40 years of Sanger sequencing

DNA sequencing has a remarkable history, in terms of inception and evolution of the technologies themselves, as well as the breadth and scope of problems to which they have been applied. This Nature collection celebrates the 40th anniversary of the Sanger method for DNA sequencing, the most widely used sequencing method, pioneered by Fred Sanger and his team in 1977.

In a Review and accompanying Milestones, Jay Shendure, Shankar Balasubramanian, George M. Church, Walter Gilbert, Jane Rogers, Jeffery A. Schloss and Robert H. Waterston review the evolution of sequencing technologies over the past 40 years. The Milestones list key advances in methods development, computational analyses and applications of genome sequencing. We also highlight a selection of key publications from these Milestones that appeared in Nature journals in the Methods, Genomes and Applications sections.

Accompanying news and commentary in Nature bring further perspectives on this 40 year anniversary of Sanger sequencing. In a Commentary Eric Green, Eddy Rubin and Maynard Olson share perspectives on the future of sequencing over the next 40 years. A Technology Feature explores recent progress in one emerging method, nanopore sequencing, showing potential to upend the DNA sequencing market. A News Feature provides context on genomics applications in direct to consumer genetic testing.

- Orli Bahcall, Senior Editor, Nature

LISTEN: Nature Podcast with NHGRI Director Eric Green on how DNA sequencing has transformed biology, and what might still be to come.

Technical milestones in DNA sequencing methods 

The milestones listed below correspond to key methods developments in the evolution of DNA sequencing technologies. This is a large topic, and we apologize for any omissions.


1953: Sequencing of insulin protein

1965: Sequencing of alanine tRNA

1968: Sequencing of cohesive ends of phage lambda DNA

1977: Maxam–Gilbert sequencing

1977: First widely adopted methods for DNA sequencing: Sanger sequencingMaxam & Gilbert.

1981: Messing’s M13 phage vector

1986–1987: Fluorescent detection in electrophoretic sequencing: Smith et al. 1986Prober et al 1987.

1987: Sequenase

1988: Early example of sequencing by stepwise dNTP incorporation

1990: Paired-end sequencing: Automated DNA sequencing of the human HPRT locus 

1992: Bodipy dyes

1993: In vitro cloning of RNA colonies

1996: Pyrosequencing

1999: In vitro DNA colonies in gels

2000: Massively parallel signature sequencing by ligation

2003: Emulsion PCR to generate in vitro DNA colonies on beads

2003: Single-molecule massively parallel sequencing-by-synthesis 

2003: Zero-mode waveguides for single-molecule analysis.

2003: Sequencing by synthesis of in vitro DNA colonies in gels

2005: Four-colour reversible terminators: Ruparel et al. Seo et al. 

2005: Sequencing by ligation of in vitro DNA colonies on beads

2007: Large-scale targeted sequence capture: Albert et al. ; Okou et al. ; Porrceca et al. ; Hodges et al. 

2010: Direct detection of DNA methylation during single-molecule sequencing

2010: Single-base resolution electron tunnelling through a solid-state detector

2011: Semiconductor sequencing by proton detection

2012: Reduction to practice of nanopore sequencing: Manrao et al. Cherf et al.

2012: Single-stranded library preparation method for ancient DNA