship may exist between ABCA4 genotype and disease severity (5– 10).
The dap mutation was originally ascribed to dapC, but feedback reports characterize it as dapA.
