Skip to main content

Thank you for visiting nature.com. 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.

  • Opinion
  • Published:

Conserved non-genic sequences — an unexpected feature of mammalian genomes

Nature Reviews Genetics volume 6, pages 151–157 (2005)Cite this article

Abstract

Mammalian genomes contain highly conserved sequences that are not functionally transcribed. These sequences are single copy and comprise approximately 1–2% of the human genome. Evolutionary analysis strongly supports their functional conservation, although their potentially diverse, functional attributes remain unknown. It is likely that genomic variation in conserved non-genic sequences is associated with phenotypic variability and human disorders. So how might their function and contribution to human disorders be examined?

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Distribution of conserved non-genic sequences in the human genome.
Figure 2: Conservation of conserved non-genic sequences and genes in mammals.
Figure 3: Long-distance regulatory conserved non-genic sequences and mutation.

Similar content being viewed by others

References

  1. Martinez-Cruzado, J. C., Swimmer, C., Fenerjian, M. G. & Kafatos, F. C. Evolution of the autosomal chorion locus in Drosophila. I. General organization of the locus and sequence comparisons of genes s15 and s19 in evolutionary distant species. Genetics 119, 663–677 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Culi, J. & Modolell, J. Proneural gene self-stimulation in neural precursors: an essential mechanism for sense organ development that is regulated by Notch signaling. Genes Dev. 12, 2036–2047 (1998).

    Article  CAS  Google Scholar 

  3. Renucci, A. et al. Comparison of mouse and human HOX-4 complexes defines conserved sequences involved in the regulation of Hox-4.4. EMBO J. 11, 1459–1468 (1992).

    Article  CAS  Google Scholar 

  4. Duret, L., Dorkeld, F. & Gautier, C. Strong conservation of non-coding sequences during vertebrates evolution: potential involvement in post-transcriptional regulation of gene expression. Nucleic Acids Res. 21, 2315–2322 (1993).

    Article  CAS  Google Scholar 

  5. Hardison, R. C. Conserved noncoding sequences are reliable guides to regulatory elements. Trends Genet. 16, 369–372 (2000).

    Article  CAS  Google Scholar 

  6. Hardison, R. C., Oeltjen, J. & Miller, W. Long human–mouse sequence alignments reveal novel regulatory elements: a reason to sequence the mouse genome. Genome Res. 7, 959–966 (1997).

    Article  CAS  Google Scholar 

  7. Dermitzakis, E. T. et al. Numerous potentially functional but non-genic conserved sequences on human chromosome 21. Nature 420, 578–582 (2002).

    Article  CAS  Google Scholar 

  8. Waterston, R. H. et al. Initial sequencing and comparative analysis of the mouse genome. Nature 420, 520–562 (2002).

    Article  CAS  Google Scholar 

  9. Frazer, K. A. et al. Evolutionarily conserved sequences on human chromosome 21. Genome Res. 11, 1651–1659 (2001).

    Article  CAS  Google Scholar 

  10. Mural, R. J. et al. A comparison of whole-genome shotgun-derived mouse chromosome 16 and the human genome. Science 296, 1661–1671 (2002).

    Article  CAS  Google Scholar 

  11. DeSilva, U. et al. Generation and comparative analysis of approximately 3.3 Mb of mouse genomic sequence orthologous to the region of human chromosome 7q11.23 implicated in Williams syndrome. Genome Res. 12, 3–15 (2002).

    Article  CAS  Google Scholar 

  12. Loots, G. G. et al. Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons. Science 288, 136–140 (2000).

    Article  CAS  Google Scholar 

  13. Hardison, R. C. et al. Covariation in frequencies of substitution, deletion, transposition, and recombination during eutherian evolution. Genome Res. 13, 13–26 (2003).

    Article  CAS  Google Scholar 

  14. Margulies, E. H., Blanchette, M., Haussler, D. & Green, E. D. Identification and characterization of multi-species conserved sequences. Genome Res. 13, 2507–2518 (2003).

    Article  CAS  Google Scholar 

  15. Meisler, M. H. Evolutionarily conserved noncoding DNA in the human genome: how much and what for? Genome Res. 11, 1617–1618 (2001).

    Article  CAS  Google Scholar 

  16. Thomas, J. W. et al. Comparative analyses of multi-species sequences from targeted genomic regions. Nature 424, 788–793 (2003).

    Article  CAS  Google Scholar 

  17. Giardine, B. et al. GALA, a database for genomic sequence alignments and annotations. Genome Res. 13, 732–741 (2003).

    Article  CAS  Google Scholar 

  18. Dermitzakis, E. T. et al. Comparison of human chromosome 21 conserved non-genic sequences (CNGs) with the mouse and dog genomes shows that their selective constraint is independent of their genic environment. Genome Res. 14, 852–859 (2004).

    Article  CAS  Google Scholar 

  19. Bejerano, G. et al. Ultraconserved elements in the human genome. Science 304, 1321–1325 (2004).

    Article  CAS  Google Scholar 

  20. Nobrega, M. A., Ovcharenko, I., Afzal, V. & Rubin, E. M. Scanning human gene deserts for long-range enhancers. Science 302, 413 (2003).

    Article  CAS  Google Scholar 

  21. Kirkness, E. F. et al. The dog genome: survey sequencing and comparative analysis. Science 301, 1898–1903 (2003).

    Article  Google Scholar 

  22. Dubchak, I. et al. Active conservation of noncoding sequences revealed by three-way species comparisons. Genome Res. 10, 1304–1306 (2000).

    Article  CAS  Google Scholar 

  23. Frazer, K. A. et al. Noncoding sequences conserved in a limited number of mammals in the SIM2 interval are frequently functional. Genome Res. 14, 367–372 (2004).

    Article  CAS  Google Scholar 

  24. Dermitzakis, E. T. et al. Evolutionary discrimination of mammalian conserved non-genic sequences (CNGs). Science 302, 1033–1035 (2003).

    Article  CAS  Google Scholar 

  25. Keightley, P. D. & Gaffney, D. J. Functional constraints and frequency of deleterious mutations in noncoding DNA of rodents. Proc. Natl Acad. Sci. USA 100, 13402–13406 (2003).

    Article  CAS  Google Scholar 

  26. Johnston, M. & Stormo, G. D. Evolution. Heirlooms in the attic. Science 302, 997–999 (2003).

    Article  CAS  Google Scholar 

  27. Elnitski, L. et al. Distinguishing regulatory DNA from neutral sites. Genome Res. 13, 64–72 (2003).

    Article  CAS  Google Scholar 

  28. Dermitzakis, E. T. & Clark, A. G. Evolution of transcription factor binding sites in mammalian gene regulatory regions: conservation and turnover. Mol. Biol. Evol. 19, 1114–1121 (2002).

    Article  CAS  Google Scholar 

  29. Glazko, G. V., Koonin, E. V., Rogozin, I. B. & Shabalina, S. A. A significant fraction of conserved noncoding DNA in human and mouse consists of predicted matrix attachment regions. Trends Genet. 19, 119–124 (2003).

    Article  CAS  Google Scholar 

  30. Croft, J. A. et al. Differences in the localization and morphology of chromosomes in the human nucleus. J. Cell Biol. 145, 1119–1131 (1999).

    Article  CAS  Google Scholar 

  31. Nielsen, J. A., Hudson, L. D. & Armstrong, R. C. Nuclear organization in differentiating oligodendrocytes. J. Cell Sci. 115, 4071–4079 (2002).

    Article  CAS  Google Scholar 

  32. Tanabe, H. et al. Evolutionary conservation of chromosome territory arrangements in cell nuclei from higher primates. Proc. Natl Acad. Sci. USA 99, 4424–4429 (2002).

    Article  CAS  Google Scholar 

  33. Muller, H. P. & Schaffner, W. Transcriptional enhancers can act in trans. Trends Genet. 6, 300–304 (1990).

    Article  CAS  Google Scholar 

  34. Duncan, I. W. Transvection effects in Drosophila. Annu. Rev. Genet. 36, 521–556 (2002).

    Article  CAS  Google Scholar 

  35. Chambeyron, S. & Bickmore, W. A. Does looping and clustering in the nucleus regulate gene expression? Curr. Opin. Cell Biol. 16, 256–262 (2004).

    Article  CAS  Google Scholar 

  36. Boffelli, D. et al. Phylogenetic shadowing of primate sequences to find functional regions of the human genome. Science 299, 1391–1394 (2003).

    Article  CAS  Google Scholar 

  37. Nobrega, M. A., Zhu, Y., Plajzer-Frick, I., Afzal, V. & Rubin, E. M. Megabase deletions of gene deserts result in viable mice. Nature 431, 988–993 (2004).

    Article  CAS  Google Scholar 

  38. Kioussis, D., Vanin, E., deLange, T., Flavell, R. A. & Grosveld, F. G. β-Globin gene inactivation by DNA translocation in γ-β-thalassaemia. Nature 306, 662–666 (1983).

    Article  CAS  Google Scholar 

  39. Driscoll, M. C., Dobkin, C. S. & Alter, B. P. γ-δ-β-Thalassemia due to a de novo mutation deleting the 5′ β-globin gene activation-region hypersensitive sites. Proc. Natl Acad. Sci. USA 86, 7470–7474 (1989).

    Article  CAS  Google Scholar 

  40. Lettice, L. A. et al. A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum. Mol. Genet. 12, 1725–1735 (2003).

    Article  CAS  Google Scholar 

  41. Lettice, L. A. et al. Disruption of a long-range cis-acting regulator for Shh causes preaxial polydactyly. Proc. Natl Acad. Sci. USA 99, 7548–7553 (2002).

    Article  CAS  Google Scholar 

  42. Van Laere, A. S. et al. A regulatory mutation in IGF2 causes a major QTL effect on muscle growth in the pig. Nature 425, 832–836 (2003).

    Article  CAS  Google Scholar 

  43. Kleinjan, D. J. & van Heyningen, V. Position effect in human genetic disease. Hum. Mol. Genet. 7, 1611–1618 (1998).

    Article  CAS  Google Scholar 

  44. Bishop, C. E. et al. A transgenic insertion upstream of sox9 is associated with dominant XX sex reversal in the mouse. Nature Genet. 26, 490–494 (2000).

    Article  CAS  Google Scholar 

  45. Wirth, J. et al. Translocation breakpoints in three patients with campomelic dysplasia and autosomal sex reversal map more than 130 kb from SOX9. Hum. Genet. 97, 186–193 (1996).

    Article  CAS  Google Scholar 

  46. Jamieson, R. V. et al. Domain disruption and mutation of the bZIP transcription factor, MAF, associated with cataract, ocular anterior segment dysgenesis and coloboma. Hum. Mol. Genet. 11, 33–42 (2002).

    Article  CAS  Google Scholar 

  47. de Kok, Y. J. et al. A duplication/paracentric inversion associated with familial X-linked deafness (DFN3) suggests the presence of a regulatory element more than 400 kb upstream of the POU3F4 gene. Hum. Mol. Genet. 4, 2145–2150 (1995).

    Article  CAS  Google Scholar 

  48. de Kok, Y. J. et al. Identification of a hot spot for microdeletions in patients with X-linked deafness type 3 (DFN3) 900 kb proximal to the DFN3 gene POU3F4. Hum. Mol. Genet. 5, 1229–1235 (1996).

    Article  CAS  Google Scholar 

  49. Spitz, F. et al. A t(2;8) balanced translocation with breakpoints near the human HOXD complex causes mesomelic dysplasia and vertebral defects. Genomics 79, 493–498 (2002).

    Article  CAS  Google Scholar 

  50. Flomen, R. H. et al. Construction and analysis of a sequence-ready map in 4q25: Rieger syndrome can be caused by haploinsufficiency of RIEG, but also by chromosome breaks approximately 90 kb upstream of this gene. Genomics 47, 409–413 (1998).

    Article  CAS  Google Scholar 

  51. Rose, C. S., Patel, P., Reardon, W., Malcolm, S. & Winter, R. M. The TWIST gene, although not disrupted in Saethre–Chotzen patients with apparently balanced translocations of 7p21, is mutated in familial and sporadic cases. Hum. Mol. Genet. 6, 1369–1373 (1997).

    Article  CAS  Google Scholar 

  52. Spitz, F., Gonzalez, F. & Duboule, D. A global control region defines a chromosomal regulatory landscape containing the HoxD cluster. Cell 113, 405–417 (2003).

    Article  CAS  Google Scholar 

  53. McArthur, M., Gerum, S. & Stamatoyannopoulos, G. Quantification of DNaseI-sensitivity by real-time PCR: quantitative analysis of DNaseI-hypersensitivity of the mouse β-globin LCR. J. Mol. Biol. 313, 27–34 (2001).

    Article  CAS  Google Scholar 

  54. Cawley, S. et al. Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of noncoding RNAs. Cell 116, 499–509 (2004).

    Article  CAS  Google Scholar 

  55. Morley, M. et al. Genetic analysis of genome-wide variation in human gene expression. Nature 430, 743–747 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank H. Attar for helping us with the analysis and collection of data. The authors are supported by grants from the Swiss National Science Foundation, the National Center of Competence in Research 'Frontiers in Genetics', the US National Institutes of Health, the European Union, the 'ChildCare' Foundation, the Jerome Lejeune Foundation and the Wellcome Trust.

Author information

Authors and Affiliations

  1. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, Cambridge, UK

    Emmanouil T. Dermitzakis

  2. Centre Integratif de Genomique, Faculte de biologie et de medecine, BEP, Lausanne, CH-1015, Switzerland

    Alexandre Reymond

  3. the Department of Genetic Medicine and Development, University of Geneva Medical School, 1 Rue Michel-Servet, Geneva, 1211, Switzerland

    Stylianos E. Antonarakis

Authors
  1. Emmanouil T. Dermitzakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexandre Reymond
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stylianos E. Antonarakis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Emmanouil T. Dermitzakis or Stylianos E. Antonarakis.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez

LMBR1

SHH

Sox9

POU3F4

FURTHER INFORMATION

National Human Genome Research Institute

Human Genome Project

Glossary

HISTONE CODE

Post-translational modifications of histone tails that involve characteristic clusters of modifications, including acetylation, phosphorylation, ubiquitylation, methylation and ADP-ribosylation, which combine to create an epigenetic mechanism for the regulation of gene expression.

IN VIVO FOOTPRINTING

An assay that detects the presence of protein binding onto DNA in an in vivo system.

PREAXIAL POLYDACTYLY

Addition of fingers or toes on the thumb side of the hand or the big toe side of the foot.

SOUTHWESTERN ANALYSIS

An assay, in which one runs proteins on a PAGE gel, blots the gel and then hybridizes the membrane with labelled DNA. The goal is to identify protein–DNA interactions.

TRANSVECTION

A phenomenon whereby homologous chromosomes are synapsed in somatic cells, as a result of which some enhancers and/or silencers can function in trans.

YEAST 1-HYBRID

An assay that uses transcriptional activation in yeast as a model to detect protein–DNA interactions.

ZONE OF POLARIZING ACTIVITY

A small region in the developing limb bud that is responsible for correct patterning of the anterior–posterior axis of the limb.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dermitzakis, E., Reymond, A. & Antonarakis, S. Conserved non-genic sequences — an unexpected feature of mammalian genomes. Nat Rev Genet 6, 151–157 (2005). https://doi.org/10.1038/nrg1527

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg1527

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing