Alternative titles; symbols
HGNC Approved Gene Symbol: HBZ
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38) : 16:152,644-154,503 (from NCBI)
Zeta is an early embryonic chain which is substituted for the alpha chain in Hb Portland-1. This unique hemoglobin was found in a newborn infant with multiple congenital anomalies and complex autosomal chromosomal mosaicism (Capp et al., 1967). Its composition was found to be gamma(2) X(2). It was originally thought that the X-chain might be the epsilon chain whose synthesis persisted until after birth because of the chromosomal anomaly; later work indicated that the X-chain is indeed different from epsilon and therefore it is now called zeta. Hb Portland-2 is the designation for zeta(2)-beta(2) found in stillborn infants with homozygous alpha-thalassemia (Randhawa et al., 1984).
Melderis et al. (1974) presented evidence for the zeta chain being homologous with the alpha chain. The zeta chains of mice, rabbits and man showed close similarities to each other and significant similarities to the alpha chains of these species. Kamuzora and Lehmann (1975) gave sequence data on the human zeta chain and pointed out a close homology to the alpha chain. Recombinant DNA experiments at Cambridge University provided suggestions that the zeta locus may be linked to the alpha loci (Housman, 1979).
Pressley et al. (1980) presented the findings in 2 infants with hemoglobin Bart's hydrops fetalis syndrome (homozygous alpha-thalassemia-1) as evidence that the 5-prime zeta locus is functional. One of the infants had lost the 3-prime-zeta-1 gene but had zeta-globin in the cord blood.
In the mouse, Whitney and Russell (1980) concluded that the embryonic alpha-like gene is closely linked to the gene of adult alpha-globin. In mouse embryos heterozygous for alpha-thalassemia, they found no decrease in the proportion of hemoglobins containing the alpha chain as compared to the hemoglobin containing the alpha-like embryonic globin chain.
Aschauer et al. (1981) found 57 amino acid differences between the zeta chain and the alpha chain. This finding indicates 'a greater phylogenetic distance' between alpha-type chains than between the beta-type chains. Several of the zeta chain replacements are at positions of structural and functional significance, particularly in relation to the Bohr effect and high oxygen affinity which characterize embryonic hemoglobins (Clegg and Gagnon, 1981). The gene order in the HBAC (hemoglobin alpha cluster) is zeta--11.5 kb--pseudozeta--pseudoalpha--alpha-2--alpha-1. What was formerly called zeta-2, the locus at the 5-prime end of the alpha-globin cluster, is the functional gene.
Chung et al. (1984) concluded that deletion of 2 alpha-globin genes on the same chromosome as in alpha-thalassemia is accompanied by the continued expression of embryonic zeta-globin genes in adults. The 3-prime zeta-1 gene, a pseudogene, is highly homologous to the functional 5-prime zeta-2 gene. By genomic mapping and oligonucleotide analysis, Hill et al. (1985) found chromosomes with a zeta-2--zeta-1 rather than a zeta-2--psi-zeta-1 arrangement. Gene conversion of the psi-zeta-1 by the psi-zeta-2 gene appears to have happened. In this interchromosomal process the only identifiable inactivating mutation in the psi-zeta-1 gene was removed. The zeta-2--zeta-1 arrangement was common in all 8 populations studied representing a 'new' type of polymorphism. Stable mRNA transcripts from the converted gene were absent at 16 to 20 weeks of gestation when transcripts from the zeta-2 gene were readily detectable. Zeta-1 (HBZP), or pseudozeta, is very similar to zeta-2 but has a premature termination codon.
Felice et al. (1986) found 4 types of chromosomes with a deletion between the human embryonic zeta- and pseudo-zeta-globin genes among 2.8% of 321 black Americans. These deletions were found in combination with alpha-globin gene deletions in trans but not in cis. No homozygotes were identified. Hematologic data on carriers of the zeta-globin gene deletions in association with hemoglobins AS, SS, and SC suggested that these deletions have no effect on the function of the adult alpha-globin genes. In eastern Polynesians, Hill et al. (1987) found a high frequency of both triplicated zeta-gene chromosomes and a specific alpha-thalassemia deletion. The deletion and a novel RFLP associated with a zeta-zeta-zeta chromosome occur only in Melanesians and Polynesians.
PSEUDOGENES
The Hb zeta pseudogene is about 11.5 kb to the 3-prime side of the zeta locus (Proudfoot et al., 1980). Actually there is a length polymorphism in the segment of DNA that separates the zeta gene from its pseudogene (Goodbourn et al., 1983). (The Hb zeta pseudogene, HBZP, was formerly symbolized HBZ1 and referred to as the 3-prime zeta locus or the psi-zeta locus.)
Leder et al. (2005) reported that a Hbz-null mice displayed an alpha-thalassemia-like syndrome. Embryonic survival of Hbz-null mice was variable and strongly influenced by genetic background. The authors identified 2 modifying loci on chromosomes 2 and 5 in the C57BL/6 background, which affected the penetrance of embryonic lethality. The authors observed an interesting effect on somatic recombination events in thalassemic embryos. These events occurred on multiple chromosomes in very early embryonic cells, prior to their allocation to the germline. Leder et al. (2005) concluded that somatic recombination events can be transmitted to subsequent generations.
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Chung, S.-W., Wong, S. C., Clarke, B. J., Patterson, M., Walker, W. H. C., Chui, D. H. K. Human embryonic zeta-globin chains in adult patients with alpha-thalassemias. Proc. Nat. Acad. Sci. 81: 6188-6191, 1984. [PubMed: 6592610] [Full Text: https://doi.org/10.1073/pnas.81.19.6188]
Clegg, J. B., Gagnon, J. Structure of the zeta chain of human embryonic hemoglobin. Proc. Nat. Acad. Sci. 78: 6076-6080, 1981. [PubMed: 6171809] [Full Text: https://doi.org/10.1073/pnas.78.10.6076]
Felice, A. E., Cleek, M. P., Marino, E. M., McKie, K. M., McKie, V. C., Chang, B. K., Huisman, T. H. J. Different zeta globin gene deletions among black Americans. Hum. Genet. 73: 221-224, 1986. [PubMed: 3015767] [Full Text: https://doi.org/10.1007/BF00401231]
Goodbourn, S. E. Y., Higgs, D. R., Clegg, J. B., Weatherall, D. J. Molecular basis of length polymorphism in the human zeta-globin gene complex. Proc. Nat. Acad. Sci. 80: 5022-5026, 1983. [PubMed: 6308667] [Full Text: https://doi.org/10.1073/pnas.80.16.5022]
Hecht, F., Jones, R. T., Koler, R. D. Newborn infants with Hb Portland 1, an indicator of alpha-chain deficiency. Ann. Hum. Genet. 31: 215-218, 1968. [PubMed: 5648744] [Full Text: https://doi.org/10.1111/j.1469-1809.1968.tb00551.x]
Higgs, D. R., Pressley, L., Aldridge, B., Clegg, J. B., Weatherall, D. J., Cao, A., Hadjiminas, M. G., Kattamis, C., Metaxatou-Mavromati, A., Rachmilewitz, E. A., Sophocleous, T. Genetic and molecular diversity in nondeletion Hb H disease. Proc. Nat. Acad. Sci. 78: 5833-5837, 1981. [PubMed: 6272319] [Full Text: https://doi.org/10.1073/pnas.78.9.5833]
Hill, A. V. S., Gentile, B., Bonnardot, J. M., Roux, J., Weatherall, D. J., Clegg, J. B. Polynesian origins and affinities: globin gene variants in eastern Polynesia. Am. J. Hum. Genet. 40: 453-463, 1987. [PubMed: 2883894]
Hill, A. V. S., Nicholls, R. D., Thein, S. L., Higgs, D. R. Recombination within the human embryonic zeta-globin locus: a common zeta-zeta chromosome produced by gene conversion of the psi-zeta gene. Cell 42: 809-819, 1985. [PubMed: 2996777] [Full Text: https://doi.org/10.1016/0092-8674(85)90277-6]
Housman, D. Personal Communication. Boston, Mass. 1979.
Kamuzora, H., Lehmann, H. Human embryonic haemoglobins including a comparison by homology of the human zeta and alpha chains. Nature 256: 511-513, 1975. [PubMed: 1160998] [Full Text: https://doi.org/10.1038/256511a0]
Leder, A., McMenamin, J., Fontaine, K., Bishop, A., Leder, P. Zeta -/- thalassemic mice are affected by two modifying loci and display unanticipated somatic recombination leading to inherited variation. Hum. Molec. Genet. 14: 615-625, 2005. [PubMed: 15649944] [Full Text: https://doi.org/10.1093/hmg/ddi058]
Melderis, H., Steinheider, G., Ostertag, W. Evidence for a unique kind of alpha-type globin chain in early mammalian embryos. Nature 250: 774-776, 1974. [PubMed: 4413329] [Full Text: https://doi.org/10.1038/250774a0]
Pressley, L., Higgs, D. R., Clegg, J. B., Weatherall, D. J. Gene deletions in alpha-thalassemia prove that the 5-prime zeta locus is functional. Proc. Nat. Acad. Sci. 77: 3586-3589, 1980. [PubMed: 6158051] [Full Text: https://doi.org/10.1073/pnas.77.6.3586]
Proudfoot, N. J., Shander, M. H. M., Manley, J. L., Gefter, M. L., Maniatis, T. Structure and in vitro transcription of human globin genes. Science 209: 1329-1336, 1980. [PubMed: 6158093] [Full Text: https://doi.org/10.1126/science.6158093]
Randhawa, Z. I., Jones, R. T., Lie-Injo, L. E. Separation of the tryptic peptides and cyanogen bromide fragments of the human embryonic zeta chains of hemoglobin Portland I and II by reverse phase high performance liquid chromatography. Hemoglobin 8: 463-482, 1984. [PubMed: 6500986] [Full Text: https://doi.org/10.3109/03630268408991732]
Whitney, J. B., III, Russell, E. S. Linkage of genes for adult alpha-globin and embryonic alpha-like globin chains. Proc. Nat. Acad. Sci. 77: 1087-1090, 1980. [PubMed: 6153802] [Full Text: https://doi.org/10.1073/pnas.77.2.1087]