A normal beta-globin allele as a modifier gene ameliorating the severity of alpha-thalassemia in mice

Thalassemia is a heritable human anemia caused by a variety of mutations th at affect expression of the alpha- or the beta-chain of hemoglobin. The exp ressivity of the phenotype is likely to be influenced by unlinked modifying genes. Indeed, by using a mouse model of Lu-thalassemia, we find that its phenotype is strongly influenced by the genetic background in which the cu- thalassemia mutation resides [129(Sv/ev)/129(sv/ev) (severe) or 129(SV/eV)/ C57BL/6 (mild)], Linkage mapping indicates that the modifying gene is very tightly linked to the beta-globin locus (Lod score = 13.3). Furthermore, th e severity of the phenotype correlates with the size of beta-chain-containi ng inclusion bodies that accumulate in red blood cells and likely accelerat e their destruction. The beta-major globin chains encoded by the two strain s differ by three amino acids, one of which is a glycine-to-cysteine substi tution at position 13. The Cys-13 should be available for interchain disulf ide bridging and consequent aggregation between excess beta-chains. This no rmal polymorphic variation between murine beta-globin chains could account for the modifying action of the unlinked beta-globin locus. Here, the varia tion in severity of the phenotype would not depend on a change in the ratio between alpha- and beta-chains but on the chemical nature of the normal be ta-chain, which is in excess. This work also indicates that modifying genes can be normal variants that-absent an apparent physiologic rationale-may b e difficult to identify on the basis of structure alone.