THE MOLECULAR-BASIS OF BETA-THALASSEMIA IN PUNJABI AND MAHARASHTRAN INDIANS INCLUDES A MULTILOCUS ETIOLOGY INVOLVING TRIPLICATED ALPHA-GLOBIN LOCI

We have analysed 201 beta-thalassaemia (beta-thal) genes from natives of the Punjab (156) and Maharashtra states of India and found the caus ative mutation in 200 of them. The most common beta-globin gene mutati ons differed significantly between these two groups and between these groups and Indian immigrants in the U.S.A. and the U.K. In the Punjabi Indians the IVS-1, nt 1(G-T) mutation accounted for nearly one-quarte r of beta-thal genes, whereas it was 5% or less in the other groups. L ikewise, the cap + 1 mutation was much more prevalent in the Punjabis, whereas the nonsense codon 15 allele had a higher frequency in the Ma harashtrans of the Bombay region. The common IVS-1, nt5 allele had a f requency of 60% of beta-thal genes in the Maharastrans, 35% in North A merican immigrants, and only 23% in the Punjabis. Two-thirds of all be ta-thal genes in Punjab were found in the merchant caste (Khatri-Arora ), whereas the menial caste (Shudra) was highly represented among thos e with beta-thal genes in Maharashtra. Two novel beta-globin alleles w ere each found once: a frameshift codon 55 (+A) in Maharashtrans and a frameshift codons 47-48 (+ ATCT) in Punjabis. Of three Punjabi patien ts with beta-thal intermedia in whom only a single severe alpha-globin gene mutation was found, two had six alpha-globin genes (homozygosity for a triplicated alpha-globin locus) instead of the normal alpha-glo bin gene number of four. Thus, these two individuals had a multilocus aetiology of beta-thal and their parents have the unusual recurrence r isk of 1 in 8 for conceiving a third with beta-thal intermedia. Since 15% of 126 alpha-globin clusters studied in Punjabis contained either single (10%) or triplicated (5%) alpha-globin genes, the alpha-globin gene number is a frequent modifier of the phenotype of beta-thal in th is ethnic group.