Editing DeCODE genetics (section)

== Genome of a nation ==
By the time [[Bill Clinton]] and [[Tony Blair]] announced the completion of the first rough draft of the human genome sequence in June 2000,<ref>See [https://clintonwhitehouse3.archives.gov/WH/Work/062600.html archived version of the announcement] in the Clinton archives</ref> deCODE was busily scaling up its gene-hunting in dozens of diseases and publishing its first discoveries.<ref>See [https://www.decode.com/publications/ deCODE publications from 1997-2000] on the company's website</ref> The company used the most scalable DNA-reading technology of the time - [[Microsatellite|microsatellite genotyping]] - to place and measure highly variable and therefore informative markers at hundreds of points along the genome. Analyzed in tandem with the genealogies, this made it possible to home in on regions of specific chromosomes that people with a given disease tended to have inherited from their common ancestors.<ref>See for example [https://www.decode.com/decode-genetics-of-iceland-maps-a-gene-linked-to-pre-eclampsia/ an early company press release], "deCODE genetics of Iceland maps a gene linked to pre-eclampsia," 19 September 1999</ref> Harbored within these regions, the thinking went, were genes or sequence variants associated with disease that could subsequently be found using finer-definition methods and tools.<ref>A good summary of the approach is in Nicholas Wade, "A genomic treasure hunt may be striking gold," ''[https://www.nytimes.com/2002/06/18/science/a-genomic-treasure-hunt-may-be-striking-gold.html New York Times]'', 18 June 2002</ref>

But the main significance of these early publications was the focus on analytics and the suggestive power of the approach. Much of the field and public attention was focused on the race between the publicly funded [[Human Genome Project]] (HGP) and the private company [[Celera Corporation|Celera]] to generate the complete sequence of a single whole genome to use as a reference for future research. This was a technical challenge to generate and assemble raw data. By contrast, deCODE was advancing a strategy for analyzing variation in tens of thousands of genomes through genetics, leveraging the nature of the genome as a means of replicating and transmitting information. The power of the genetics was on full view by 2002, when deCODE published a genetic map of the genome consisting of 5000 microsatellite markers, which the genealogies made it possible to order correctly across all the chromosomes. The map was critical to correcting and completing the public reference genome sequence in 2003, improving the accuracy of the HGP assembly from 93% to 99%.<ref>A Kong ''et al.'', "A high resolution recombination map of the human genome," ''[https://www.nature.com/articles/ng917z Nature Genetics]'' (subscription required), Volume 31, pp 241–247, 10 June 2002</ref>

One key to this approach has been mass participation. From its early days, over 90% of people asked to participate in deCODE's disease research have agreed to do so.<ref>Participation rate over 90% even while IHD controversy was still fresh, in [http://getfilings.com/o0000893220-03-000634.html deCODE's annual report from 2002] filed with the SEC, p 8; company profile in ''[[doi:10.1517|Pharmacogenomics]]'', 4 Nov 2004</ref> Participation is voluntary but not trivial. It requires going to a data collection center to have blood drawn, answer questionnaires, and undergo clinical examinations and tests relevant to a given disease.<ref>A good early description of how people are asked to participate and how their data is used in research is on pp 7-9 of [http://getfilings.com/o0000893220-03-000634.html deCODE's 2002 annual report] filed with the SEC</ref> By 2003, more than 100,000 people had volunteered to take part in one or more of deCODE's three-dozen common diseases research programs.<ref>Helen Pearson, "Profile: Kari Stefansson," ''[https://www.nature.com/articles/nm0903-1099 Nature Medicine]'', volume 9, page 1099, 1 September 2003; participation rate in [http://getfilings.com/o0000893220-03-000634.html deCODE's annual report from 2002] filed with the SEC, p 8</ref> This number rose to 130,000 by 2007,<ref>James Butcher, "Kari Stefansson, general of genetics," ''[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(07)60133-0/fulltext The Lancet],'' 27 January 2007</ref> and more than 160,000 by 2018. This represents two-thirds of all adult citizens. The genomes of some 60,000 of these participants had been directly sequenced by 2019, with thousands more being sequenced every month.<ref>Anna Azvolinsky, ''[https://www.the-scientist.com/profile/master-decoder--a-profile-of-kri-stefnsson-65517 op. cit]''</ref>

A second and unique pillar of deCODE's work is the genealogies. Geneticist [[Mary-Claire King|Mary Claire King]], whose family-based research in the early 1990s led to the discovery of the BRCA1 and BRCA2 breast cancer genes, predicted not long after deCODE's founding that the ability "to trace the genealogy of an entire nation...could become one of the treasures of modern medicine."<ref>Michael Specter, "Decoding Iceland," ''[http://archives.newyorker.com/?i=1999-01-18#folio=CV1 The New Yorker]'' (subscription required), 18 January 1999</ref> In 1997, deCODE formed a partnership with local software firm [[FRISK Software International|Fridrik Skulason ehf]] to accelerate the creation of a comprehensive, computerized national genealogy database. It drew on all available sources, from the earliest calfskin records and sagas through the [[Icelandic census of 1703|1703 census]] and parish records to the contemporary national registry.<ref>See Islendingabok's English [[Íslendingabók (genealogical database)|wikipedia page]]</ref>

By the early 2000s they had created what is still today the most comprehensive genealogy of an entire country. It links together all living citizens through virtually complete records back to 1703 (itself [http://www.unesco.org/new/en/communication-and-information/memory-of-the-world/register/full-list-of-registered-heritage/registered-heritage-page-1/1703-census-of-iceland/ recognized by UNESCO as the world's first nominal national census]) and stretches back to before the settlement of the country in the ninth century. In the research version of the database, the identities of individuals are encrypted via the same anonymization system used for DNA and medical data, so that the data can be correlated.<ref>Olga Khazan, "How Iceland's Genealogy Obsession Leads to Scientific Breakthroughs," ''[https://www.theatlantic.com/health/archive/2014/10/how-icelands-genealogy-obsession-leads-to-scientific-breakthroughs/381097/ The Atlantic]'', 7 October 2014</ref> And In 2003, deCODE launched a public-facing, online version of the database, called {{Lang|is|[[Íslendingabók (genealogical database)|Íslendingabók]]|italic=no}}, or the Book of Icelanders. Anyone with an Icelandic social security number could request a password and then research their family tree and see their nearest family connection to anyone else in the country. Within its first month online, more than one-third of the population had requested a password.<ref>[https://www.mbl.is/greinasafn/grein/709474/ ''Morgunblaðið''] on Islendingabok launch - with photo</ref> By 2020, it had over 200,000 registered users and more than 900,000 linked entries, comprising the majority of Icelanders who have ever lived. On an average day, nearly 6000 people, or close to two percent of all citizens, consult the database.<ref>[https://www.islendingabok.is/n Islendingabok.is]{{Dead link|date=August 2023 |bot=InternetArchiveBot |fix-attempted=yes }}, accessed as user</ref>

In a country that is essentially a huge extended family with a correspondingly keen interest in how its members are related, Islendingabok has become a constant in national life and a daily and direct means of social engagement with deCODE's work. But in scientific terms, the ability to understand the precise genealogical relationships of all participants in its research projects has given deCODE an abiding advantage as a discovery enterprise, ensuring that its genomic and medical datasets have remained among the largest and best powered collections anywhere.<ref>Meg Tirrell, "Iceland's genetic goldmine," ''[https://www.cnbc.com/2017/04/06/icelands-genetic-goldmine-and-the-man-behind-it.html CNBC]'', 6 April 2017</ref>

At each successive advance in technology for reading DNA the genealogies have amplified both the amount of data that can be generated from them as well as the power to extract information from the data.<ref>Yekaterina Vaydylevich, "Iceland study provides insights into disease, paves way for large-scale genomic studies," [https://www.genome.gov/27561444/iceland-study-provides-insights-into-disease-paves-way-for-largescale-genomic-studies online news item] for National Human Genome Research Institute, 1 May 2015</ref> In the era of [[microsatellite]]s, it was possible to establish that participants shared certain markers and segments of the genome not by chance but [[Identity by descent|by descent]]. With the advent in the mid-2000s of [[SNP array|genotyping chips]], which could measure hundreds of thousands of single-letter variations ([[Single-nucleotide polymorphism|SNPs]]) across the genome, deCODE statisticians were able to accurately phase segments of the genome - to understand the parental source of segments -  and then impute genotypes measured in some people across the entire population.<ref>A Kong ''et al.'', "Detection of sharing by descent, long-range phasing and haplotype imputation," ''[https://www.nature.com/articles/ng.216 Nature Genetics]'', Vol. 40, Number 9, pp 1068–1075 (August 2008)</ref>

This effectively multiplies the size and power of any study. When [[Illumina, Inc.|Illumina]] began selling machines that could economically sequence whole genomes, deCODE was able to directly sequence several thousand Icelanders and then impute whole genome sequence (WGS) data for virtually the entire population. This represents one of the largest single collections of WGS data in the world, and the first results of its analysis were published in 2015 in a special edition of ''[[Nature Genetics]]''.<ref>"The Genomes of Icelanders," [https://www.nature.com/collections/hkpwscptyt Nature], permanent link, 25 March 2015</ref> The direct sequencing of tens of thousands of more people since then has enabled routine searches for ever rarer variants at an unprecedented scale.<ref>DO Arnar and R Palsson, "Genetics of common complex diseases: a view from Iceland," ''[https://www.ejinme.com/article/S0953-6205(17)30122-X/pdf European Journal of Internal Medicine]'', Vol. 40, pp 3-9 (2017)</ref>