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The α globin gene cluster
Comparing human, chicken, mouse, and pufferfish sequences
By Barbra Rodriguez

An international team of investigators has compared the a globin gene cluster on human chromosome 16 to similar DNA sequences from the mouse, chicken and two types of pufferfish. The team identified the stretch of DNA that likely contains all that is needed for human a globin gene expression, and they determined that a comparative method they used may facilitate future cross-species gene comparisons.

Detail from diagram of a globin cluster. View full

The a globin gene cluster contains different types of a hemoglobin, which help form the oxygen-transporting structure inside red blood cells. Defective a globin genes cause a thalassemia, resulting in mild to severe anemia and even death. But efforts to evaluate gene therapy in mice for this disease have been disappointing, possibly because some regulators of globin gene expression have been missing from the constructs used. The current study did not yield new regulators for the human gene cluster.

The researchers cloned and sequenced DNA containing the mouse, chicken, and pufferfish a globin genes. Using computer software programs and sequence databases, they verified the sequence identities and compared them to the human sequence. This revealed that the gene order in all four species was fairly similar. It also identified the outer limits of homology for all but the chicken sequence, thus defining the minimal chromosomal unit likely needed for human a globin gene expression.

A search also was done for a globin gene regulatory elements. It included looking for stretches of DNA rich in paired cytosine and guanine bases that often occur in gene promoters, but vary in prominence among the species studied. The researchers also searched for continuous, 100-base pair or longer regions with more than 70 percent identical base pairs. Two such regions were identified in the human and mouse clusters. However, further study suggested that these regions represent regulatory elements used to remove non-coding sections from cluster genes.

The investigators also compared how well human and mouse sequence matched in length and base pair identity when stretches of unmatched sequence were permitted in the comparisons. This approach confirmed the presence of many previously identified regulatory elements in the evolutionarily similar species, and may prove useful for future studies. However, it failed to identify new elements in chicken or pufferfish a globin clusters. Sequences resembling a human and mouse a globin gene regulator were identified upstream of the genes in these related species, though, and were able to promote expression of a 'marker' gene.

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Flint J., et al. Comparative genome analysis delimits a chromosomal domain and identifies key regulatory elements in the a globin cluster. Hum Mol Genet 10, 371-382 (February 2001).

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