A novel α-globin gene arrangement in man

Abstract

The human genome has two linked alpha-globin genes on chromosome 16. Deletion of one or more of them, as occurs in alpha-thalassaemia, leads to a reduced output of alpha-globin mRNA in proportion to the number of alpha-globin genes lost. In some racial groups deletion of one of the pair of alpha-globin genes may result from unequal crossing over between the genes on homologous chromosomes by a mechanism resembling that postulated for the formation of the delta beta fusion genes of the Lepore haemoglobins. By analogy, the opposite chromosome in this cross-over should have three alpha-globin genes just as the 'anti-Lepore chromosome has three non-alpha chain genes. We describe here a Welsh family in which three members have five alpha-globn increased alpha mRNA output and it may therefore produce the phenotype of mild beta-thalassaemia.

Molecular analysis of the beta-thalassemia phenotype associated with inheritance of hemoglobin E (alpha 2 beta2(26)Glu leads to Lys).

“…1 and 3, Table III) patients with homozygous 3-thalassemia were derived from our previous studies (13)(14)(15)(16) served by lowering a-globin and a-globin mRNA. The recently described condition in which more than the normal number of a-genes are inherited (34) could conceivably account for our data if the extra a-genes were functional. However, these genes do not appear to alter a-and /8-globin balance in patients studied thus far (35).…”

Two different molecular organizations account for the single alpha-globin gene of the alpha-thalassemia-2 genotype.

“…These, too, are highly homologous sequences (27), bounded on one stretch of chromosome by an Hpa I site and on the other by a Bgl II site. The detection of the apparent reciprocal crossover product of an interchromosomal event causing the rightward deletion, a chromosome bearing three a-globin loci (28,29), suggests that the rightward deletion is the result of an interchromosomal crossover. The finding of the rightward deletion a-thal-2 genotype in all three races commonly afflicted with a-thalassemia suggests that the determinants of this deletion, possibly specific DNA sequences that regulate DNA recombination (30), are widespread in the population of the world.…”

Different hematologic phenotypes are associated with the leftward (-alpha 4.2) and rightward (-alpha 3.7) alpha+-thalassemia deletions.

“…Two -a-haplotypes were not classified because of insufficient DNA. All aaa-chromosomes were of the aaaanu 3-7 type (20). In five of the -a3 7/aa cases and one of the -a37/aaa cases, Hb JTgi (24) was found on hemoglobin electrophoresis.…”

“…In 3 of the 15 cases this is probably due to the presence of a triplicated a-gene arrangement (20,21) on the other chromosome (giving a total of four a-genes), which should compensate for the a-chain deficit due to the deletion. In the other 12 cases of genotype -a/aa, the a-chain deficiency is presumably insufficient to produce a detectable amount of Hb Bart's.…”