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Cited by 711Chromosomal and Genetic VariationsGenomics and Phylogenetic StudiesEvolution and Paleontology Studies

Genome of the marsupial Monodelphis domestica reveals innovation in non-coding sequences

Open access
Broad Institute Genome Sequencing Platform, Mikkelsen, Tarjei S., Broad Institute Whole Genome Assembly Team, Wakefield, Matthew J., Aken, Bronwen, Amemiya, Chris T., Chang, Jean L., Duke, Shannon +56 more·2007·Nature
DOI 10.1038/nature05805
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Abstract

We report a high-quality draft of the genome sequence of the grey, short-tailed opossum (Monodelphis domestica). As the first metatherian ('marsupial') species to be sequenced, the opossum provides a unique perspective on the organization and evolution of mammalian genomes. Distinctive features of the opossum chromosomes provide support for recent theories about genome evolution and function, including a strong influence of biased gene conversion on nucleotide sequence composition, and a relationship between chromosomal characteristics and X chromosome inactivation. Comparison of opossum and eutherian genomes also reveals a sharp difference in evolutionary innovation between protein-coding and non-coding functional elements. True innovation in protein-coding genes seems to be relatively rare, with lineage-specific differences being largely due to diversification and rapid turnover in gene families involved in environmental interactions. In contrast, about 20% of eutherian conserved non-coding elements (CNEs) are recent inventions that postdate the divergence of Eutheria and Metatheria. A substantial proportion of these eutherian-specific CNEs arose from sequence inserted by transposable elements, pointing to transposons as a major creative force in the evolution of mammalian gene regulation.

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Claims the paper makes

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  • Findingcitation

    Orthologues of CD4 and CD8 were identified in opossum, which had not been successfully identified by cloning in metatherian species.

    “Notably, we identified orthologues of key T-cell lineage markers such as CD4 and CD8, which had not been successfully identified by cloning in metatherian species 39 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Wong, E. S., Young, L. J., Papenfuss, A. T. & Belov, K. In silico identification of opossum cytokine genes suggests the complexity of the marsupial immune system rivals that of eutherian mammals. Immunome Res. 2, 4 (2006) source

      Not checked in the free run.

  • Findingown data

    No XIST homologue was found in the opossum genome sequence.

    “We searched all assembled and unassembled opossum WGS sequence for homology to the human and mouse XIC non-coding genes but, in agreement with a recent report 66 , did not find any significant alignments.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66] Duret, L. et al. The Xist RNA gene evolved in eutherians by pseudogenization of a protein-coding gene. Science 312, 1653–1655 (2006) source

      Not checked in the free run.

  • Findingown data

    In mouse, LINE/L1 density is elevated in both the XCR (35%) and the XAR (32%).

    “In mouse, we found that the LINE/L1 density is elevated in both the XCR (35%) and the XAR (32%), which is consistent with the observation that genes that escape inactivation on the human XAR are often inactivated in mouse 69 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Disteche, C. M., Filippova, G. N. & Tsuchiya, K. D. Escape from X inactivation. Cytogenet. Genome Res. 99, 36–43 (2002) source

      Not checked in the free run.

  • Findingreasoning

    The opossum sequence composition is more homogeneous than that of other amniotes.

    “Indeed, the sequence composition is also more homogeneous than seen in other amniotes (Fig. 1).”
    Quote in the paperSubstantial claim
  • Findingown data

    The XAR-XCR fusion point maps to 46.85 Mb on human chromosome band Xp11.3.

    “Using our high-resolution synteny map we can now confidently map the XAR-XCR fusion point to 46.85 Mb on human chromosome band Xp11.3 (Fig. 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fig. 2

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  • May combine two claims. 47
  • Classified as probably not a substantial claim. 21
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    The mean autosomal CpG density in opossum is 0.9%, twofold lower than in other amniotes.

    “and, in particular, the mean autosomal density of CpGs (0.9%) is twofold lower than in other amniotes (1.7-2.2%).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Unambiguous human orthologues were identified for 15,320 (82%) opossum predicted genes, with 12,898 cases having a single copy in each species.

    “We could identify unambiguous human orthologues for 15,320 (82%) of the opossum predicted genes, with 12,898 cases having a single copy in each species (1:1 orthologues).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Goodstadt, L. & Ponting, C. P. Phylogenetic reconstruction of orthology, paralogy, and conserved synteny for dog and human. PLoS Comput. Biol. 2, e133 (2006) source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The opossum X chromosome has mean G+C content 40.9% and CpG density 1.4%, substantially higher than any autosome.

    “The mean G1C content (40.9%) and CpG density (1.4%) of the X chromosome are substantially higher than for any of the autosomes (Supplementary Table 11).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Supplementary Table 11

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Opossum segmental duplications are more locally distributed: 76% are intrachromosomal versus 46% in human, and the median distance between related duplications is 175 kb versus 2.2 Mb in human.

    “Additionally, the segmental duplications are more locally distributed: 76% are intrachromosomal (versus 46% for human) and the median distance between related duplications is 175 kb (versus 2.2 Mb for human).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The mean autosomal G+C content in opossum is 37.7%, lower than in other sequenced amniotes.

    “Consistent with the proposed model, the mean autosomal G1C content (37.7%) is also lower than in other sequenced amniotes (40.9-41.8%)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The XAR and XCR homologous regions experienced several major rearrangements in the opossum lineage (about 15 breakpoints) and in the eutherian lineage before the eutherian radiation (about 9 breakpoints).

    “Consistent with this hypothesis, our synteny map reveals that the XAR and XCR homologous regions have experienced several major rearrangements both in the opossum lineage (,15 lineage-specific synteny breakpoints) and in the eutherian lineage before the eutherian radiation (,9 lineage-specific breakpoints; Supplementary Table 15).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Supplementary Table 15

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    At least 52% of the opossum genome is recognized as transposable elements and other interspersed repeats, more than in other sequenced amniotes.

    “At least 52% of the opossum genome can be recognized as transposable elements and other interspersed repeats (Table 2) 33,35 , which is more than in any of the other sequenced amniotes (34-43%).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [33] Gentles, A. J. et al. Evolutionary dynamics of transposable elements in the short-tailed opossum Monodelphis domestica. Genome Res. doi: 10.1101/gr.6070707 (2007) source

      Not checked in the free run.

    • cites [35] Gu, W. et al. Phylogenetic detection, population genetics, and distribution of active SINEs in the genome of Monodelphis domestica. Gene doi: 10.1016/j.gene.2007.02.028 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The rat X chromosome has accumulated about 4 lineage-specific synteny breakpoints after divergence from mouse and is enriched for LINE/L1 in both the XCR (36.7%) and the XAR (34.5%).

    “The rat X chromosome has accumulated ,4 lineagespecific synteny breakpoints after the divergence from mouse 61 , and is similarly enriched for LINE/L1 in both the XCR (36.7%) and the XAR (34.5%).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Ross, M. T. et al. The DNA sequence of the human X chromosome. Nature 434, 325–337 (2005) source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The opossum genome is significantly enriched in non-LTR retrotransposons, with LINEs comprising 29%.

    “Notably, the opossum genome is significantly enriched in non-long terminal repeat (LTR) retrotransposons (LINEs, 29%), comprising copies of various LINE subfamilies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The mouse X chromosome has experienced 15 lineage-specific synteny breakpoints, so the XAR and XCR are no longer separate segments.

    “We note that unlike in human, the mouse X chromosome has experienced several rearrangements (with 15 lineage-specific synteny breakpoints), such that the XAR and XCR are no longer two separate segments.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The overall proportion of segmental duplication in opossum is 1.7%, substantially lower than in other sequenced amniotes.

    “The overall proportion of segmental duplication in opossum (1.7%) is indeed substantially lower than in other sequenced amniotes (2.5-5.3%).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    Within about 10 Mb of opossum chromosome ends, mean G+C content is 41.6% and CpG density is 1.9%, significantly elevated relative to the rest of the autosomes.

    “Consistent with a higher sex-averaged rate of recombination, mean G1C-content (41.6%) and CpG density (1.9%) are significantly elevated within ,10 Mb of the chromosome ends (Supplementary Fig. 4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Supplementary Fig. 4

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The average autosomal recombination rate in opossum is about 0.2-0.3 cM/Mb, lower than in other sequenced amniotes.

    “Current linkage data 38 show that the average recombination rate for the autosomes (,0.2-0.3 cM Mb 21 ) is lower than in other sequenced amniotes (0.5-.3 cM Mb 21 ).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Samollow, P. B. et al. A microsatellite-based, physically anchored linkage map for the gray, short-tailed opossum (Monodelphis domestica). Chromosome Res. advance online publication, doi:10.1007/s10577-007-1123-4 (25 February 2007) source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    LINE/L1 density on the opossum X chromosome is 22%, lower than in the eutherian XCR and slightly less than in autosomal regions homologous to the eutherian XAR (23%).

    “In contrast to human and mouse, the LINE/L1 density on the opossum X chromosome (22%) is significantly lower than in the eutherian XCR, and is in fact slightly less than in the autosomal regions homologous to the eutherian XAR (23%).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    The dog X chromosome is collinear with human and is enriched for LINE/L1 only in the XCR (33.4% versus 16.8% for the XAR).

    “The dog X chromosome is collinear with human and is enriched for LINE/L1 only in the XCR (33.4% versus 16.8% for the XAR).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    The opossum genome contains a new T-cell receptor isotype that is expressed early in ontogeny, before conventional T-cell receptors.

    “The opossum genome also contains a new T-cell receptor isotype that is expressed early in ontogeny, before conventional T-cell receptors, and may provide early immune function in the altricial young 37 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Parra, Z. E. et al. A new T-cell receptor discovered in marsupials. Proc. Natl Acad. Sci. USA (submitted).

      Not checked in the free run.

  • May combine two claims.

    Findingnone given

    The mature form of hsa-mir-194-1 is identical to a second conserved miRNA, hsa-mir-194-2, which has an opossum orthologue.

    “(The mature form of this miRNA is identical to a second conserved miRNA, hsa-mir-194-2, which does have an opossum orthologue; this apparent redundancy may have made it more susceptible to lineage-specific loss.)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The median intraspecies KA/KS ratio between opossum paralogues is 0.51, which is sixfold higher than the interspecies ratio for 1:1 orthologues, 0.086.

    “The median intraspecies ratio of nonsynonymous to synonymous substitution rates (K A /K S ) between paralogues is 0.51, which is sixfold higher than the interspecies ratio seen for 1:1 orthologues (0.086).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Eutherian conserved elements cover 104 Mb, or 3.7%, of the human genome, and about 29% of them overlap protein-coding sequence.

    “We identified a collection of eutherian conserved elements that cover 104 Mb (3.7%) of the human genome, using the phylo-HMM approach 14 ; ,29% of them overlap protein-coding sequence (Supplementary Data).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Siepel, A. et al. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 15, 1034–1050 (2005) source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    There are approximately 133,000 conserved intervals between opossum and chicken covering 68 Mb, and about half overlap protein-coding regions.

    “We focused on ,133,000 conserved intervals between opossum and chicken (68 Mb), ,50% of which overlaps protein-coding regions (Supplementary Data).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The median Ks of 1:1 opossum-human orthologues is substantially smaller than the chicken-human Ks value of 1.7, with the ratio close to the ratio of prior divergence-time estimates.

    “Consistent with expectation, this value is substantially smaller than the chickenhuman K S value (1.7), with the ratio being very close to the ratio of prior estimates of the divergence times for the two lineages (,180 Myr ago for opossum and ,310 Myr ago for chicken).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    The eight functional opossum genes without human homologues include CPD-photolyase, malate synthase, and inosine/uridine hydrolase.

    “These include CPDphotolyase, which is part of an ancestral photorepair system still active in opossum 71 , malate synthase 72 and inosine/uridine hydrolase.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [71] Kato, T. et al. Cloning of a marsupial DNA photolyase gene and the lack of related nucleotide sequences in placental mammals. Nucleic Acids Res. 22, 4119–4124 (1994) source

      Not checked in the free run.

    • cites [72] Kondrashov, F. A. et al. Evolution of glyoxylate cycle enzymes in Metazoa: evidence of multiple horizontal transfer events and pseudogene formation. Biol. Direct 1, 31 (2006) source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    An 87-bp eutherian-specific CNE corresponds to hsa-mir-28, which was previously detected by northern blot in human and mouse but not in non-mammalian species.

    “An example is an 87-bp eutherian-specific CNE corresponding to hsa-mir-28; it has previously been detected by northern blot analysis in human and mouse, but not in any non-mammalian species 79 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Lagos-Quintana, M., Rauhut, R., Lendeckel, W. & Tuschl, T. Identification of novel genes coding for small expressed RNAs. Science 294, 853–858 (2001) source

      Not checked in the free run.

  • May combine two claims.

    Findingreasoning

    Approximately 14.8 Mb of eutherian conserved elements are eutherian-specific, calculated from 1.1% of 30 Mb of coding sequence and 20.5% of 74 Mb of CNEs.

    “Taking the results from ungapped syntenic intervals as a conservative estimate for the proportion of total innovation, we conclude that approximately 14.8 Mb (1.1% of 30 Mb of coding sequence and 20.5% of 74 Mb of CNEs) of the eutherian conserved elements are eutherian specific.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    Apparent innovation is highest among short and moderately conserved elements, with median length 37 bp and median log2-odds score 22.

    “The amount of apparent innovation is highest among short and moderately conserved elements (median length of 37 bp; median log 2 -odds score 5 22), probably reflecting, in part, that shorter elements may more readily diverge beyond recognition (see also refs 36, 76).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Protein-coding sequence makes up 50% of all amniote conserved elements but only 4% of the elements lost in one lineage.

    “Notably, although protein-coding sequence comprises 50% of all amniote conserved elements, they comprise only 4% of the elements lost in one of the lineages.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    The median overlap with human RepeatMasker annotations for transposon-derived eutherian CNEs is 100% across all elements and 54% for those with log2-odds score ≥60.

    “Eutherian CNEs were classified as transposableelement-derived if they showed more than 20% nucleotide overlap (median 5 100% for all elements, 54% for elements with log 2 -odds score $ 60) with human RepeatMasker annotations.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Among opossum genes with human orthologues, 12,898 are 1:1 orthologues.

    “| 1:1 | 1 2 ,898 |”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Among opossum genes with human orthologues, 451 are 1:many.

    “| 1:Many | 451 |”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The initial set of predicted opossum protein-coding genes contains 18,648 genes.

    “| Initial predictions | 18,648 |”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Comparison of the opossum and eutherian X chromosomes revealed that the evolution of random X chromosome inactivation correlates with acquisition of XIST, elevation in LINE/L1 density and suppression of large-scale rearrangements.

    “In addition, comparison of the opossum and eutherian X chromosomes revealed that the evolution of random X chromosome inactivation correlates with acquisition of XIST, elevation in LINE/L1 density and suppression of large-scale rearrangements.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Under a less conservative criterion, where an element was considered present if its alignment score merely surpassed that of the permuted sequence, 15% of eutherian CNEs in ungapped regions and 8% of those with log2-odds score ≥60 were classified as eutherian-specific.

    “(Conservatively calling an element found if its score simply exceeded the score of the permuted element resulted in 15% of eutherian CNEs in ungapped regions and 8% of those with log 2 -odds score $ 60 being called eutherian-specific.)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Among opossum genes with human orthologues, 582 are many:many.

    “| Many:Many | 582 |”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingcitation

    35% of all eutherian CNEs and 49% of all amniote CNEs in ungapped syntenic regions lie within the 204 largest CNE clusters in the human genome.

    “For example, 35% of all eutherian CNEs and 49% of all amniote CNEs (in ungapped syntenic regions) lie within the 204 largest clusters of CNEs in the human genome (described in ref. 10).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Lindblad-Toh, K. et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438, 803–819 (2005) source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    The approximately 240 key developmental genes in these regions have relatively low amino acid divergence, with median KA/KS = 0.03, and show little evidence of lineage-specific loss or duplications.

    “The ,240 key developmental genes in these regions have relatively low rates of amino acid divergence (median K A /K S 5 0.03) and show little evidence of lineage-specific loss or duplications.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The overlapping transposable elements originate from most major transposon families found in eutherians and are not clearly differentiated from other CNEs in their distribution across the genome.

    “The overlapping transposable elements originate from most major transposon families found in eutherians (Table 4), and are not clearly differentiated from other CNEs in terms of distribution across the genome.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For eutherian-specific conserved non-coding elements with log2-odds score ≥60, 1,243 are overlapped by transposons, covering 203 kb.

    “| Total | 33,760 | 1,383 | 1,243 | 203 |”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The opossum X chromosome pattern is opposite to that in eutherians, where the X chromosome has low recombination and low G+C content and CpG density.

    “The opossum pattern is thus the opposite of that seen in eutherians, in which the X chromosome has low recombination and low G1C content and CpG density (Table 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 2

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Metatherians and eutherians diverged about 180 million years ago.

    “Metatherians and eutherians diverged ,180 million years (Myr) ago, long before the radiation of the extant eutherian clades ,100 Myr ago 1,2 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Kumar, S. & Hedges, S. B. A molecular timescale for vertebrate evolution. Nature 392, 917–920 (1998) source

      Not checked in the free run.

    • cites [2] Woodburne, M. O., Rich, T. H. & Springer, M. S. The evolution of tribospheny and the antiquity of mammalian clades. Mol. Phylogenet. Evol. 28, 360–385 (2003) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The average effective recombination rate on the opossum X chromosome is at least 0.44 cM/Mb, larger than for the autosomes.

    “Although few linkage data are currently available for opossum X chromosome, the average effective recombination rate must be at least 0.44 cM Mb 21 , and thus larger than for the autosomes.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [53] Holm, P. B. Ultrastructural analysis of meiotic recombination and chiasma formation. Tokai J. Exp. Clin. Med. 11, 415–436 (1986)

      Not checked in the free run.

    • cites [54] Samollow, P. B. et al. First-generation linkage map of the gray, short-tailed opossum, Monodelphis domestica, reveals genome-wide reduction in female recombination rates. Genetics 166, 307–329 (2004) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Previous studies have shown that eutherian and amniote CNEs are enriched in large, gene-poor regions surrounding key developmental genes, primarily transcription factors, morphogens and axon guidance receptors.

    “Previous studies have shown that both eutherian and amniote CNEs are enriched in certain large, gene-poor regions surrounding genes that have key roles in development, primarily encoding transcription factors, morphogens and axon guidance receptors 10,81,82 .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10] Lindblad-Toh, K. et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438, 803–819 (2005) source

      Not checked in the free run.

    • cites [81] Sandelin, A. et al. Arrays of ultraconserved non-coding regions span the loci of key developmental genes in vertebrate genomes. BMC Genom. 5, 99 (2004) source

      Not checked in the free run.

    • cites [82] Woolfe, A. et al. Highly conserved non-coding sequences are associated with vertebrate development. PLoS Biol. 3, e7 (2005) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The fraction of miRNAs corresponding to eutherian-specific CNEs is slightly lower, 15%, which is consistent with their higher average conservation scores.

    “The fraction of miRNAs that correspond to eutherian-specific CNEs is slightly lower (15%), which is consistent with their higher average conservation scores.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The remaining 1.0% of amniote elements could not be found even by a more sensitive alignment algorithm and seem to have been lost in the human lineage.

    “The remaining 1.0% of amniote elements could not be found even by a more sensitive alignment algorithm (Fig. 5b), and thus seem to have been lost in the human lineage.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The elevated Ks on the XCR is opposite to what is observed within Eutheria and is consistent with the expectation that higher G+C content and recombination rate on the opossum X chromosome imply a higher mutation rate.

    “This is the opposite to what is observed within Eutheria 10 , but is consistent with the expectation that the higher G1C-content and recombination rate on the opossum X chromosome relative to its autosomes implies a higher rate of mutation 47 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Jensen-Seaman, M. I. et al. Comparative recombination rates in the rat, mouse, and human genomes. Genome Res. 14, 528–538 (2004) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The opossum genome probably contains 18,000-20,000 protein-coding genes, with the vast majority having eutherian orthologues.

    “On the basis of our comparison, we conclude that the opossum genome probably contains ,18,000-20,000 protein-coding genes, with the vast majority having eutherian orthologues.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Monodelphis domestica is sufficiently representative of metatherians that conclusions drawn from its genome apply to the metatherian lineage generally.

  • May combine two claims.

    Interpretationown data

    Most of the 624 opossum genes without clear human homologues are short and probably originate from pseudogenes or spurious open reading frames.

    “Inspection revealed that most of these are short (median length of 120 amino acids, compared with 445 for 1:1 orthologues) and probably originate from pseudogenes or spurious open reading frames.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The number of opossum lineage-specific duplications is one-third fewer than the number of human lineage-specific duplications, which may reflect the lower rate of segmental duplication in the opossum genome.

    “The number of duplications is one-third fewer than the number of human lineage-specific duplications (4,037; 20%), which may reflect the lower rate of segmental duplication in the opossum genome.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Monodelphis domestica is sufficiently representative of metatherians that conclusions drawn from its genome apply to the metatherian lineage generally.

  • May combine two claims.

    Interpretationown data

    A 269-bp eutherian-specific CNE in intron 2 of BCL2 overlaps a DNase hypersensitive site, suggesting that it has a cis-regulatory function.

    “An example is a 269-bp eutherian-specific CNE in intron 2 of the apoptosis regulator BCL2, which overlaps a DNase hypersensitive site, suggesting it has a cis-regulatory function (Fig. 5f).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    The first complete genome sequence for a marsupial, Monodelphis domestica, provides an important resource for genetic analysis in this model organism and the first reference sequence for metatherian mammals.

    “The generation of the first complete genome sequence for a marsupial, Monodelphis domestica, provides an important resource for genetic analysis in this unique model organism, as well as the first reference sequence for metatherian mammals.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Individual instances of CNEs derived from transposable elements have been described previously.

    “Individual instances of CNEs derived from transposable elements have been described previously 14,94,95 .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [14] Siepel, A. et al. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 15, 1034–1050 (2005) source

      Not checked in the free run.

    • cites [94] Cooper, G. M. et al. Distribution and intensity of constraint in mammalian genomic sequence. Genome Res. 15, 901–913 (2005) source

      Not checked in the free run.

    • cites [95] Silva, J. C. et al. Conserved fragments of transposable elements in intergenic regions: evidence for widespread recruitment of MIR- and L2-derived sequences within the mouse and human genomes. Genet. Res. 82, 1–18 (2003) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The opossum genome sequence has provided the first estimate of the genome-wide rate of CNE innovation in eutherian evolution and identification of tens of thousands of lineage-specific elements.

    “The opossum genome sequence has provided the first estimate of the genome-wide rate of CNE innovation in eutherian evolution, as well as identification of tens of thousands of lineage-specific elements.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    No comparative data were used in the opossum genome assembly process.

    “No comparative data were used in the assembly process.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Transposable elements contain functional subunits that can be exapted and modified by the host genome, and they can mediate duplication of existing CNEs to distant genomic locations.

    “Transposable elements contain a variety of functional subunits that can be exapted and modified by the host genome 89,91 , and they can mediate duplication of existing CNEs to distant genomic locations through transduction or chimaerism 92 .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [89] Britten, R. J. Mobile elements inserted in the distant past have taken on important functions. Gene 205, 177–182 (1997) source

      Not checked in the free run.

    • cites [91] Brosius, J. Genomes were forged by massive bombardments with retroelements and retrosequences. Genetica 107, 209–238 (1999) source

      Not checked in the free run.

    • cites [92] Kazazian, H. H. Mobile elements: drivers of genome evolution. Science 303, 1626–1632 (2004) source

      Not checked in the free run.

  • Classified as probably not a substantial claim. The quote only partly states this claim.

    Study design and conductnone given

    A randomly permuted version of each conserved element was realigned as a control.

    “A randomly permuted version of each element was also realigned.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    It is widely suspected that the latter proportion is a significant underestimate because transposable elements inserted more than about 100-200 Myr ago are difficult to recognize.

    “It is widely suspected that the latter proportion is a significant underestimate owing to the difficulty of recognizing transposable elements that inserted more than ,100-200 Myr ago 7,33 .”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] Mouse Genome Sequencing Consortium Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002) source

      Not checked in the free run.

    • cites [33] Gentles, A. J. et al. Evolutionary dynamics of transposable elements in the short-tailed opossum Monodelphis domestica. Genome Res. doi: 10.1101/gr.6070707 (2007) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationcitation

    Availability of the genome sequence now facilitates more systematic study of the metatherian immune response.

    “Availability of the genome sequence now facilitates more systematic study of the metatherian immune response 39 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Wong, E. S., Young, L. J., Papenfuss, A. T. & Belov, K. In silico identification of opossum cytokine genes suggests the complexity of the marsupial immune system rivals that of eutherian mammals. Immunome Res. 2, 4 (2006) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The monDom5 assembly has identical sequence content and scaffold structure to monDom4, but includes additional FISH data.

    “The most recent version (monDom5) has identical sequence content and scaffold structure, but includes additional FISH data as described in Supplementary Note 2.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Improved annotations that do not rely on homology to distant species will be required to complete the opossum gene catalogue.

    “Lineagespecific genes seem to be largely limited to gene families that are rapidly turning over in all mammals, although improved annotations that do not rely on homology to distant species will be required to complete the opossum gene catalogue.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    For SNP discovery, only discrepancies of high quality that had support from at least two reads were used.

    “The SNP discovery was performed using ARACHNE by comparison of the two haplotypes derived from the opossum assembly using only high-quality discrepancies supported by two or more reads each.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    It has been unclear whether the evolution of CNEs from transposable elements represents a general mechanism or a rare exception.

    “It has thus been unclear whether the evolution of CNEs from transposable elements represents a general mechanism or a rare exception.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S2 (checkable), S3 (load-bearing).

    Premisecitation

    Transposable elements offer an obvious and ideal substrate for the evolution of lineage-specific functions.

    “A number of researchers have argued that transposable elements offer an obvious and ideal substrate for the evolution of lineage-specific functions [89][90][91][92][93] .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89][90][91][92][93]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Elements thought to be eutherian-specific, such as XIST, were additionally queried against every opossum sequencing read with discontiguous MegaBLAST.

    “Putatively eutherian-specific elements, including XIST, were also searched against all opossum sequencing reads using discontiguous MegaBLAST.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Exapted sequences would be expected to diverge beyond recognition at a rate similar to inactive insertions if transposable-element hallmarks are not essential to the subsequent CNE or if a new function did not follow immediately after insertion.

    “In cases where the transposable-elementrelated sequence hallmarks are not essential to the subsequent CNE, or where evolution of a new function did not follow immediately after the transposable element insertion, exapted sequences would be expected to have diverged to the point that they can no longer be readily recognized at a rate similar to inactive insertions.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    An amniote element was designated lost, and a eutherian element was designated eutherian-specific, only when its Smith-Waterman realignment score divided by element length did not exceed the permuted element's score by more than one.

    “Amniote elements were called lost, and eutherian elements were called eutherian-specific if their Smith-Waterman realignment score, divided by the length of the element, did not exceed the corresponding score for the permuted element plus one.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Lineage-specific loss seems to be relatively rare for both amniote elements and eutherian elements.

    “But, lineage-specific loss seems to be relatively rare for both amniote elements, as shown above, and for eutherian elements 10 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Lindblad-Toh, K. et al. Genome sequence, comparative analysis and haplotype structure of the domestic dog. Nature 438, 803–819 (2005) source

      Not checked in the free run.

65 of 65

  • The paper relies on this without support.

    Monodelphis domestica is sufficiently representative of metatherians that conclusions drawn from its genome apply to the metatherian lineage generally.

    “As the first metatherian ('marsupial') species to be sequenced, the opossum provides a unique perspective on the organization and evolution of mammalian genomes.”

  • The authors state this as an assumption.

    Every eutherian-specific conserved element arose by one of three mechanisms: divergence of an ancestral functional element beyond detectability, duplication of an ancestral functional element without a 1:1 orthologue in other clades, or evolution of a novel functional element from sequence that was absent or nonfunctional in the ancestral genome.

    “In general, each eutherian-specific element must have arisen by one of three mechanisms: (1) divergence of an ancestral functional element to such an extent that its similarity is no longer detectable; (2) duplication of an ancestral functional element giving rise to an element without a 1:1 orthologue in other clades; or (3) evolution of a novel functional element from sequence that was absent or”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Many conserved noncoding elements were derived from transposable elements, and the number of conserved noncoding elements is sharply increased in the genome of placental mammals.

    “Many conserved noncoding elements were derived from transposable elements. Comparison of placental and marsupial genomes demonstrates that the number of conserved noncoding elements is sharply increased in the genome of placental mammals (Lindblad-Toh et al., 2011; Mikkelsen et al., 2007).”

    From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Mikkelsen et al., 2007

  • E1m shows homology at its 3' end to LINE-4/RTE, a family of retrotransposons active in early mammals after divergence from marsupials.

    “E1m itself shows homology at its 3′ end to a long interspersed nuclear element (LINE)–4/RTE, a family of retrotransposons active in early mammals after divergence from marsupials (20).”

    From Evolutionarily Dynamic Alternative Splicing of <i>GPR56</i> Regulates Regional Cerebral Cortical Patterning (2014) · cites this paper as [20]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Segmental-duplication range omits chicken

    Minor

    The prose gives 2.5-5.3% as the range for other sequenced amniotes, but Table 2 lists chicken at 10.4%.

  • Repeat-content range excludes values in Table 2

    Minor

    The stated 34-43% range for other sequenced amniotes excludes both the human value of 45.5% and the chicken value of 9.4% in Table 2.

2 of 2

The citation lists haven’t been fetched yet

References 108 · Cited by 711

Research works printed but not linked: 8

  1. VandeBerg, J. L. in UFAW Handbook on the Management of Laboratory Animals. Vol. 1 Terrestrial Vertebrates (eds Poole, T. & English, P.) 193–209 (Blackwell Science, Oxford, 1999)
  2. Mahony, S., Corcoran, D. L., Feingold, E. & Benos, P. V. Regulatory conservation of protein coding and miRNA genes in vertebrates: lessons from the opossum genome. Genome Biol. (in the press).
  3. Parra, Z. E. et al. A new T-cell receptor discovered in marsupials. Proc. Natl Acad. Sci. USA (submitted).
  4. Holm, P. B. Ultrastructural analysis of meiotic recombination and chiasma formation. Tokai J. Exp. Clin. Med. 11, 415–436 (1986)
  5. Lyon, M. F. Do LINEs have a role in X–chromosome inactivation? J. Biomed. Biotechnol. 2006, 59746 (2006)
  6. Michael, M. Z. et al. Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol. Cancer Res. 1, 882–891 (2003)
  7. de la Calle-Mustienes, E. et al. A functional survey of the enhancer activity of conserved non-coding sequences from vertebrate Iroquois cluster gene deserts. Genome Res. 15, 1061–1072 (2005) · DOI
  8. Yang, Z. PAML: a program package for phylogenetic analysis by maximum likelihood. Comput. Appl. Biosci. 13, 555–556 (1997)

Authors
Broad Institute Genome Sequencing Platform, Mikkelsen, T. S., Broad Institute Whole Genome Assembly Team, Wakefield, M. J., Aken, B., Amemiya, C. T., Chang, J. L., Duke, S., Garber, M., Gentles, A. J., Goodstadt, L., Heger, A., Jurka, J., Kamal, M., Mauceli, E., Searle, S. M. J., Sharpe, T., Baker, M. L., Batzer, M. A., Benos, P. V., Belov, K., Clamp, M., Cook, A., Cuff, J., Das, R., Davidow, L., Deakin, J. E., Fazzari, M. J., Glass, J. L., Grabherr, M., Greally, J. M., Gu, W., Hore, T. A., Huttley, G. A., Kleber, M., Jirtle, R. L., Koina, E., Lee, J. T., Mahony, S., Marra, M. A., Miller, R. D., Nicholls, R. D., Oda, M., Papenfuss, A. T., Parra, Z. E., Pollock, D. D., Ray, D. A., Schein, J. E., Speed, T. P., Thompson, K., VandeBerg, J. L., Wade, C. M., Walker, J. A., Waters, P. D., Webber, C., Weidman, J. R., Xie, X., Zody, M. C., Graves, J. A. M., Ponting, C. P., Breen, M., Samollow, P. B., Lander, E. S., & Lindblad-Toh, K.
Affiliations
  • Broad Institute (US)
  • Walter and Eliza Hall Institute of Medical Research (AU)
  • Wellcome Sanger Institute (GB)
  • Benaroya Research Institute (US)
  • North Carolina State University (US)
  • Genetic Information Research Institute (US)
  • University of Oxford (GB)
  • University of New Mexico (US)
  • Louisiana State University (US)
  • University of Pittsburgh (US)
  • The University of Sydney (AU)
  • Duke Medical Center (US)
  • Harvard University (US)
  • Australian National University (AU)
  • Albert Einstein College of Medicine (US)
  • University of Colorado Health (US)
  • BC Cancer Agency (CA)
  • West Virginia University (US)
  • Texas Biomedical Research Institute (US)
  • Texas A&M University (US)
Corresponding author
  • Mikkelsen, Tarjei S.
  • Lander, Eric S.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2007-05
Volume
447
Issue
7141
Pages
167-177
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature05805
OpenAlex
W2164207497
Semantic Scholar
ab580d585b369a1f951e906f130f378844a05ce2
Cited by
711
References
108
Citations by year
2026: 6 · 2025: 12 · 2024: 16 · 2023: 10 · 2022: 15 · 2021: 27 · 2020: 10 · 2019: 26 · 2018: 29 · 2017: 26 · 2016: 30 · 2015: 41 · 2014: 34 · 2013: 44 · 2012: 60
FWCI
107.39
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Civil War Book Review (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
  • ANU Open Research (Australian National University) (submittedVersion)
Funders
  • National Science Foundation
  • Pittsburgh Foundation
  • Louisiana Board of Regents
  • Wellcome Trust (062023)
  • Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation
  • Broad Institute
  • National Institutes of Health
  • Medical Research Council
  • Australian Research Council
  • National Human Genome Research Institute
  • National Institute of Allergy and Infectious Diseases
  • Telemedicine and Advanced Technology Research Center
Topics
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
  • Physical Sciences › Earth and Planetary Sciences › Paleontology › Evolution and Paleontology Studies
Keywords
Monodelphis domestica, marsupial genome, conserved non-coding elements, transposable elements, biased gene conversion, X chromosome inactivation, genome evolution, gene expression regulation, immune system genetics
MeSH terms
Animals, Base Composition, DNA Transposable Elements, Humans, Opossums, Protein Biosynthesis, Genome, Conserved Sequence, Evolution, Molecular, Polymorphism, Single Nucleotide, Genomics, Synteny, X Chromosome Inactivation

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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