Gene Selection in Hemoglobin and in Antibody-Synthesizing Cells

Abstract

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.

Hemoglobin F synthesis in vitro: evidence for control at the level of primitive erythroid stem cells.

“…4 (17), the selective proliferation of precursors programmed for Hb F formation (18), or a translational control operating in less-differentiated cells (19). Other studies have failed to reveal translational (20) or globin gene excision mechanisms (21,22) in Hb F regulation.…”

Stimulation of fetal hemoglobin synthesis in bone marrow cultures from adult individuals.

“…In man, and a few other mammals, fetal hemoglobin (Hb F, chain composition ay272, is the predominant hemoglobin of the fetus and it is replaced by adult hemoglobin (Hb A: a2.2) soon after birth. Although hypotheses to explain this switch from y to fi globin formation in man have been proposed (1)(2)(3)(4)(5), the factors involved in this process are unknown. Delineation of the mechanisms of regulation of fetal hemoglobin in man, however, might be of considerable biological interest and of possible practical importance for treatment of sickle cell anemia and homozygous ,f-thalassemia.…”

POU2AF1, an amplification target at 11q23, promotes growth of multiple myeloma cells by directly regulating expression of a B-cell maturation factor, TNFRSF17

“…The most frequent losses we observed were in the 14q32 region, where the immunoglobulin heavy constant gamma 1 gene (IGHG1) is located (88.9%, Figure 1a; Supplementary Table S1). Translocation in MM is mainly mediated by errors in two different generearrangement mechanisms; it can result in the excision of DNA in the interval between a particular V gene and the corresponding C gene (Kabat, 1972). The prevalence of IgH translocations is about 85% in primary plasma cell leukemias and more than 90% in MM cell lines (Fonseca et al, 2002;Kuehl and Bergsagel, 2002).…”