Abstract
The transfer of mitochondrial genetic material into the nuclear genomes of eukaryotes is a well-established phenomenon that has been previously limited to the study of static reference genomes. The recent advancement of high throughput sequencing has enabled an expanded exploration into the diversity of polymorphic nuclear mitochondrial insertions (NumtS) within human populations. We have developed an approach to discover and genotype novel Numt insertions using whole genome, paired-end sequencing data. We have applied this method to a thousand individuals in 20 populations from the 1000 Genomes Project and other datasets and identified 141 new sites of Numt insertions, extending our current knowledge of existing NumtS by almost 20%. We find that recent Numt insertions are derived from throughout the mitochondrial genome, including the D-loop, and have integration biases that differ in some respects from previous studies on older, fixed NumtS in the reference genome. We determined the complete inserted sequence for a subset of these events and have identified a number of nearly full-length mitochondrial genome insertions into nuclear chromosomes. We further define their age and origin of insertion and present an analysis of their potential impact to ongoing studies of mitochondrial heteroplasmy and disease.
Highlights
The presence of mitochondrial DNA in the nuclear genomes of eukaryotes has been well established, and recent reports have shown that this transfer of genetic material is an ongoing evolutionary process (Mourier et al 2001; Ricchetti et al 2004; Hazkani-Covo and Covo 2008; Hazkani-Covo et al 2010; Soto-Calderon et al 2012)
We applied our method to 946 low coverage, whole genomes that were sequenced in Phase 1 of the 1000 Genomes Project (Genomes Project et al 2012) as well as 53 additional genomes sequenced to higher coverage from the HGDP (Cann et al 2002; Martin et al 2014) and were able to identify 141 polymorphic nuclear insertions of mitochondrial origin among all nuclear chromosomes except chrY, (Fig. 2), including 3 which had been previously characterized (Lang et al 2012)
There are approximately 755 annotated nuclear mitochondrial insertions (NumtS) in the reference genome (Calabrese et al 2012), though this number is variable depending on the methods and parameters used to identify their presence
Summary
The presence of mitochondrial DNA in the nuclear genomes of eukaryotes has been well established, and recent reports have shown that this transfer of genetic material is an ongoing evolutionary process (Mourier et al 2001; Ricchetti et al 2004; Hazkani-Covo and Covo 2008; Hazkani-Covo et al 2010; Soto-Calderon et al 2012). While these fragments appear to be randomly selected from different regions of the mitochondria, an underrepresentation of the D-loop region has been reported, though why this is observed is currently unknown (Tsuji et al 2012)
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