LENGTH HETEROPLASMY IN THE FIRST HYPERVARIABLE SEGMENT OF THE HUMAN MTDNA CONTROL REGION

The first hypervariable segment of the human mtDNA control region cont ains a homopolymeric tract of cytosines between nt 16184 and 16193, in terrupted at position 16189 by a thymine, according to the Cambridge r eference sequence. A variant commonly found in population screening is a T-to-C transition at nt 16189, resulting in an uninterrupted homopo lymeric tract. Direct sequencing of individuals with this variant prod uces a characteristic blurred sequence in nucleotides beyond the tract . Sequencing clones from these individuals revealed that this is cause d by high levels of length heteroplasmy in the homopolymeric tract and low levels of length heteroplasmy in the four adenines following the tract. We have developed a rapid method involving densitometry of sequ encing gels to quantify the relative proportions of different length v ariants present in an individual. We have used this to study the propo rtions of length variants in individuals from three twin pairs and two maternal lineages. While unrelated individuals usually have different proportions of length variants, all maternally related individuals st udied have the same proportions, even if they are only distantly relat ed. It is not obvious how identical heteroplasmic profiles are maintai ned in maternally related individuals, but some possible mechanisms ar e suggested.