Biparental Inheritance of Mitochondrial DNA in Humans

Abstract

Although there has been considerable debate about whether paternal mitochondrial DNA (mtDNA) transmission may coexist with maternal transmission of mtDNA, it is generally believed that mitochondria and mtDNA are exclusively maternally inherited in humans. Here, we identified three unrelated multigeneration families with a high level of mtDNA heteroplasmy (ranging from 24 to 76%) in a total of 17 individuals. Heteroplasmy of mtDNA was independently examined by high-depth whole mtDNA sequencing analysis in our research laboratory and in two Clinical Laboratory Improvement Amendments and College of American Pathologists-accredited laboratories using multiple approaches. A comprehensive exploration of mtDNA segregation in these families shows biparental mtDNA transmission with an autosomal dominantlike inheritance mode. Our results suggest that, although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring. Elucidating the molecular mechanism for this unusual mode of inheritance will provide new insights into how mtDNA is passed on from parent to offspring and may even lead to the development of new avenues for the therapeutic treatment for pathogenic mtDNA transmission.

Keywords: biparental inheritance; human genetics; mitochondria; mtDNA; paternal transmission.

Fig. 1.

Biparental mtDNA inheritance pattern in Family A. (A) Pedigree of Family A. The black filled symbols indicate the four family members (II-1, II-3, II-4, and III-6) showing biparental mtDNA transmission, and the diagonal filled symbols indicate the six family members (III-1, III-2, III-5, IV-1, IV-2, and IV-3) carrying a high number and level of mtDNA heteroplasmy but with normal maternal transmission. The IDs of the 11 family members tested by whole mtDNA sequencing analysis have been underlined in the pedigree. (B) Schematic of the mtDNA genotypes defined by the homoplasmic and/or heteroplasmic variants aligned from the reference mitochondrial genome. Blue bars represent the genotype of paternally derived mtDNA, whereas purple-red and orange-red bars represent maternally derived mtDNA. Entries labeled (D) represent deduced mtDNA genotypes. (C) Summary of the haplogroup and mtDNA variant numbers in Family A.

Fig. 2.

Biparental mtDNA inheritance pattern shown in Family B. (A) Pedigree of Family B. The black filled symbols indicate the two family members (II-3 and III-2) showing biparental mtDNA transmission. The IDs of five family members tested by whole mtDNA sequencing analysis have been underlined in the pedigree. (B) Schematic of the mtDNA genotype defined by the homoplasmic and/or heteroplasmic variants aligned from the reference mitochondrial genome. Blue bars represent the genotype of paternally derived mtDNA, whereas purple-red and orange-red bars represent maternally derived mtDNA. Entries labeled (D) represent deduced mtDNA genotypes. (C) Summary of the haplogroup and mtDNA variant numbers in Family B.

Fig. 3.

Biparental mtDNA inheritance pattern in Family C. (A) Pedigree of Family C. The black filled symbols indicate the three family members (II-3, III-6, and III-7) showing biparental mtDNA transmission, and the diagonal filled symbols indicate the two family members (IV-1 and IV-2) carrying a high number and level of mtDNA heteroplasmy but with normal maternal transmission. The IDs of the five family members tested by whole mtDNA sequencing analysis have been underlined in the pedigree. (B) Schematic of the mtDNA genotypes defined by the homoplasmic and/or heteroplasmic variants aligned from the reference mitochondrial genome. Blue bars represent the genotype of paternally derived mtDNA, whereas purple-red and orange-red bars represent maternally derived mtDNA. Entries labeled (D) represent deduced mtDNA genotypes. (C) Summary of the haplogroup and mtDNA variant numbers in Family C.