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The transmission of human mitochondrial DNA in four‐generation pedigrees
Author(s) -
Liu Qi,
Iqbal Muhammad Faaras,
Yaqub Tahir,
Firyal Sehrish,
Zhao Yiqiang,
Stoneking Mark,
Li Mingkun
Publication year - 2022
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24390
Subject(s) - biology , pedigree chart , mitochondrial dna , genetics , transmission (telecommunications) , dna , evolutionary biology , computational biology , gene , computer science , telecommunications
Abstract Most of the pathogenic variants in mitochondrial DNA (mtDNA) exist in a heteroplasmic state (coexistence of mutant and wild‐type mtDNA). Understanding how mtDNA is transmitted is crucial for predicting mitochondrial disease risk. Previous studies were based mainly on two‐generation pedigree data, which are limited by the randomness in a single transmission. In this study, we analyzed the transmission of heteroplasmies in 16 four‐generation families. First, we found that 57.8% of the variants in the great grandmother were transmitted to the fourth generation. The direction and magnitude of the frequency change during transmission appeared to be random. Moreover, no consistent correlation was identified between the frequency changes among the continuous transmissions, suggesting that most variants were functionally neutral or mildly deleterious and thus not subject to strong natural selection. Additionally, we found that the frequency of one nonsynonymous variant (m.15773G>A) showed a consistent increase in one family, suggesting that this variant may confer a fitness advantage to the mitochondrion/cell. We also estimated the effective bottleneck size during transmission to be 21−71. In summary, our study demonstrates the advantages of multigeneration data for studying the transmission of mtDNA for shedding new light on the dynamics of the mutation frequency in successive generations.