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• GENOME RESEARCH
• • History of genome research
  • Technologies of genome research
  • Human genome project
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In the mid 1980s it was the time to start a huge project with no comparison in life sciences: the mapping of the entire human genetic information in order to identify all genes on the 3,2 billion basepairs of the DNA within the 23 chromosomes.
Molecular biologist Robert Sinsheimer, then Chancellor of the University of California, Santa Cruz (UCSC), was setting the ball rolling: he thought about sequencing the human genome as the core of a fund-raising opportunity in late 1984. He and others convened a group of eminent scientists to discuss the idea in May 1985. 1988 the Human Genome Organisation (HUGO) was founded –an autonomous association composed of scientists and genome research institutes. HUGOs task was to coordinate all the teams from all over the world.
The actual Human genome project (HGP) began in 1990 as a public, initially U.S. American large-scale research project. Shortly afterwards numerous genome research projects from more than 30 countries joined the network. 60 percent of sequencing was done by centres in the USA; the British Sanger-centre undertook 25 percent. The remaining sequences were determined by researchers from France, Japan, China and Germany. The goal was to be finished till 2005. The approximately cost: 3 billion US dollars – about one dollar per base pair!

One distinctive aspect to keep faith with such a huge undertaking in only 15 years was the development of new technologies, that changed the genetics to genetic engineering: Using molecular DNA-scissors- the so-called restriction enzymes- the scientists could now selectively fragment the long DNA. Beforehand, the long DNA was always balling, so that it could not be sequenced anymore. Now, the HPG-researches could handle the 3.2 billion basepair genome much better. The DNA for the Humane genome project was obtained from sperms and leukocytes of different donors.

To be able to sequence a whole genome, the three following steps are essential: Cutting, sequencing, reassembling. First, the scientists of HPG fragmented the genome with restriction enzymes in sections of defined size. In order to have a sufficient amount available to be able to sequence the DNA-fragments, the abundance of DNA-fragments has to be increased. This can be done by putting the DNA-fragments into bacteria: If the bacteria divide and double their DNA, they will also double the introduced DNA-fragment.

To infiltrate DNA-fragments into bacteria, fragments have to be introduced into small circular DNA molecules, the so-called vectors. This technique is facilitated by restriction enzymes as “molecular scissors” and ligases as “DNA-lute”. Subsequently, the bacterial cell envelope is perforated and the vectors – including the DNA-fragments of the human genome – can enter the bacteria.
In this way, single DNA-fragments augment in bacteria. Because every bacteria colony contains a specific DNA-fragment, gene libraries can be generated.
That followed, the human DNA included in the bacteria was fragmented again, till the fragments had the size required for sequencing. Finally, the peaces of different donors were combined. Thus, the sequenced genome is not the DNA of one single person but a universal sample of the human genome. To be able to reassemble the DNA-fragments from the gene libraries in the right order, researchers of HGP used chromosomal maps. Using markers, the position of fragments is indicated in those maps.

In this way, only 3 percent of the human genome was sequenced until 1998.

At that time, scientist Craig Venter announced, in a solo attempt he would decipher the entire human genome with his company Celera Genomics. Venter was using a less precise but faster approach to sequence the DNA. He relied on maximal automation and concentrated computer power. He did not use restriction enzymes to divide the DNA but mechanical force (ultrasound), so that fragments were generated by pure chance, small enough to be sequenced from both ends. Surprisingly enough, the total human DNA sequenced in his project was Craig Venters own DNA. The reassembling should be done by computers. He thought he did not need the painful mapping – a mistake. What worked out for flies and bacteria did not work with the human genome. The reason: in the human genome, 40 percent of the DNA are high repetitive DNA segments. Without the chromosomal maps of the HGP the computers lost orientation. Thereupon, Craig Venter and the scientists of the HGP worked partially together. With success: Already in June 2000, the “working version” of the human genome was announced. It was published the 12th of February 2001. HUGO and Celera Genomics deciphered the precise sequence of the 3,2 billiards gene letters: an immense “text”, that would fill about 3000 books with 1000 pages per book and 1000 letters per page. It became evident, that this “text” is 99,9 percent identical in all humans. Scientists were also able to read the approximate number of human genes in the sequence. This was a surprise: it turned out, that human have about 20 000 up to 25 000 genes, only double as much as for example a fly! Scientists reckoned with many more genes in the human genome.
Since April 2003 the entire human genome is considered as deciphered and the human genome project as completed. As follow-up project, the National Human Genome Research Institute (NHGRI) initiated the ENCODE project.

The Sequencing of the entire human genome is considered as a milestone in the genome research. However, to be able to use this information for the prediction of potential disease risks or for the development of new therapies, the identity and precise position of all the human genes have to be determined. Additionally, the identity and position of other functional elements that for example determine the structure of chromosomes or regulate the transcription have to be defined. For this reason, the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH) launched a highly interactive public research consortium named ENCODE, the Encyclopedia Of DNA Elements, in September 2003 to carry out a project to identify all functional elements in the human genome sequence. The project started with two components - a pilot phase and a technology development phase. The pilot phase tested and compared existing methods to rigorously analyze a defined portion of the human genome sequence. The conclusions from this pilot project were published in June 2007 in Nature and Genome Research as well as released into public databases. Since September 2007 the ENCODE project is in its production phase in which the entire human genome will be mapped as cost-effective and reliable as possible and all functional elements will be identified and characterized.
More about ENCODE

In an unprecedented achievement, the Human Genome Project provided the first drafts of nearly complete human genome sequences. The long-term goal of the Personal Genome Project (PGP) is that every person has access to his genotype in order to advance the understanding of genetic and environmental contributions to human traits and to improve the ability to diagnose, treat, and prevent illness. It was initiated by George Church (Harvard, USA) and announced in January 2006 with the goal to enroll at least 100,000 informed participants from the general public worldwide.  All data will be published along with the volunteer's name. An important part of the project will be the exploration of the resulting risks to the participants, such as possible discrimination by insurers and employers if the genome shows a predisposition for certain diseases.
More about the Personal Genome Project

Drawing on the expertise of multidisciplinary research teams, within the international 1.000 Genomes Project, launched in January 2008, the genomes of at least a thousand people 1000 people will be sequenced. The scientific goal is to provide a detailed catalogue of human genetic variations including SNPs and structural variants, and their haplotype contexts. This resource will support genome-wide association studies and other medical research studies.
More about the 1000 Genomes Project

Five years after publication of the Human Genome Project the International Cancer Genome Project was launched. With the objective of maximizing efficiency among the scientists working to understand, treat, and prevent cancer, the genetic changes in 50 different tumor types and/or subtypes are analyzed. Whereas in the human genome project the sequence of 3 billion bases of an archetype of a human being was identified, the goal of the Cancer Genome Project is to sequence the genotype of 12.500 different tumor samples. This represents 12.500 times the sequencing effort of the Human genome project!
More about the Cancer Genome Project