MtDNA substitution rate and segregation of heteroplasmy in coding and noncoding regions

The mitochondrial DNA (mtDNA) substitution rate and segregation of heteropl asmy were studied for the non-coding control region (D-loop) and 500 bp of the coding region between nucleotide positions 5550 and 6050, by sequence a nalysis of blood samples from 194 individuals, representing 33 maternal lin eages. No homoplasmic nucleotide substitutions were detected in a total of 292 transmissions. The estimated substitution rate per nucleotide per milli on pears for the control region (mu>0.21, 95% CI 0-0.6) was not significant ly different from that for the coding region (mu>0.54, 95% CI 0-1.0). Varia tion in the length of homopolymeric C streches was observed at three sites in the control region (positions 65, 309 and 16,189), all of which were in the heteroplasmic state. Segregation of heteroplasmic genotypes between gen erations was observed in several maternal pedigrees. At position 309, a lon ger poly C tract length was strongly associated with a higher probability f or heteroplasmy and rapid segregation between generations. The length heter oplasmy at positions 65 and 16,189 was found at low frequency and was confi ned to a few families.