sequence and organization of the human mitochondrial genome pdf

Sequence and organization of the human mitochondrial genome pdf

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Sequence and organization of the human mitochondrial genome

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Natural selection acts on the phenotype. Therefore, many mistakenly expect to observe its signatures only in the organism, while overlooking its impact on tissues, cells and subcellular compartments.

Mitochondrial genome organization and vertebrate phylogenetics. E-mail: sergiolp ib. With the advent of DNA sequencing techniques the organization of the vertebrate mitochondrial genome shows variation between higher taxonomic levels.

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Mitochondrial pseudogenes in the human nuclear genome have been previously described, mostly as a source of artifacts during the analysis of the mitochondrial genome. With the availability of the complete human genome sequence, we performed a comprehensive analysis of mtDNA insertions into the nucleus.

We found independent integrations that are evenly distributed among all chromosomes as well as within each individual chromosome. The identified pseudogenes account for a content of at least 0. These observations indicate that the migrations of mitochondrial DNA sequences to the nucleus were predominantly DNA mediated.

Phylogenetic analysis of the mtDNA pseudogenes and mtDNA sequences of primates indicate a continuous transfer into the nucleus. Because of the limited window of opportunity for mtDNA transfer to the germline, sperm mtDNA, which is released from degenerating mitochondria after fertilization, could be an important source of nuclear mtDNA pseudogenes. Moreover, these findings have been reported for a variety of species, including more than 60 animal species and plants for a recent review, see Bensasson et al.

Nuclear insertions of mtDNA are also called pseudogenes because those fragments, despite their significant sequence homology, are not transcribed or translated into functional proteins. Part of this is because of the different genetic codes in mitochondrial DNA. The process of integration of mitochondrial DNA fragments into the nucleus is a very old process that presumably started when the first endosymbionts were established as organelles Margulis Ever since, at least in the lineage leading to animals, there has been a downsizing trend of mitochondrial DNA to relocate the genes coding for mitochondrial proteins into the nucleus.

Unsuccessful establishment of a functional nuclear copy would manifest itself as a pseudogene. This concept is well illustrated by the findings that specific genes, commonly present in the mtDNA, are present and expressed in the nucleus of Chlamydomonad algae Perez-Martinez et al.

With the availability of the human genome DNA sequence Lander et al. Our analysis revealed the presence of independent integrations of mtDNA fragments into the human genome. Only three entries, located at position 1 of chromosome 10, appeared to be duplicates of the same entry.

Most of the fragments show an uninterrupted stretch of sequence, whereas some have acquired additional, non-mtDNA sequences of — bp in length or even experienced a deletion of up to bp of DNA. A first look at the complete map of mitochondrial pseudogenes in the human genome see Fig. Pseudogenes can be found evenly distributed across all the human chromosomes.

For each individual chromosome, visual inspection showed that there was no apparent preference for certain loci of integration Fig. MtDNA pseudogenes on chromosome 2 of the public draft of the human genome. The schematic shows the arrangement of mitochondrial pseudogenes on chromosome 2 of the human genome public draft version from July 16, Pseudogenes protein coding genes, rRNAs, and tRNAs are represented as arrows, the length of which corresponds to the extent of alignment of a particular pseudogene with the mtDNA equivalent as shown on the top of the map.

The representation is on scale. The arrows are shaded in four different colors depending on the degree of homology. For ease of orientation, regions corresponding to genes that belong to the same subunit have the same background color, that is, rRNAs and Complex I, IV, and V.

A Mitochondrial pseudogene locations and chromosome gene densities. The diagram compares the location of mitochondrial pseudogenes with the known gene densities for chromosomes 1—22, X, Y, and the yet unassigned contigs Un of the human genome.

The colored bars to the right side of the chromosomes mark the presence of mtDNA fragments that were integrated into the genome. Each bar shows a single integration event and can represent the integration of a single gene or a larger piece of mtDNA. Figure 2 continued on following page. B Number of mtDNA integrations into the nucleus in relation to the degree of homology. The number of mtDNA integrations into the nucleus was calculated for each chromosome.

In addition to isolated pseudogenes, every single pseudogene being part of a larger piece of integrated mtDNA was regarded as one hit. Depending on the degree of homology, the numbers were split into four groups following the grading that was used before see Fig. The height of each bar represents the sum of all unique pseudogenes on one chromosome. C Frequency of integration of mtDNA as a function of fragment size.

The extent to which an integrated fragment covered the full-length mtDNA was calculated in percentage for each contiguous fragment of the map in Figure 1. The number of fragments covering a certain range of percentages was calculated and shown as five groups that are plotted separately for each chromosome.

If analyzed for the number of integrations with a certain degree of homology, the chromosomes show a relatively even distribution of hits throughout all four chosen grades of homology Fig. Most of the high homology hits are part of larger fragments, whereas the entities with lower homology often comprise only a single gene.

Although the number of integrations is representative of the frequency of independent transfer events, it does not reflect the extent of transfer in terms of fragment size. The data were therefore also analyzed in regard to the length of the fragments that were integrated with each event.

Fragment lengths, spanning a contiguous region, were calculated in base pairs and expressed as percentages of mtDNA. Non-mtDNA insertions were not included. Pseudogene fragments were then placed in one of five groups depending on the percentage of coverage as shown in the legend of Figure 2 c.

Chromosomes 17 through 22 contain comparably low numbers of larger fragments. This is not surprising considering the overall smaller size of these chromosomes and the lower total number of hits, which would decrease the statistical chance of finding a larger fragment.

With the total count of base pairs of the human genome being 3,,, bp as of July 16, , the contribution of mitochondrial pseudogenes to the human genome is at least 0. Many mitochondrial pseudogenes in animals and other species have been identified and characterized during the last 15 years.

In most cases a discussion followed concerning the mechanism by which these pseudogenes were generated. Examples for two major candidate mechanisms, transfer by DNA Lopez et al.

Several findings in this report allow us to suggest that the major route of mtDNA sequence transfer into the human genome was by nonhomologous recombination of mtDNA fragments with chromosomal DNA.

Of all contigs that contain pseudogenes, 17 have a fragment that covers the control region of mtDNA, the D-loop, and the promoter region.

Although this number seems small, it is significant, because not all the contigs contain fragments that are in the proximity of this region to begin with. Because part of the D-loop and promoter region is a DNA-only entity i. For a number of fragments, we analyzed the surrounding sequence for each single pseudogene in detail.

We found that those regions matched the corresponding regions in the mtDNA in sequence length and spacing. Mitochondrial mRNA from the primary heavy-strand transcript is spliced post-transcriptionally and polyadenylated Hirsch and Penman ; Ojala and Attardi ; Ojala et al. We were not able to detect poly A -stretches in the intergenic space of adjacent pseudogenes within one fragment, indicating that the pseudogenes must have been derived from an unmodified piece of mtDNA.

Although mtDNA transcription is polycistronic, the large transcripts are quickly processed, and the steady-state levels of the polycistronic precursors are extremely low Attardi et al. Most genes are translated from a single, monocistronic mRNA, and 18 relatively stable transcripts have been identified Ojala et al.

In the case of an RNA-based transfer mechanism, it would be unlikely to see pseudogene assemblies in the human genome spanning more than one of the prevalent RNA species. We therefore determined the number of integrations for four pairs of adjacent genes, counting the insertion events of the single genes, or of the two genes on one contiguous fragment.

Figure 3 A shows those numbers for the pair nd6 and cyt. Because many integrations are smaller than a single gene, it is expected that most pseudogenes would not span the intersection of adjacent genes.

It is clear that in many cases the two genes were transferred as one piece into the human genome. This result is in favor of a predominantly DNA-mediated transfer. Numbers of loci containing adjacent pseudogenes or their respective isolated entities.

This is the case for the four examples shown. Panel A shows the number of integrations of isolated nd6 and cyt. Early work has shown that the mitochondrial mRNA steady-state levels can differ by a factor of 10 between the mitochondrial genes Attardi et al.

In the case of an RNA-based transfer, the integration frequency of any given gene into the human genome would be expected to correlate with the mRNA steady-state levels for that particular gene. A Comparison of steady-state amounts of mitochondrial RNA and the occurrence of the corresponding pseudogene in the nuclear genome. B Comparison of steady-state levels of mitochondrial mRNA and the occurrence of the corresponding pseudogene in the nuclear genome.

Although we did not intend to repeat the analysis as detailed as we already had for the public version, we wondered whether we would find similar results with the CELERA draft. Therefore we focused our attention on the overall pattern of mitochondrial pseudogenes derived from a6, coxI, coxII, and coxIII.

The frequencies of coxI integration into the nuclear DNA and the even distribution of hits throughout the complete genome data not shown are similar for both datasets, being 82 for the public and 77 for the private version.

However, there are some significant differences in the exact loci positions, because not all pseudogene positions from one set are matched with the positions of the other set. Pseudogenes are like molecular fossils inside nuclear genomes and therefore might give insights into evolutionary relationships. To find out how mitochondrial pseudogene sequences compare in homology with each other and with the mtDNA sequences of several other species, we performed multiple alignments of those DNA sequences with ClustalW.

Still, we wanted an alignment that did not consider the length of a fragment for its placement in the tree but rather its homology as the main determinant. The resulting alignment file was then used to build the tree as described in the Methods section. As shown in Figure 5 for coxII -derived pseudogenes, the primate branch has few pseudogenes.

The majority of pseudogenes is located outside this branch. They form a series of sub-branches that indicate the presence of pseudogenes within a range of overlapping homologies, a fact that is reflected by the BLASTN scores of those pseudogenes see above.

Consensus tree of the phylogenetic analysis of mitochondrial gene coxII and coxII pseudogenes in the human genome. Pseudogene sequences were labeled with their contig number, which can also be found in Figure 1.

The tree was constructed using maximum parsimony analysis and represents the consensus tree of equally parsimonious trees. Bootstrap values, calculated from repetitions, are placed at each branchpoint.

A gray box is highlighting the primate branch. There were independent integrations of mtDNA sequences in the human nuclear genome. The number of identified pseudogene fragments together with the size of each fragment translates into a content of at least 0. The same calculations or estimates for other species have been performed before Blanchard and Schmidt ; Bensasson et al.

First, it is likely that, depending on the species involved, different rates of DNA exchange throughout the cytoplasm will be observed, with the result of a more or less successful establishment of mtDNA copies inside the nuclear genome Blanchard and Lynch Second, because pseudogenes are typically located in noncoding regions of nuclear DNA, gene densities might play an important role.

The human genome, on the basis of today's knowledge, contains a large percentage of noncoding DNA. This could explain the comparably high content of mitochondrial pseudogenes in Homo sapiens as opposed to the content in species with more compact genomes, such as Drosophila melanogaster or Caenorhabditis elegans Bensasson et al.

Sequence and organization of the human mitochondrial genome

Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. The complete sequence of the 16,base pair human mitochondrial genome is presented. The sequence shows extreme economy in that the genes have none or only a few noncoding bases between them, and in many cases the termination codons are not coded in the DNA but are created post-transcriptionally by polyadenylation of the mRNAs.


Human mtDNA is a double-stranded, circular DNA molecule consisting of 16, base pairs [21]. The mitochondrial genome is comprised of


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The Human Mitochondrial Genome: From Basic Biology to Disease offers a comprehensive, up-to-date examination of human mitochondrial genomics, connecting basic research to translational medicine across a range of disease types. Here, international experts discuss the essential biology of human mitochondrial DNA mtDNA , including its maintenance, repair, segregation, and heredity. Furthermore, mtDNA evolution and exploitation, mutations, methods, and models for functional studies of mtDNA are dealt with. Disease discussion is accompanied by approaches for treatment strategies, with disease areas discussed including cancer, neurodegenerative, age-related, mtDNA depletion, deletion, and point mutation diseases. With increasing funding for mtDNA studies, many clinicians and clinician scientists are turning their attention to mtDNA disease association.

Neil Howell, P. Chinnery, S. Ghosh, E. Fahy, D. The segregation and transmission of mitochondrial genomes in humans are complicated processes, but are particularly important for understanding the inheritance and clinical abnormalities of mitochondrial disorders.

Burzio, Bios Chile I. Marathon , Santiago, Chile. Telephone: - Fax:

Review ARTICLE

Mitochondrial pseudogenes in the human nuclear genome have been previously described, mostly as a source of artifacts during the analysis of the mitochondrial genome. With the availability of the complete human genome sequence, we performed a comprehensive analysis of mtDNA insertions into the nucleus. We found independent integrations that are evenly distributed among all chromosomes as well as within each individual chromosome. The identified pseudogenes account for a content of at least 0. These observations indicate that the migrations of mitochondrial DNA sequences to the nucleus were predominantly DNA mediated. Phylogenetic analysis of the mtDNA pseudogenes and mtDNA sequences of primates indicate a continuous transfer into the nucleus.

2 comments

  • Ildegunda S. 02.06.2021 at 16:59

    The complete sequence of the base pair human mitochondrial genome is presented. The genes for the 12S and 16S rRNAs, 22 tRNAs.

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  • Zack F. 05.06.2021 at 19:47

    Energy efficient buildings with solar and geothermal resources pdf internal audit manual for microfinance institutions pdf

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