THE FUSION OF TWO PEPTIDE CHAINS IN HEMOGLOBIN LEPORE AND ITS INTERPRETATION AS A GENETIC DELETION

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Abstract
There is now a large body of evidence which suggests that the structural gene for a protein determines its primary amino acid sequence. The structural genes seem to be separated by regions, which establish boundaries between them and allow their function to be expressed individually. In the well-studied region r11 of phage T4 there are 2 adjacent cistrons, called A and B. In the mutant r 1589 of T4, there is a deletion of the region separting A from the B cistron and the 2 cistrons appear to be joined with loss of the A function but with preservation of the B function. The insertion of certain deletions in the A cistron of r 1589 prevents the B cistron from functioning. This suggest that in r 1589 a protein may be produced "which consists of part of the protein from the A cistron and part of the B cistron, joined together in the same polypeptide chain. The xB peptide chain of Hb-Lepore Boston seems to consist of part of the [beta] chain and part of the [delta] chain joined together. That part of the [delta] gene corresponding to the N-terminal portion of the [delta] chain is presumably joined to that part of the [delta] gene which determines the C-terminal portion of the [beta] chain. The fact that the [beta] and [delta] genes are linked suggests that the joining may be due to a deletion of parts of the [beta] and [delta] genes and of the region separting them. If this postulated joining of part the [beta] gene with part of the [delta] geneweredue toarandom deletion, it would be difficult to understand why the peptide chain made by the hybrid [beta]- [delta] gene would have the same length as the [beta] or [delta] chain. The evidence so far suggests that there is no amino acid sequence in the xg chain that is not also present either in the [beta] or in the [delta] chain. One would not expect to find such a situation if the corresponding genes were randomly joined by a deletion. A specific mechanism that laccounts for the joining of the [beta] to the [delta] gene in such an exactly complementary way is a nonhomologous crossing-over between corresponding points of the [beta] and the [delta] genes, resulting in the formation of unequal products. Unequal crossing-over is known to involve frequently chromosomal duplications, such as the bar duplication of Drosophila melanogaster, leading to recombinants with deletion of the duplication (wild type) or insertion of 4 extra bas duplication (double-bar). It has been suggested that the [delta] gene originated from a duplication of the [beta] gene, because the primary sequence of the [delta] chain is extremely similar to the primary sequence of the [beta] chain. The similarity of the [beta] and [delta] genes may increase the probability of nonhomologous crossing-overs. It is suggestive that Hb- Lepore Boston and Hb- LeporeHollandia have been observed in different populations. The corresponding genes may have been formed by different nonhomologous crossing-overs, which have involved different points of the [beta] and [delta] genes.