The genomic landscape of polymorphic human nuclear mitochondrial insertions

Abstract

The transfer of mitochondrial genetic material into the nuclear genomes of eukaryotes is a well-established phenomenon. Many studies over the past decade have utilized reference genome sequences of numerous species to characterize the prevalence and contribution of nuclear mitochondrial insertions to human diseases. The recent advancement of high throughput sequencing technologies has enabled the interrogation of genomic variation at a much finer scale, and now allows for an exploration into the diversity of polymorphic nuclear mitochondrial insertions (NumtS) in human populations. We have developed an approach to discover and genotype previously undiscovered Numt insertions using whole genome, paired-end sequencing data. We have applied this method to almost a thousand individuals in twenty populations from the 1000 Genomes Project and other data sets and identified 138 novel sites of Numt insertions, extending our current knowledge of existing Numt locations in the human genome by almost 20%. Most of the newly identified NumtS were found in less than 1% of the samples we examined, suggesting that they occur infrequently in nature or have been rapidly removed by purifying selection. We find that recent Numt insertions are derived from throughout the mitochondrial genome, including the D-loop, and have integration biases consistent with previous studies on older, fixed NumtS in the reference genome. We have further determined the complete inserted sequence for a subset of these events to define their age and origin of insertion as well as their potential impact on studies of mitochondrial heteroplasmy.

Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells

“…During endosymbiotic co-evolution, most of the genetic information present in the ancestral mitochondrion has transferred to the nuclear genome (Gray et al 1999;Adams and Palmer 2003;Timmis et al 2004). An apparent burst of mtDNA transfer occurred during primate evolution ∼54 million years ago (Gherman et al 2007) and occasional, probably more recent, transfer in humans has been observed in the germline (Turner et al 2003;Goldin et al 2004;Chen et al 2005;Millar et al 2010;Dayama et al 2014).…”

The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease

“…Complementary in vitro replication assays of the small origin of light strand replication were able to demonstrate that mutations decreased replication efficiency, implying that these missing mutations were likely to have been copied less, creating the illusion of a reduced mutation rate in the mouse 61 . However, the analysis of these naturally occurring human mutations must be confirmed by additional studies, especially in light of the individual-by-individual variation in the number of copies of mitochondrial pseudogenes (NUMTs 45 ) found within the nuclear DNA 46 , which may confound short-read deep-coverage analyses.…”

“…Long-read technologies have even greater intrinsic error rates. Using either short-or long-read sequencing technologies, the data can be contaminated with nuclear mitochondrial DNA sequences (NUMTs) 45,46 or DNA base damage, which can appear as real sequence variants. There is evidence of individual-level variation in NUMTs 46 , so when using short-read next-generation sequencing data, these polymorphic NUMTs can be very difficult to filter out in silico.…”

Endosymbiotic gene transfer from prokaryotic pangenomes: Inherited chimerism in eukaryotes

“…Numts, for nuclear mitochondrial DNA copies (and nupts for the plastid) (94), are typical components of eukaryotic genomes (93)(94)(95) whereas segments of bacterial chromosomes are not. For example, our genomes harbor 53 numts that are specific to the human lineage (96), with 12 numts that are polymorphic in human populations (93), and more numts continuously being found in the human 1,000 Genomes data (97). Five human numts are associated with disease (93), one of which involves a 72-bp numt insertion into exon 14 of the GLI3 gene, causing a premature stop codon, in a rare case of Pallister-Hall syndrome stemming from the Chernobyl incident (98).…”