Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes

Abstract

DNA transfer from cytoplasmic organelles to the cell nucleus is a legacy of the endosymbiotic event—the majority of nuclear-mitochondrial segments (NUMTs) are thought to be ancient, preceding human speciation1–3. Here we analyse whole-genome sequences from 66,083 people—including 12,509 people with cancer—and demonstrate the ongoing transfer of mitochondrial DNA into the nucleus, contributing to a complex NUMT landscape. More than 99% of individuals had at least one of 1,637 different NUMTs, with 1 in 8 individuals having an ultra-rare NUMT that is present in less than 0.1% of the population. More than 90% of the extant NUMTs that we evaluated inserted into the nuclear genome after humans diverged from apes. Once embedded, the sequences were no longer under the evolutionary constraint seen within the mitochondrion, and NUMT-specific mutations had a different mutational signature to mitochondrial DNA. De novo NUMTs were observed in the germline once in every 104 births and once in every 103 cancers. NUMTs preferentially involved non-coding mitochondrial DNA, linking transcription and replication to their origin, with nuclear insertion involving multiple mechanisms including double-strand break repair associated with PR domain zinc-finger protein 9 (PRDM9) binding. The frequency of tumour-specific NUMTs differed between cancers, including a probably causal insertion in a myxoid liposarcoma. We found evidence of selection against NUMTs on the basis of size and genomic location, shaping a highly heterogenous and dynamic human NUMT landscape.

Dysfunctional mitochondrial processes contribute to energy perturbations in the brain and neuropsychiatric symptoms

“…Thus, pathogen-induced cognitive alterations may benefit the reproductive capacity of neuronal viruses and other CNS pathogens. Indeed, neuronal cell mitochondria become compromised after the integration of the viral genome ( Wei et al, 2022 ). The resulting cognitive impairment benefits viral spread, as infected individuals exhibit behaviors that reduce host protection against infection ( Stefano et al, 2021 ).…”

“…Once the mitochondria have been infected, the virus may then have direct access to the nuclear genome. The intracellular transport of mitochondrial (mt)DNA as nuclear-mitochondrial segments (NUMTs) is an evolutionarily ancient phenomenon (Wei et al, 2022). Of interest, Wei et al (2022) analyzed whole-genome sequences from 66,083 individuals and found that this transfer process is ongoing and that 90% of these NUMTs underwent transfer Frontiers in Pharmacology frontiersin.org comparatively recently in evolutionary terms, i.e., after humans diverged from apes.…”

“…The intracellular transport of mitochondrial (mt)DNA as nuclear-mitochondrial segments (NUMTs) is an evolutionarily ancient phenomenon (Wei et al, 2022). Of interest, Wei et al (2022) analyzed whole-genome sequences from 66,083 individuals and found that this transfer process is ongoing and that 90% of these NUMTs underwent transfer Frontiers in Pharmacology frontiersin.org comparatively recently in evolutionary terms, i.e., after humans diverged from apes. Hence, the evolutionary competition between ancestral prokaryotes and viruses based on natural selection and conformational matching of chemical messengers may have been carried forward by mitochondria into eukaryotic cells, emerging most notably in tissues that involve high energy and oxygen demands, such as the brain.…”

Cellular and environmental dynamics influence species-specific extents of organelle gene retention

“…However, although the present-day oDNA gene profile of an organism is shaped by many factors over its entire evolutionary history (including serial endosymbiosis events in the case of plastids (Keeling, 2010)), and not just its present-day situation (Janouškovec et al, 2017), some biological observations do at least qualitatively suggest that the compatibility of gene profiles of modern organisms and their environments does not conflict with our predictions (Figure 5). Recent work has shown that the transfer of mtDNA to the nucleus is ongoing in modern humans, estimating that one in every few thousand births experiences a de novo transfer of mtDNA material (Wei et al, 2022). It is known that transfer of ptDNA to the nucleus occurs frequently even over an individual plant’s lifetime (Stegemann et al, 2003).…”

Technical specificities of the study of the mitochondrial genome

“…These portions of DNA, called pseudogenes or nuclear-encoded mitochondrial sequences (NUMTs), are thought to be nonfunctional ( Puertas and González-Sánchez, 2020 ). The recent article by Wei et al (2022) published in Nature , reinforces the knowledge on NUMTs and their importance in the study of the mitochondrial genome. These pseudogenes make the study of mtDNA complex since any amplification of the mitochondrial genome may be accompanied by artifactual amplifications in parallel from nuclear pseudogenes.…”