Low sequence variation in the gene encoding the human beta-myosin heavy chain

Over 40 different mutations in the cardiac myosin heavy chain gene (MYH7) h ave been associated with familial hypertrophic cardiomyopathy (FHC), but no study has analyzed variation at this locus within the normal human populat ion. Here we determine the extent and distribution of nucleotide variation in the 5808-bp MYH7 coding sequence in 25 normal individuals without FHC. W e identified six single-nucleotide polymorphisms, none of which changes the encoded amino acid. At one of these sites, the frequencies of both alleles are equal; at the other five sites, the frequency of the rarer allele vari es from 0.02 to 0.08. The nucleotide diversity (pi) calculated from these d ata is 1.73 x 10(-4) 0.49 x 10(-4). which is lower than the nucleotide dive rsity found in most other human autosomal genes. Substitution analysis of h omologous genes between human and rodent also indicates that the MYH7 seque nce has evolved at a very slow rate. The rate of both synonymous and nonsyn onymous substitutions, especially in the portion of the sequence that encod es the alpha -helical myosin rod, is extremely low. The low level of even s ilent sequence variation in MYH7 in comparisons between human sequences and between human and rodent sequences may be a consequence of strong selectiv e pressure against mutations that cause cardiomyopathy.