THE DIFFERENCES IN QUANTITIES OF ALPHA-2-GLOBIN AND ALPHA-1-GLOBIN GENE VARIANTS IN HETEROZYGOTES

We have identified through sequencing of amplified DNA the mutations i n the alpha 2- and alpha 1-globin genes in 63 individuals with a heter ozygosity for an alpha chain abnormal haemoglobin (Hb). Moreover, we d eveloped a reverse transcription/polymerase chain reaction (RT/PCR) ba sed procedure for the determination of the alpha 2- and alpha 1-mRNA r atio in normal individuals. The numbers of alpha 2 and alpha 1 variant s were nearly the same. The average percentage of the abnormal Hb in h eterozygotes with alpha 2 mutations (23.5%) was slightly higher than t hat in heterozygotes with alpha 1 mutations (19.7%) (stable Hbs only). These percentages correspond to a ratio of alpha 2 to alpha 1 of 1.19 to 1 at the protein level. Variations in the number of active cu-glob in genes and in the stability of the variants (greatly) affected the p ercentages of the abnormal protein. The average ratio between the alph a 2- and alpha 1-mRNAs in 12 normal individuals was 2.6-2.75 to 1, abo ut as expected from published data, and 2.0 to 1 for two persons with an alpha-thalassaemia-2 (alpha-thal-2) (-.37 kb) heterozygosity. The h igh relative mRNA (alpha 2) level which is about twice the relative le vel of the alpha 2 protein suggests a less efficient translation of th e alpha 2-mRNA.