Gene selection in hemoglobin and in antibody-synthesizing cells.

Close linkage of mutually exclusive genes occurs in the non-alpha chain hemoglobin genes and in the immunoglobulin genes of man and other mammals. The expression of one gene in the cluster precludes the expression of any other linked gene. A simple, testable theory of gene selection called "looping-out excision"which was designed only to explain this mutual exclusivity in the hemoglobin system is described. The theory is closely concordant with a wide range of previously unexplained findings concerning hematopoiesis- including the developmental changes of hemoglobins, the increases in immature or fetal forms of hemoglobin that accompany anemia, and with the distribution of adult and fetal hemoglobins among erythrocytes during normal embryogenesis and in various pathological conditions. One corollary of this theory is that erythroid tissue in the normal adult bone marrow is constantly recapitulating the developmental stages of its embryogenesis. Another corollary is that the selection from among the linked globin genes occurs independently on the two chromosomes of the diploid organism. Both of these corollaries are supported by the available data. The same theory of gene selection is also remarkably consistent with known data for immunoglobulin synthesis; it could explain not only the mutually exclusive activation of linked variable genes but also the splicing which occurs between genetically linked variable and constant region genes for the immunoglobulin polypeptide chains. The agreement between these two different tissues is considered to be strong evidence that the proposed mechanism is correct at least in broad outline. Evidence from the genetics of maize and of drosophila also supports this theory of somatic tissue variegation. On the basis of these comparisons, I suggest that looping-out excision probably occurs also in other tissues and may be one means of gene selection and activation in differentiating cells.