Comprehensive analysis of nuclear mitochondrial DNA transfer in the modern human genome

Abstract

During eukaryotic evolution, mitochondria have gradually transferred their genes to the nucleus, shaping the eukaryotic genome. Despite its significance on evolution and involvement in various disorders and aging, however, the nuclear mitochondrial DNA transfer (NUMT) has not yet been thoroughly investigated in the human genome. Here I aimed to analyze the NUMTs in the modern human genome comprehensively. Using 6,575 whole-genome sequences from the diverse human population, I identified 1,374 polymorphic NUMTs, which exhibited heterogeneous distribution over major ethnic groups. This analysis revealed that NUMTs are being integrated into the human genome with a rate of ~2x10$^{-5}$ per germ cell per year, and more than ~10% of the human population have de novo NUMTs at present. Five of them were found in exonic regions, disrupting exon-intron junctions or start codon of a gene, which suggests the potential involvement of NUMTs on the translation of a gene. I estimated the insertion timing of NUMTs and their distribution over major ethnic groups and identified several genetic bottlenecks during the human migration out of Africa. In addition, this data demonstrated that the structure of NUMTs is not just a single stretch of mitochondrial DNA but has a complex structure suggesting the involvement of various DNA repair mechanisms, including nonhomologous end-joining repair. Collectively, this study represents the most comprehensive analysis of NUMTs in the modern human genome to date, providing the population colonization dynamics of NUMTs and their molecular characteristics.