From early methods for DNA diagnostics to genomes and epigenomes at high resolution during four decades – a personal perspective
Keywords:
Genomics, genetics, SNP genotyping, polymerase chain reaction, microarrays, next generation sequencing, epigenomics, systemic lupus erythematosus, acute lymphoblastic leukemia, Finnish disease heritage, whole genome sequencing, single cell transcriptomics
Abstract
In the 1980s, my research career begun with microbial DNA diagnostics at Orion Pharmaceutica in Helsinki, Finland, where I was part of an innovative team that developed novel methods based on the polymerase chain reaction (PCR) and the biotin–avidin interaction. One of our key achievements during this time was the invention of the solid-phase minisequencing method for genotyping single nucleotide polymorphisms (SNPs). In the 1990s, I shifted focus to human genetics, investigating mutations of the ‘Finnish disease heritage’. During this period, I also developed quantitative methods using PCR and minisequencing of mitochondrial mutations and for forensic analyses. In the late 1990s and early 2000s, microarray-based SNP genotyping became a major topic for my research, first in Helsinki and later with my research group at Uppsala University in Sweden. By the mid-2000s, I began collaborating with leading clinicians on genetics of autoimmune disease, specifically systemic lupus erythematosus and later worked on the classification and clinical outcome of pediatric acute lymphoblastic leukemia, when large-scale genomics and epigenomics emerged. These collaborations, which focused on integrating genomics into clinical practice, lasted almost two decades until I retired from research in 2022. In parallel with my research activities, I led the SNP/DNA Technology Platform in the Wallenberg Consortium North program from 2001 to 2006. I continued as Director of the SNP&SEQ Technology Platform, which expanded rapidly during the 2010s, and became part of Science for Life Laboratory in 2013. Today (in 2024), the SNP&SEQ Technology Platform is one of the largest units of the Swedish National Genomics Infrastructure hosted by SciLifeLab. The present article provides a personal perspective on nearly four decades of research, highlighting projects and methods I found particularly exciting or important.
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References
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2. Ranki M, Palva A, Virtanen M, Laaksonen M, Söderlund H. Sandwich hybridization as a convenient method for the detection of nucleic acids in crude samples. Gene. 1983;21(1–2):77–85. doi: 10.1016/0378-1119(83)90149-X
3. Virtanen M, Palva A, Laaksonen M, Halonen P, Söderlund H, Ranki M. Novel test for rapid viral diagnosis: detection of adenovirus in nasopharyngeal mucus aspirates by means of nucleic-acid sandwich hybridisation. Lancet. 1983;1(8321):381–3. doi: 10.1016/S0140-6736(83)91500-3
4. Virtanen M, Syvänen AC, Oram J, Söderlund H, Ranki M. Cytomegalovirus in urine: detection of viral DNA by sandwich hybridization. J Clin Microbiol. 1984;20(6):1083–8. doi: 10.1128/jcm.20.6.1083-1088.1984
5. Syvänen AC, Tchen P, Ranki M, Söderlund H. Time-resolved fluorometry: a sensitive method to quantify DNA-hybrids. Nucleic Acids Res. 1986;14(2):1017–28. doi: 10.1093/nar/14.2.1017
6. Dahlén P, Syvänen AC, Hurskainen P, Kwiatkowski M, Sund C, Ylikoski J, et al. Sensitive detection of genes by sandwich hybridization and time-resolved fluorometry. Mol Cell Probes. 1987;1(2):159–68. doi: 10.1016/0890-8508(87)90024-7
7. Syvänen AC, Laaksonen M, Söderlund H. Fast quantification of nucleic acid hybrids by affinity-based hybrid collection. Nucleic Acids Res. 1986;14(12):5037–48. doi: 10.1093/nar/14.12.5037
8. Mullis KB, Faloona FA. Specific synthesis of DNA in vitro via a polymerase-catalyzed chain reaction. Methods Enzymol. 1987;155:335–50. doi: 10.1016/0076-6879(87)55023-6
9. Mullis KB. The unusual origin of the polymerase chain reaction. Sci Am. 1990;262(4):56–61, 64–5. doi: 10.1038/scientificamerican0490-56
10. Syvänen AC, Bengtström M, Tenhunen J, Söderlund H. Quantification of polymerase chain reaction products by affinity-based hybrid collection. Nucleic Acids Res. 1988;16(23):11327–38. doi: 10.1093/nar/16.23.11327
11. International HapMap Consortium. A haplotype map of the human genome. Nature. 2005;437(7063):1299–320. doi: 10.1038/nature04226
12. Touma M. COVID-19: molecular diagnostics overview. J Mol Med (Berl). 2020;98(7):947–54. doi: 10.1007/s00109-020-01931-w
13. Syvänen AC, Aalto-Setälä K, Kontula K, Söderlund H. Direct sequencing of affinity-captured amplified human DNA application to the detection of apolipoprotein E polymorphism. FEBS Lett. 1989;258(1):71–4. doi: 10.1016/0014-5793(89)81618-7
14. Paik YK, Chang DJ, Reardon CA, Davies GE, Mahley RW, Taylor JM. Nucleotide sequence and structure of the human apolipoprotein E gene. Proc Natl Acad Sci U S A. 1985;82(10):3445–9. doi: 10.1073/pnas.82.10.3445
15. Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988;240(4852):622–30. doi: 10.1126/science.3283935
16. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261(5123):921–3. doi: 10.1126/science.8346443
17. Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977;74(12):5463–7. doi: 10.1073/pnas.74.12.5463
18. Syvänen AC, Hultman T, Aalto-Setälä K, Söderlund H, Uhlén M. Genetic analysis of the polymorphism of the human apolipoprotein E using automated solid-phase sequencing. Genet Anal Tech Appl. 1991;8(4):117–23. doi: 10.1016/1050-3862(91)90027-O
19. Syvänen AC, Aalto-Setälä K, Harju L, Kontula K, Söderlund H. A primer-guided nucleotide incorporation assay in the genotyping of apolipoprotein E. Genomics. 1990;8(4):684–92. doi: 10.1016/0888-7543(90)90255-S
20. Jalanko A, Kere J, Savilahti E, Schwartz M, Syvänen AC, Ranki M, et al. Screening for defined cystic fibrosis mutations by solid-phase minisequencing. Clin Chem. 1992;38(1):39–43. doi: 10.1093/clinchem/38.1.39
21. Syvänen AC. Accessing genetic variation: genotyping single nucleotide polymorphisms. Nat Rev Genet. 2001;2(12):930–42. doi: 10.1038/35103535
22. Norio R. Finnish disease heritage II: population prehistory and genetic roots of Finns. Hum Genet. 2003;112(5–6):457–69. doi: 10.1007/s00439-002-0876-2
23. Sajantila A, Salem AH, Savolainen P, Bauer K, Gierig C, Pääbo S. Paternal and maternal DNA lineages reveal a bottleneck in the founding of the Finnish population. Proc Natl Acad Sci U S A. 1996;93(21):12035–9. doi: 10.1073/pnas.93.21.12035
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Published
2024-12-10
How to Cite
Syvänen A.-C. (2024). From early methods for DNA diagnostics to genomes and epigenomes at high resolution during four decades – a personal perspective. Upsala Journal of Medical Sciences, 129, e11134. https://doi.org/10.48101/ujms.v129.11134
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Review Articles
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