Polymorphic NumtS trace human population relationships

Abstract

The human genome is constantly subjected to evolutionary forces which shape its architecture. Insertions of mitochondrial DNA sequences into nuclear genome (NumtS) have been described in several eukaryotic species, including Homo sapiens and other primates. The ongoing process of the generation of NumtS has made them valuable markers in primate phylogenetic studies, as well as potentially informative loci for reconstructing the genetic history of modern humans. Here, we report the identification of 53 human-specific NumtS by inspection of the UCSC genome browser, showing that they may be direct insertions of mitochondrial DNA into the human nuclear DNA after the human-chimpanzee split. In silico analyses allowed us to identify 14 NumtS which are polymorphic in terms of their presence/absence within the human genome in individuals of different ancestry. The allele frequencies of these polymorphic NumtS were calculated for 1000 Genomes Project sequence data from 13 populations worldwide, and principal components analysis and hierarchical clustering methods allowed the detection of strong signals of geographical structure related to the genetic diversity of these loci. All identified polymorphic human-specific NumtS together with a tandemly duplicated NumtS have also been validated by PCR amplification on a panel of 60 samples belonging to five native populations worldwide, confirming the expected NumtS variability. On the basis of these findings, we have succeeded in depicting the landscape of variation of a series of NumtS in several ethnic groups, making an advance in their identification as useful markers in the study on human population genetics.

The genomic landscape of polymorphic human nuclear mitochondrial insertions

“…as well as the human-specific NumtS described in Lang et al. (37) and were able to replicate their results. This difference at the insertion sites could represent a bona fide change in the integration mechanism for recent NumtS, but may also be an artifact from the way reference NumtS have been annotated relative to the mitochondria genome sequence.…”

“…We applied our method to 946 low coverage, whole genomes that were sequenced in Phase 1 of the 1000 Genomes Project (38) as well as 53 additional genomes sequenced to higher coverage from the HGDP (21,39) and were able to identify 141 polymorphic nuclear insertions of mitochondrial origin among all nuclear chromosomes except chrY, (Figure 2), including three which had been previously characterized (37). On average, ∼1.5 non-reference NumtS were seen in each sample, which showed a statistically significant but modest correlation with coverage ( r 2 = 0.12, Supplementary Figure S1) suggesting that although some NumtS may be missed due to low coverage, they are likely minimal.…”

“…MEGA v5.2.2 (http://www.megasoftware.net) was used with our larger Numt insertions and previously reported human-specific NumtS present in the reference (13,19,37) to determine the evolutionary phylogeny of each sequence. Mitochondrial genomes were obtained for Human (Hg19), Chimpanzee (PanTro4), Gorilla (Gorgor3.1) and Orangutan (PonAbe2) from the UCSC Genome Browser, as well as mitochondrial sequences from Neanderthals (NCBI Accessions: KC879692, FM865411, FM865410, FM865408, FM865407), old European fossil (Homo heidelbergensis) (NCBI Accession: NC_023100) and Denisova (NCBI Accession: FN673705) that were downloaded from the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov).…”

“…In contrast to the many studies that have utilized NumtS present in the reference sequences of many species, there has been comparably little exploration into the landscape of polymorphic NumtS in humans (35,36) and the largest such investigation to date has identified only 14 segregating events through investigation of the 1000 Genomes Project INDEL catalog (37). While rigorous, this analysis was limited in its ability to find novel insertion polymorphisms not present in the human genome reference due to the size of the sequence reads in which the variants could be discovered, resulting in the identification of only four such events.…”

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).…”