Molecular poltergeists: mitochondrial DNA copies (numts) in sequenced nuclear genomes

Abstract

The natural transfer of DNA from mitochondria to the nucleus generates nuclear copies of mitochondrial DNA (numts) and is an ongoing evolutionary process, as genome sequences attest. In humans, five different numts cause genetic disease and a dozen human loci are polymorphic for the presence of numts, underscoring the rapid rate at which mitochondrial sequences reach the nucleus over evolutionary time. In the laboratory and in nature, numts enter the nuclear DNA via non-homolgous end joining (NHEJ) at double-strand breaks (DSBs). The frequency of numt insertions among 85 sequenced eukaryotic genomes reveal that numt content is strongly correlated with genome size, suggesting that the numt insertion rate might be limited by DSB frequency. Polymorphic numts in humans link maternally inherited mitochondrial genotypes to nuclear DNA haplotypes during the past, offering new opportunities to associate nuclear markers with mitochondrial markers back in time.

Figure 1. Dating numt insertion.

(A) Dating numt insertion based on a mitochondrial phylogenetic tree (black branches). An arrow indicates time of insertion and the numt branch is shown in red. The methodology can be used only in species where the mitochondrial rate of evolution is lower than the nuclear rate of evolution (e.g., mammals but not plants) and when the numts are long enough (>1 kb) to carry enough evolutionary signal. (B) Dating numt insertion based on patterns of presence and absence on a phylogeny. Few nuclear genomes and their genome alignment are used to identify numt insertions. Species that share the descendant from the common ancestor where the transfer occurred include the numts (red rectangle) whereas this numt is missing in the others.

Figure 2. Human polymorphic numts and numts that cause diseases.

Human mitochondrial DNA (NC_001807) is shown in the inner circle, and numt insertions are shown in the outer circle. Polymorphic numts are shown in light green (numts exist in the reference genome) or dark green (numts are missing from the reference genome). Numts causing disease are shown in red. In each case, the reference and the SNP accession numbers (if available) are given. When a numt is inserted within gene, the gene name is indicated (green and red ellipses for polymorphic numts and for numts causing disease, respectively).

Figure 3. Numt content is correlated to genome size.

A log–log scale graph showing the dependency between numt content in genomes and genome size. Information regarding genome size is from http://www.ncbi.nlm.nih.gov/genomes/leuks.cgi.

Figure 4. Mechanism of numt insertion.

Mitochondrial DNA has been suggested to get into the nucleus via a few different pathways. (A) The most supported pathway so far involve the degradation of abnormal mitochondria . Several yme (yeast mitochondrial escape) strains show high level of DNA escape to the nucleus. yme1 mutant cause the inactivation of YMe1p protein, a mitochondrial-localized ATP-dependent metallo-protease leading to high escape rate of mtDNA to the nucleus. Mitochondria of yme1 strain are taken up for degradation by the vacuole more frequently than the wild-type strain. Other pathways to get mitochondrial DNA into the nucleus were suggested including: (B) lysis of mitochondrial compartment, (C) encapsulation of mitochondrial DNA inside the nucleus, (D) direct physical association between the mitochondria and the nucleus and membrane fusions. (E) Mitochondrial DNA that enters the nucleus can integrate into nuclear chromosomes. mtDNA integrated into the chromosome during the repair of DSBs in a mechanism known as non-homologous end-joining (NHEJ). The insertion involves two DSB repair events. Each can be repaired with or without the involvement of short microhomology. In microhomology-mediated NHEJ, base-pair complements are available between the numt and the chromosome ends, similar to the sticky ends created by restriction enzymes.