Use of long sequence alignments to study the evolution and regulation of mammalian globin gene clusters

R. Hardison, W. Miller

Research output: Contribution to journalArticle

81 Scopus citations

Abstract

The determination of long segments of DNA sequences encompassing the β- and α-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 β-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 β-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 ε- and γ-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 ε-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 ≥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 β-like globin gene clusters, the α-like globin gene clusters of many mammals occur in very G+C-rich isochores and contain prominent CpG islands. The regions between the α-like globin genes are evolving faster than the intergenic regions of the β-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 α-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 α-globin gene cluster may interface with the distinctive α-globin promoter in ways different from the interaction between the β LCR and the promoters of β- like globin genes. The net result, however, is balanced and coordinated expression of these different genes in erythroid cells.

Original languageEnglish (US)
Pages (from-to)73-102
Number of pages30
JournalMolecular biology and evolution
Volume10
Issue number1
StatePublished - 1993

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics

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