Assessing Mitochondrial DNA Variation and Copy Number in Lymphocytes of ~2,000 Sardinians Using Tailored Sequencing Analysis Tools

English version České info

We present a new program that provides a general solution for the analysis of variation of mtDNA (the small circular genome in mitochondria, separate from the DNA in the nucleus). This is needed because many large-scale genetic studies are using new DNA sequencing technologies to help assess genetic variation and its effects on disease, but the mitochondrial genome is often ignored because it exists in many copies in a cell, complicating analyses. Our approach both identifies variants on mitochondrial genome and estimates mtDNA copy number. Applying the programs to DNA sequence from ~2,000 SardiNIA project participants, we show that heteroplasmies (mtDNA variants with more than one allele at a DNA site) increase with age, and that copy number is relatively highly heritable and is correlated with metabolic traits, particularly central fat levels. The program package can facilitate comprehensive mtDNA analysis from any whole-genome sequencing data, with an increase in the understanding of mtDNA dynamics and its potential role in aging and metabolism.

Vyšlo v časopise: Assessing Mitochondrial DNA Variation and Copy Number in Lymphocytes of ~2,000 Sardinians Using Tailored Sequencing Analysis Tools. PLoS Genet 11(7): e32767. doi:10.1371/journal.pgen.1005306
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005306

Souhrn

Zdroje

1. Chinnery PF, Samuels DC, Elson J, Turnbull DM. Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial disease: is there a common mechanism? The Lancet. 2002;360: 1323–1325. doi: 10.1016/S0140-6736(02)11310-9

2. Wallace DC. Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science. 1992;256: 628–632. doi: 10.1126/science.1533953 1533953

3. Wallace DC. Mitochondrial DNA sequence variation in human evolution and disease. Proc Natl Acad Sci. 1994;91: 8739–8746. 8090716

4. Consortium T 1000 GP. A map of human genome variation from population-scale sequencing. Nature. 2010;467: 1061–1073. doi: 10.1038/nature09534 20981092

5. Yi X, Liang Y, Huerta-Sanchez E, Jin X, Cuo ZXP, Pool JE, et al. Sequencing of 50 human exomes reveals adaptation to high altitude. Science. 2010;329: 75–78. doi: 10.1126/science.1190371 20595611

6. DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43: 491–498. doi: 10.1038/ng.806 21478889

7. Li Y, Sidore C, Kang HM, Boehnke M, Abecasis GR. Low-coverage sequencing: Implications for design of complex trait association studies. Genome Res. 2011;21: 940–951. doi: 10.1101/gr.117259.110 21460063

8. Pilia G, Chen W-M, Scuteri A, Orrú M, Albai G, Dei M, et al. Heritability of Cardiovascular and Personality Traits in 6,148 Sardinians. PLoS Genet. 2006;2: e132. doi: 10.1371/journal.pgen.0020132 16934002

9. Lan Q, Lim U, Liu C-S, Weinstein SJ, Chanock S, Bonner MR, et al. A prospective study of mitochondrial DNA copy number and risk of non-Hodgkin lymphoma. Blood. 2008;112: 4247–4249. doi: 10.1182/blood-2008-05-157974 18711000

10. Thyagarajan B, Wang R, Nelson H, Barcelo H, Koh W-P, Yuan J-M. Mitochondrial DNA Copy Number Is Associated with Breast Cancer Risk. PLoS ONE. 2013;8: e65968. doi: 10.1371/journal.pone.0065968 23776581

11. He Y, Wu J, Dressman DC, Iacobuzio-Donahue C, Markowitz SD, Velculescu VE, et al. Heteroplasmic mitochondrial DNA mutations in normal and tumour cells. Nature. 2010;464: 610–614. doi: 10.1038/nature08802 20200521

12. Li M, Schönberg A, Schaefer M, Schroeder R, Nasidze I, Stoneking M. Detecting Heteroplasmy from High-Throughput Sequencing of Complete Human Mitochondrial DNA Genomes. Am J Hum Genet. 2010;87: 237–249. doi: 10.1016/j.ajhg.2010.07.014 20696290

13. Ye K, Lu J, Ma F, Keinan A, Gu Z. Extensive pathogenicity of mitochondrial heteroplasmy in healthy human individuals. Proc Natl Acad Sci. 2014;111: 10654–10659. doi: 10.1073/pnas.1403521111 25002485

14. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38: e164–e164. doi: 10.1093/nar/gkq603 20601685

15. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25: 2078–2079. doi: 10.1093/bioinformatics/btp352 19505943

16. Chu H-T, Hsiao WW, Tsao TT, Chang C-M, Liu Y-W, Fan C-C, et al. Quantitative assessment of mitochondrial DNA copies from whole genome sequencing. BMC Genomics. 2012;13: S5. doi: 10.1186/1471-2164-13-S7-S5

17. Goto H, Dickins B, Afgan E, Paul IM, Taylor J, Makova KD, et al. Dynamics of mitochondrial heteroplasmy in three families investigated via a repeatable re-sequencing study. Genome Biol. 2011;12: R59. doi: 10.1186/gb-2011-12-6-r59 21699709

18. Rebolledo-Jaramillo B, Su MS-W, Stoler N, McElhoe JA, Dickins B, Blankenberg D, et al. Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA. Proc Natl Acad Sci. 2014;111: 15474–15479. doi: 10.1073/pnas.1409328111 25313049

19. Sosa MX, Sivakumar IKA, Maragh S, Veeramachaneni V, Hariharan R, Parulekar M, et al. Next-Generation Sequencing of Human Mitochondrial Reference Genomes Uncovers High Heteroplasmy Frequency. PLoS Comput Biol. 2012;8: e1002737. doi: 10.1371/journal.pcbi.1002737 23133345

20. Kennedy SR, Salk JJ, Schmitt MW, Loeb LA. Ultra-Sensitive Sequencing Reveals an Age-Related Increase in Somatic Mitochondrial Mutations That Are Inconsistent with Oxidative Damage. PLoS Genet. 2013;9: e1003794. doi: 10.1371/journal.pgen.1003794 24086148

21. Ashar FN, Moes A, Moore AZ, Grove ML, Chaves PHM, Coresh J, et al. Association of mitochondrial DNA levels with frailty and all-cause mortality. J Mol Med. 2014; 1–10. doi: 10.1007/s00109-014-1233-3

22. Cibulskis K, Lawrence MS, Carter SL, Sivachenko A, Jaffe D, Sougnez C, et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 2013;31: 213–219. doi: 10.1038/nbt.2514 23396013

23. Kleinman CL, Majewski J. Comment on “Widespread RNA and DNA Sequence Differences in the Human Transcriptome.” Science. 2012;335: 1302–1302. doi: 10.1126/science.1209658

24. Li M, Wang IX, Li Y, Bruzel A, Richards AL, Toung JM, et al. Widespread RNA and DNA Sequence Differences in the Human Transcriptome. Science. 2011;333: 53–58. doi: 10.1126/science.1207018 21596952

25. Li M, Wang IX, Cheung VG. Response to Comments on “Widespread RNA and DNA Sequence Differences in the Human Transcriptome.” Science. 2012;335: 1302–1302. doi: 10.1126/science.1210419

26. Lin W, Piskol R, Tan MH, Li JB. Comment on “Widespread RNA and DNA Sequence Differences in the Human Transcriptome.” Science. 2012;335: 1302–1302. doi: 10.1126/science.1210624

27. Pickrell JK, Gilad Y, Pritchard JK. Comment on “Widespread RNA and DNA Sequence Differences in the Human Transcriptome.” Science. 2012;335: 1302–1302. doi: 10.1126/science.1210484

28. Kitzman JO, Snyder MW, Ventura M, Lewis AP, Qiu R, Simmons LE, et al. Noninvasive Whole-Genome Sequencing of a Human Fetus. Sci Transl Med. 2012;4: 137ra76–137ra76. doi: 10.1126/scitranslmed.3004323 22674554