Evolution of a Genetic Disease in an Ethnic Isolate: β-Thalassemia in the Jews of Kurdistan

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 88; no. 1; pp. 310 - 314
• Main Authors: Rund, Deborah, Cohen, Tirza, Filon, Dvora, Dowling, Carol E., Warren, Tina C., Barak, Igal, Rachmilewitz, Eliezer, Kazazian, Haig H., Oppenheim, Ariella
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01.01.1991; National Acad Sciences
• Subjects: 550201 - Biochemistry- Tracer Techniques; Alleles; ANEMIAS; Anemias. Hemoglobinopathies; ASIA; Base Sequence; BASIC BIOLOGICAL SCIENCES; Biological and medical sciences; Chromosomes; DEVELOPING COUNTRIES; DISEASES; Diseases of red blood cells; DNA; DNA POLYMERASES; DNA SEQUENCING; ENZYMES; Evolutionary genetics; Female; GENE AMPLIFICATION; GENES; Genetic mutation; Geographic regions; GLOBINS; Globins - genetics; Haplotypes; Hematologic and hematopoietic diseases; HEMIC DISEASES; HEREDITARY DISEASES; Humans; Iran - ethnology; IRAQ; Iraq - ethnology; ISRAEL; Jews - genetics; Male; Medical sciences; MIDDLE EAST; MOLECULAR BIOLOGY; Molecular Sequence Data; Mutation; NUCLEOTIDYLTRANSFERASES; Oligonucleotide Probes; ORGANIC COMPOUNDS; Pedigree; PHOSPHORUS-GROUP TRANSFERASES; Polymerase Chain Reaction; POLYMERASES; Population genetics; PROTEINS; STRUCTURAL CHEMICAL ANALYSIS; SYMPTOMS; THALASSEMIA; Thalassemia - genetics; TRANSFERASES; Turkey - ethnology; Turkey; Iraq; Israel; Iran; Characterization; Globin; Infection; Proteins; Hemoglobinopathy; Protozoal disease; Malaria; β-Thalassemia; Selection pressure; Hemopathy; Mutation; Genetic disease
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.88.1.310

β-Thalassemia is a hereditary disease caused by any of 90 different point mutations in the β-globin gene. Specific populations generally carry a small number of mutations, the most common of which are those that are widely distributed regionally. The present study constitutes an extensive molecular characterization of this disease in a small, highly inbred ethnic group with a high incidence of β-thalassemia--the Jews of Kurdistan. An unusual mutational diversity was observed. In 42 sibships 13 different mutations were identified, of which 3 are newly discovered: a C$\longrightarrow$A transversion at -88 to the cap site, a frameshift in codon 36/37, and an A$\longrightarrow$G transition in the polyadenylylation signal. Four of the mutations are unique to Kurdish Jews and have not been discovered in any other population. A fifth was found outside Kurdish Jews only in an Iranian from Khuzistan, a region bordering Kurdistan. Two-thirds of the mutant chromosomes carry the mutations unique to Kurdish Jews. We traced the origin of the mutations to specific geographic regions within Kurdistan. This information, supported by haplotype analysis, suggests that thalassemia in central Kurdistan (northern Iraq) has evolved primarily from multiple mutational events. In Turkish Kurdistan, the primary mechanism is genetic admixture with the local population. In Iranian Kurdistan, a founder effect appears to be partly responsible. We conclude that several evolutionary mechanisms contributed to the evolution of β-thalassemia in this small ethnic isolate.