Molecular Biology and Evolution, Vol 10, 73-102, Copyright © 1993 by Society for Molecular Biology and Evolution
R Hardison and W Miller
The determination of long segments of DNA sequences encompassing the beta-
and alpha-globin gene clusters has provided an unprecedented data base for
analysis of genome evolution and regulation of gene clusters. A newly
developed computer tool kit generates local alignments between such long
sequences in a space-efficient manner, helps the user analyze the
alignments effectively, and finds consistently aligning blocks of sequences
in multiple pairwise comparisons. Such sequence analyses among the
beta-like globin gene clusters of human, galago, rabbit, and mouse have
revealed the general patterns of evolution of this gene cluster. Alignments
in the flanking regions are very useful in assigning orthologous
relationships. Investigation of such matches between the mouse and human
beta-like globin gene clusters has led to a reassessment of some
orthologous assignments in mouse and to a revision of the proposed pathway
for evolution of this gene cluster. In general, the interspersed repetitive
elements have inserted independently, presumably via a retrotransposition
mechanism, in the different mammalian lineages. However, some examples of
ancient L1 repeats are found, including one between the epsilon- and
gamma-globin genes that appears to have been in the ancestral eutherian
gene cluster. Prominent matching sequences are found in a long region 5' to
the epsilon-globin gene, the locus control region (LCR) that is a positive
regulator of the entire gene cluster. Three-way alignments among the human,
goat, and rabbit sequences can extend for > or = 3 kb in part of the LCR
(DNase hypersensitive site 3), indicating that the cis-acting components of
this complex regulatory region cover a long segment of DNA. In contrast to
the beta-like globin gene clusters, the alpha-like globin gene clusters of
many mammals occur in very G+C-rich isochores and contain prominent CpG
islands. The regions between the alpha-like globin genes are evolving
faster than the intergenic regions of the beta-like globin gene clusters.
The contrasts between the two gene clusters can be attributed to
differences in DNA metabolism in the isochore. The proximal control
elements of the rabbit alpha-globin gene are located both 5' to and within
the gene. All of this region is part of a prominent CpG island that may be
acting as an extended, enhancer- independent promoter. One can hypothesize
that the analogue to the LCR in the alpha-globin gene cluster may interface
with the distinctive alpha-globin promoter in ways different from the
interaction between the beta LCR and the promoters of beta-like globin
genes.(ABSTRACT TRUNCATED AT 400 WORDS)
REVIEW ARTICLE
Use of long sequence alignments to study the evolution and regulation of mammalian globin gene clusters
Department of Molecular and Cell Biology, Pennsylvania State University, University Park 16802.
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