The cardiac myosin heavy chain genes

The beta- and alpha-myosin cardiac heavy chain genes are tandemly arrayed on chromosome 14q12, separated by 4.5 kb. Comparison of the human and hamster sequences (Jaenicke et al. 90, Liew et al. 90, Epp et al. 93, Wang et al. 94 and Wang et al. 95) using RepeatMasker output giving positions of human repeats and hamster repeats, plus exon locations in the human sequence, yields PIP output showing very high conservation of coding regions, together with somewhat less pronounced matches throughout the entire region.

The strongest matches in non-coding regions are in first few hundred bp upstream of (non-coding) exon 1 of the beta gene and the first 100 bp upstream of (non-coding) exon 1 of the alpha gene; other potentially interesting matches are spread for more than 2000 bp further upstream of the alpha gene. Experimental results based largely on transient transfection of cultured cells, indicated that regulatory signals necessary for high level transcription of both genes, as well as responsiveness to thyroid hormone and contractile activity, are located in the first 400 bp upstream of the transcription start site. However, recent experiments using transgenic mice suggest that in fact several thousand bp of upstream sequence is needed for proper regulation of these genes. For a review of these studies see Robbins 96.

The tissue- and developmental stage-specificities of the alpha and beta cardiac myosin heavy chain genes differ between humans and rodents. In all mammals studied, alpha is the major atrial isoform. In small mammals, it is also the major isoform in ventricular myocytes from postpartum to adulthood (beta is predominately expressed in the embryonic and fetal ventricle), whereas in the human ventricle the beta isoform is expressed almost exclusively. (The alpha protein has a higher speed of contraction, and rodent hearts beat much faster than does a human heart.) This difference may limit what can be learned about gene regulation by comparing the human and rodent sequences.

[Note: The human genomic sequences for the beta and the alpha gene, resp., are in GenBank entries HSCBMYHC (25000 bp) and HSCAMHCA (31462 bp). The first 271 bp of HSCAMHCA are identical to positions 24359-24629 of HSCBMYHC, but the final 25000 - 24626 = 364 nucleotides of HSCBMYHC do not match with HSCAMHCA. To fuse these entries, we equated position 24359 of HSCBMYHC with position 1 of HSCAMHCA. This produces a sequence of 55,820 bp, which agrees with the figure cited by Epp et al. 93). Fusing the hamster entries was more straightforward because the final 60 nucleotides of HAMBMHC (33960 bp) are identical to the first 60 of HAMSHCA (32415 bp).]