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Complete sequencing of 62 mitochondrial DNAs (mtDNAs) belonging (or very closely related) to haplogroup H revealed that this mtDNA haplogroup--by far the most common in Europe--is subdivided into numerous subhaplogroups, with at least 15 of them (H1-H15) identifiable by characteristic mutations. All the haplogroup H mtDNAs found in 5,743 subjects from 43 populations were then screened for diagnostic markers of subhaplogroups H1 and H3. This survey showed that both subhaplogroups display frequency peaks, centered in Iberia and surrounding areas, with distributions declining toward the northeast and southeast--a pattern extremely similar to that previously reported for mtDNA haplogroup V. Furthermore, the coalescence ages of H1 and H3 (~11,000 years) are close to that previously reported for V. These findings have major implications for the origin of Europeans, since they attest that the Franco-Cantabrian refuge area was indeed the source of late-glacial expansions of hunter-gatherers that repopulated much of Central and Northern Europe from ~15,000 years ago. This has also some implications for disease studies. For instance, the high occurrence of H1 and H3 in Iberia led us to re-evaluate the haplogroup distribution in 50 Spanish families affected by nonsyndromic sensorineural deafness due to the A1555G mutation. The survey revealed that the previously reported excess of H among these families is caused entirely by H3 and is due to a major, probably nonrecent, founder event.

Thirty-five mitochondrial (mt) DNAs from Spain that harbor the mutation A3243G in association with either MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) syndrome or a wide array of disease phenotypes (ranging from diabetes and deafness to a mixture of chronic progressive external ophthalmoplegic symptoms and strokelike episodes) were studied by use of high-resolution restriction fragment length polymorphism analysis and control-region sequencing. A total of 34 different haplotypes were found, indicating that all instances of the A3243G mutation are probably due to independent mutational events. Haplotypes were distributed into 13 haplogroups whose frequencies were close to those of the general Spanish population. Moreover, there was no statistically significant difference in haplogroup distribution between patients with MELAS and those with disease phenotypes other than MELAS. Overall, these data indicate that the A3243G mutation harbors all the evolutionary features expected from a severely deleterious mtDNA mutation under strong negative selection, and they reveal that European mtDNA backgrounds do not play a substantial role in modulating the mutation's phenotypic expression.