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, 11 (7), 1883-1896

The Genomic Origins of Small Mitochondrial RNAs: Are They Transcribed by the Mitochondrial DNA or by Mitochondrial Pseudogenes Within the Nucleus (NUMTs)?

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The Genomic Origins of Small Mitochondrial RNAs: Are They Transcribed by the Mitochondrial DNA or by Mitochondrial Pseudogenes Within the Nucleus (NUMTs)?

Andrea Pozzi et al. Genome Biol Evol.

Abstract

Several studies have linked mitochondrial genetic variation to phenotypic modifications; albeit the identity of the mitochondrial polymorphisms involved remains elusive. The search for these polymorphisms led to the discovery of small noncoding RNAs, which appear to be transcribed by the mitochondrial DNA ("small mitochondrial RNAs"). This contention is, however, controversial because the nuclear genome of most animals harbors mitochondrial pseudogenes (NUMTs) of identical sequence to regions of mtDNA, which could alternatively represent the source of these RNAs. To discern the likely contributions of the mitochondrial and nuclear genome to transcribing these small mitochondrial RNAs, we leverage data from six vertebrate species exhibiting markedly different levels of NUMT sequence. We explore whether abundances of small mitochondrial RNAs are associated with levels of NUMT sequence across species, or differences in tissue-specific mtDNA content within species. Evidence for the former would support the hypothesis these RNAs are primarily transcribed by NUMT sequence, whereas evidence for the latter would provide strong evidence for the counter hypothesis that these RNAs are transcribed directly by the mtDNA. No association exists between the abundance of small mitochondrial RNAs and NUMT levels across species. Moreover, a sizable proportion of transcripts map exclusively to the mtDNA sequence, even in species with highest NUMT levels. Conversely, tissue-specific abundances of small mitochondrial RNAs are strongly associated with the mtDNA content. These results support the hypothesis that small mitochondrial RNAs are primarily transcribed by the mitochondrial genome and that this capacity is conserved across Amniota and, most likely, across most metazoan lineages.

Keywords: NUMT; genomics; miRNA; mitochondria; mitonuclear.

Figures

<sc>Fig</sc>. 1.
Fig. 1.
—The abundance of small mitochondrial RNAs across species exhibiting different NUMT contents. In (A), the percentage of small RNAs, relative to the total RNAs in the sample, that align exclusively to the mtDNA in five distinct tissues of six separate species. The NUMT content of each species is denoted in parentheses beside the species name, and the species are ordered by ascending NUMT content. Furthermore, the percentage of NUMTs present in their nuclear genome is denoted below the name of each species. Different tissues are represented by distinct colors: Brain (violet), cerebellum (cyan), heart (light blue), kidney (light brown), and testis (yellow). The percentage of reads mapping to the mtDNA, both mtDNA-only and NUMT reads together, is shown on the Y-axis. On the same axis, the percentage of reads in the RNA libraries that map both to the mtDNA and to the nuclear genome (NUMTs reads) is highlighted in light green. For example, in the case of Ornithorhynchus anatinus (platypus), the heart samples show ∼3% of NUMT reads and ∼7.5% of mtDNA-only reads, for a total of 10.5% mtDNA reads. In (B), the percentage of NUMT reads as a proportion of the overall mtDNA reads, for each sample. While in Gallus gallus, <10% of mtDNA reads map the NUMTs, in most samples of the other species almost half of the mtDNA reads map jointly to the NUMT sequence. Despite this, even in species with the highest level of NUMT sequence, around one-third of the mtDNA reads map uniquely to the mtDNA.
<sc>Fig</sc>. 2.
Fig. 2.
—The relationship between the percentage of small mitochondrial RNAs in each tissue and NUMT content (kb), across six species. There are six samples for each combination species/tissue, and each data point represents a sample of a single tissue from a single species. For example in the top left plot we can see a data point at the 2,000 mark on the X-axis, which indicates that small mitochondrial RNAs comprised <2% of the RNA library extracted from the kidney of a species with over 2,000 kb NUMTs length (Opossum).
<sc>Fig</sc>. 3.
Fig. 3.
—Boxplots of percentages of NUMT reads (those mapping both to the mtDNA and the nuclear genome) and mtDNA-only reads in the brain, heart, and liver, across samples taken from chicken and mouse. The percentage of reads in the RNA library mapping to the mtDNA is shown on the vertical axis. The NUMT boxes show the percentage of reads mapping jointly to both mtDNA and NUMT sequence (NUMT reads). The mtDNA-only boxes show reads mapping exclusively to the mtDNA and not to NUMT sequences (mtDNA-only reads). The horizontal line in each box indicates the median of the distribution, and the light gray circles indicate individual data points. The distributions were tested using Mann–Whitney U test and significance (P < 0.05) is indicated with an asterisk.
<sc>Fig</sc>. 4.
Fig. 4.
—Boxplots showing the percentages of NUMT reads and mtDNA-only reads across all tissues pooled (heart, brain, and liver) of chicken and mouse. The percentage of reads in the RNA library mapping to the mtDNA is shown on the Y-axis. The NUMT boxes show the percentage of reads mapping to both mtDNA and NUMT sequence (NUMT reads). The mtDNA-only boxes show the reads mapping only the mtDNA and not the NUMTs (mtDNA-only reads). The horizontal line in each box indicates the median of the distribution, and the light gray circles indicate individual data points. The distributions were tested using Mann–Whitney U test and significance (P < 0.05) is indicated with an asterisk.
<sc>Fig</sc>. 5.
Fig. 5.
—Expression profiles of small mitochondrial RNAs across three tissues of chicken (A & B) and mouse (C & D). Circular representations of (A) chicken mtDNA and (C) mouse mtDNA, in which three concentric circles show the number of reads aligning to each portion of the genome across the three tissue types. From the outer to the inner circle, we can see the expression of mtDNA reads in the liver (brown), heart (magenta), and brain (blue). The scale of each circle is not constant but changed accordingly to highlight the differences in expression among samples within a given tissue. However, within each tissue and species, the scale is constant across different regions of the mtDNA. The makers placed every 2 kb show the approximate location of the genes in the genome. These markers are placed to facilitate the comparison with the linear representations. Linear representations of the chicken (B) and mouse (D) mtDNA, in which small mitochondrial RNAs are mapped to the sequence position, with both mtDNA reads (blue) and mtDNA-only reads (red). The portion of the mtDNA reads not covered by the mtDNA-only reads represents the sequences that map both the mtDNA and the nucleus (NUMT reads). The median number of reads mapping to a specific portion of the mtDNA represents the level of expression in this plot.
<sc>Fig</sc>. 6.
Fig. 6.
—The percentage of small mitochondrial RNAs mapping to the mtDNA in the brain (putatively mitochondria-rich) and bladder epithelium (mitochondria-poor) tissue of humans. The percentage of mtDNA reads in the bladder epithelium can barely be seen because the amount is so low when compared with the brain mtDNA reads (<0.5% of all aligned reads). The horizontal line in each box indicates the median of the distribution, and the light gray circles indicate individual data points. The distributions were tested using Mann–Whitney U test and significance (P < 0.05) is indicated with an asterisk.
<sc>Fig</sc>. 7.
Fig. 7.
—The percentage of small mitochondrial RNAs mapping to the mtDNA in two different types of cells: Healthy (control) and cancerous (cancer). The horizontal line in each box indicates the median of the distribution, and the light gray circles indicate individual data points. The distributions were tested using Mann–Whitney U test and significance (P < 0.05) is indicated with an asterisk.

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