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A Population Phylogenetic View of Mitochondrial Heteroplasmy.

ABSTRACT: The mitochondrion has recently emerged as an active player in myriad cellular processes. Additionally, it was recently shown that >200 diseases are known to be linked to variants in mitochondrial DNA or in nuclear genes interacting with mitochondria. This has reinvigorated interest in its biology and population genetics. Mitochondrial heteroplasmy, or genotypic variation of mitochondria within an individual, is now understood to be common in humans and important in human health. However, it is still not possible to make quantitative predictions about the inheritance of heteroplasmy and its proliferation within the body, partly due to the lack of an appropriate model. Here, we present a population-genetic framework for modeling mitochondrial heteroplasmy as a process that occurs on an ontogenetic phylogeny, with genetic drift and mutation changing heteroplasmy frequencies during the various developmental processes represented in the phylogeny. Using this framework, we develop a Bayesian inference method for inferring rates of mitochondrial genetic drift and mutation at different stages of human life. Applying the method to previously published heteroplasmy frequency data, we demonstrate a severe effective germline bottleneck comprised of the cumulative genetic drift occurring between the divergence of germline and somatic cells in the mother, and the separation of germ layers in the offspring. Additionally, we find that the two somatic tissues we analyze here undergo tissue-specific bottlenecks during embryogenesis, less severe than the effective germline bottleneck, and that these somatic tissues experience little additional genetic drift during adulthood. We conclude with a discussion of possible extensions of the ontogenetic phylogeny framework and its possible applications to other ontogenetic processes in addition to mitochondrial heteroplasmy.

SUBMITTER: Wilton PR

PROVIDER: S-EPMC5844335 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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A Population Phylogenetic View of Mitochondrial Heteroplasmy.

Wilton Peter R PR Zaidi Arslan A Makova Kateryna K Nielsen Rasmus R

Genetics 20180117 3

The mitochondrion has recently emerged as an active player in myriad cellular processes. Additionally, it was recently shown that >200 diseases are known to be linked to variants in mitochondrial DNA or in nuclear genes interacting with mitochondria. This has reinvigorated interest in its biology and population genetics. Mitochondrial heteroplasmy, or genotypic variation of mitochondria within an individual, is now understood to be common in humans and important in human health. However, it is s ...[more]

PMID: 29343499

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Project description:Herein, we evaluated the concordance of population inferences and conclusions resulting from the analysis of short mitochondrial fragments (i.e., partial or complete D-Loop nucleotide sequences) versus complete mitogenome sequences for 53 bobwhites representing six ecoregions across TX and OK (USA). Median joining (MJ) haplotype networks demonstrated that analyses performed using small mitochondrial fragments were insufficient for estimating the true (i.e., complete) mitogenome haplotype structure, corresponding levels of divergence, and maternal population history of our samples. Notably, discordant demographic inferences were observed when mismatch distributions of partial (i.e., partial D-Loop) versus complete mitogenome sequences were compared, with the reduction in mitochondrial genomic information content observed to encourage spurious inferences in our samples. A probabilistic approach to variant prediction for the complete bobwhite mitogenomes revealed 344 segregating sites corresponding to 347 total mutations, including 49 putative nonsynonymous single nucleotide variants (SNVs) distributed across 12 protein coding genes. Evidence of gross heteroplasmy was observed for 13 bobwhites, with 10 of the 13 heteroplasmies involving one moderate to high frequency SNV. Haplotype network and phylogenetic analyses for the complete bobwhite mitogenome sequences revealed two divergent maternal lineages (dXY = 0.00731; FST = 0.849; P < 0.05), thereby supporting the potential for two putative subspecies. However, the diverged lineage (n = 103 variants) almost exclusively involved bobwhites geographically classified as Colinus virginianus texanus, which is discordant with the expectations of previous geographic subspecies designations. Tests of adaptive evolution for functional divergence (MKT), frequency distribution tests (D, FS) and phylogenetic analyses (RAxML) provide no evidence for positive selection or hybridization with the sympatric scaled quail (Callipepla squamata) as being explanatory factors for the two bobwhite maternal lineages observed. Instead, our analyses support the supposition that two diverged maternal lineages have survived from pre-expansion to post-expansion population(s), with the segregation of some slightly deleterious nonsynonymous mutations.

Dataset Information

A Population Phylogenetic View of Mitochondrial Heteroplasmy.

Publications

A Population Phylogenetic View of Mitochondrial Heteroplasmy.

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