Factors that influence PIG-A mutant frequency
Several human PIG-A studies have also looked to identify individual factors that may result in mutant frequency variation. The fact that humans have higher PIG-A mutant frequencies compared to laboratory rodents (Olsen et al., 2017) could be due the fact that humans are long-lived and are exposed to a wider range of lifestyle genotoxins compared to laboratory confined rodents. Some of the human studies mentioned above explored whether mutant frequency differs between sexes, producing contrasting results (Figure 4). Dobrovolsky and colleagues found that females had significantly higher erythrocyte mutant frequencies compared to males (p=0.025), although only 26 females were included in this cohort (Dobrovolsky et al., 2011). Conversely, Cao and colleagues measured higher mutant erythrocytes in males compared to females (p<0.0001) (Cao et al., 2016). The other publications presented in Figure 2 (Cao, Wang, Xi, et al., 2020; Cao et al., 2021; Haboubi et al., 2019; Lawrence et al., 2020) as well as the study by Dertinger and colleagues (Dertinger et al., 2015) (not shown in Figure 4) revealed no significant differences in erythrocyte PIG-Amutant frequencies between sexes. A study measuring reticulocytePIG-A identified a higher level of mutant reticulocytes in males compared to females (Torous et al., 2020). Even though the reason behind these sex differences is unclear it may be due to the different ethnicities studied in these particular two groups with one research group measuring PIG-A mutation status in an ethnic Chinese population (Cao et al., 2016) and the other in a mainly Caucasian/Hispanic population (Dobrovolsky et al., 2011).This suggested difference in gender may also be due to limited sample sizes and lack of integration of alternative factors (known or unknown) that can confound mutation status at the PIG-A locus.