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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., (Copyright © 2018 by the Genetics Society of America.)

Two sequentially Markov coalescent models (SMC and SMC') are available as tractable approximations to the ancestral recombination graph (ARG). We present a Markov process describing coalescence at two fixed points along a pair of sequences evolving under the SMC'. Using our Markov process, we derive a number of new quantities related to the pairwise SMC', thereby analytically quantifying for the first time the similarity between the SMC' and the ARG. We use our process to show that the joint distribution of pairwise coalescence times at recombination sites under the SMC' is the same as it is marginally under the ARG, which demonstrates that the SMC' is, in a particular well-defined, intuitive sense, the most appropriate first-order sequentially Markov approximation to the ARG. Finally, we use these results to show that population size estimates under the pairwise SMC are asymptotically biased, while under the pairwise SMC' they are approximately asymptotically unbiased., (Copyright © 2015 by the Genetics Society of America.)