Skip to main content
SpringerLink
Log in

Novel mechanism of conjoined gene formation in the human genome

  • Original Paper
  • Published:
Functional & Integrative Genomics Aims and scope Submit manuscript

Abstract

Recently, conjoined genes (CGs) have emerged as important genetic factors necessary for understanding the human genome. However, their formation mechanism and precise structures have remained mysterious. Based on a detailed structural analysis of 57 human CG transcript variants (CGTVs, discovered in this study) and all (833) known CGs in the human genome, we discovered that the poly(A) signal site from the upstream parent gene region is completely removed via the skipping or truncation of the final exon; consequently, CG transcription is terminated at the poly(A) signal site of the downstream parent gene. This result led us to propose a novel mechanism of CG formation: the complete removal of the poly(A) signal site from the upstream parent gene is a prerequisite for the CG transcriptional machinery to continue transcribing uninterrupted into the intergenic region and downstream parent gene. The removal of the poly(A) signal sequence from the upstream gene region appears to be caused by a deletion or truncation mutation in the human genome rather than post-transcriptional trans-splicing events. With respect to the characteristics of CG sequence structures, we found that intergenic regions are hot spots for novel exon creation during CGTV formation and that exons farther from the intergenic regions are more highly conserved in the CGTVs. Interestingly, many novel exons newly created within the intergenic and intragenic regions originated from transposable element sequences. Additionally, the CGTVs showed tumor tissue-biased expression. In conclusion, our study provides novel insights into the CG formation mechanism and expands the present concepts of the genetic structural landscape, gene regulation, and gene formation mechanisms in the human genome.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Akiva P, Toporik A, Edelheit S, Peretz Y, Diber A, Shemesh R, Novik A, Sorek R (2006) Transcription-mediated gene fusion in the human genome. Genome Res 16(1):30–36

    Article  PubMed  CAS  Google Scholar 

  • Beroud C, Tuffery-Giraud S, Matsuo M, Hamroun D, Humbertclaude V, Monnier N, Moizard MP, Voelckel MA, Calemard LM, Boisseau P, Blayau M, Philippe C, Cossee M, Pages M, Rivier F, Danos O, Garcia L, Claustres M (2007) Multiexon skipping leading to an artificial DMD protein lacking amino acids from exons 45 through 55 could rescue up to 63% of patients with Duchenne muscular dystrophy. Hum Mutat 28(2):196–202

    Article  PubMed  CAS  Google Scholar 

  • Gingeras TR (2009) Implications of chimaeric non-co-linear transcripts. Nature 461(7261):206–211

    Article  PubMed  CAS  Google Scholar 

  • Kim DS, Kim TH, Huh JW, Kim IC, Kim SW, Park HS, Kim HS (2006a) LINE FUSION GENES: a database of LINE expression in human genes. BMC Genomics 7:139

    Article  PubMed  Google Scholar 

  • Kim N, Kim P, Nam S, Shin S, Lee S (2006b) ChimerDB—a knowledgebase for fusion sequences. Nucleic Acids Res 34(Database issue):D21–D24

    Article  PubMed  CAS  Google Scholar 

  • Kim RN, Kim DW, Choi SH, Chae SH, Nam SH, Kim A, Kang A, Park KH, Lee YS, Hirai M, Suzuki Y, Sugano S, Hashimoto K, Kim DS, Park HS (2011) Major chimpanzee-specific structural changes in sperm development-associated genes. Funct Integr Genomics 11:507–517

    Article  PubMed  CAS  Google Scholar 

  • Kumar-Sinha C, Tomlins SA, Chinnaiyan AM (2008) Recurrent gene fusions in prostate cancer. Nat Rev Cancer 8(7):497–511

    Article  PubMed  CAS  Google Scholar 

  • Maher CA, Kumar-Sinha C, Cao X, Kalyana-Sundaram S, Han B, Jing X, Sam L, Barrette T, Palanisamy N, Chinnaiyan AM (2009) Transcriptome sequencing to detect gene fusions in cancer. Nature 458(7234):97–101

    Article  PubMed  CAS  Google Scholar 

  • Mitelman F, Johansson B, Mertens F (2004) Fusion genes and rearranged genes as a linear function of chromosome aberrations in cancer. Nat Genet 36(4):331–334

    Article  PubMed  CAS  Google Scholar 

  • Nacu S, Yuan W, Kan Z, Bhatt D, Rivers CS, Stinson J, Peters BA, Modrusan Z, Jung K, Seshagiri S, Wu TD (2011) Deep RNA sequencing analysis of readthrough gene fusions in human prostate adenocarcinoma and reference samples. BMC Med Genomics 4:11

    Article  PubMed  CAS  Google Scholar 

  • Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J, Cook K, Stepansky A, Levy D, Esposito D, Muthuswamy L, Krasnitz A, McCombie WR, Hicks J, Wigler M (2011) Tumour evolution inferred by single-cell sequencing. Nature 472(7341):90–94

    Article  PubMed  CAS  Google Scholar 

  • Nilsen TW, Graveley BR (2010) Expansion of the eukaryotic proteome by alternative splicing. Nature 463(7280):457–463

    Article  PubMed  CAS  Google Scholar 

  • Parra G, Reymond A, Dabbouseh N, Dermitzakis ET, Castelo R, Thomson TM, Antonarakis SE, Guigo R (2006) Tandem chimerism as a means to increase protein complexity in the human genome. Genome Res 16(1):37–44

    Article  PubMed  CAS  Google Scholar 

  • Prakash T, Sharma VK, Adati N, Ozawa R, Kumar N, Nishida Y, Fujikake T, Takeda T, Taylor TD (2010) Expression of conjoined genes: another mechanism for gene regulation in eukaryotes. PLoS One 5(10):e13284

    Article  PubMed  Google Scholar 

  • Sampson MJ, Ross L, Decker WK, Craigen WJ (1998) A novel isoform of the mitochondrial outer membrane protein VDAC3 via alternative splicing of a 3-base exon. Functional characteristics and subcellular localization. J Biol Chem 273(46):30482–30486

    Article  PubMed  CAS  Google Scholar 

  • Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448(7153):561–566

    Article  PubMed  CAS  Google Scholar 

  • Sorek R (2007) The birth of new exons: mechanisms and evolutionary consequences. RNA 13(10):1603–1608

    Article  PubMed  CAS  Google Scholar 

  • Vilkki S, Tsao JL, Loukola A, Poyhonen M, Vierimaa O, Herva R, Aaltonen LA, Shibata D (2001) Extensive somatic microsatellite mutations in normal human tissue. Cancer Res 61(11):4541–4544

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank the members of the Genome Resource Center (GRC) in the Korea Research Institute of Bioscience and Biotechnology (KRIBB) for their active assistance in conducting this research project. This research was supported by grant 2009-0084206 from the Ministry of Education, Science and Technology (MEST) and grant KGM5411011 from KRIBB.

Competing financial interests

The authors declare no competing financial interests.

Author information

Authors and Affiliations

  1. Genome Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 305-806, South Korea

    Ryong Nam Kim, Aeri Kim, Sang-Haeng Choi, Dae-Soo Kim, Seong-Hyeuk Nam, Dae-Won Kim, Dong-Wook Kim, Aram Kang, Min-Young Kim, Kun-Hyang Park, Byoung-Ha Yoon, Kang Seon Lee & Hong-Seog Park

  2. University of Science and Technology (UST), Daejeon, 305-333, South Korea

    Aeri Kim, Aram Kang, Byoung-Ha Yoon & Hong-Seog Park

Authors
  1. Ryong Nam Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aeri Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sang-Haeng Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dae-Soo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Seong-Hyeuk Nam
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dae-Won Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dong-Wook Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Aram Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Min-Young Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kun-Hyang Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Byoung-Ha Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kang Seon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hong-Seog Park
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hong-Seog Park.

Additional information

Ryong Nam Kim, Aeri Kim, and Sang-Haeng Choi contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 801 kb)

ESM 2

(PDF 230 kb)

ESM 3

(PDF 26 kb)

ESM 4

(PDF 1330 kb)

ESM 5

(PDF 9 kb)

ESM 6

(PDF 17 kb)

ESM 7

(PDF 345 kb)

ESM 8

(PDF 100 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, R.N., Kim, A., Choi, SH. et al. Novel mechanism of conjoined gene formation in the human genome. Funct Integr Genomics 12, 45–61 (2012). https://doi.org/10.1007/s10142-011-0260-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10142-011-0260-1

Keywords

Search

Navigation