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Most detailed map of human genetic variation

The “1000 Genomes Project Consortium” is a major international collaboration that seeks to systematically investigate the genetic variation of human populations. It has recently published the results of an analysis of the pilot phase in the journal “Nature”. German groups that are part of the project include researchers from the Max Planck Institute for Molecular Genetics, the University of Kiel and researchers from the European Molecular Biology Laboratory in Heidelberg.

The 1000 Genomes Project is a public-private consortium that brings together scientists from research institutions and sequencing companies in the USA, Europe and Asia. The goal of the project is to build the most detailed map of human genetic variation to date and store the data in a public database.

This information could shed light on how a person’s genetic makeup may contribute to specific illnesses such as diabetes and cancer. The consortium members will sequence the genome of Europeans, West Africans and East Asians.

In earlier sequencing projects such as the Human Genome Project, the genome of several people was mixed to produce what is known as a reference genome. This does not allow specific inferences to be made about individual genomes. However, huge progress in sequencing technologies now makes it possible to read entire genomes, “letter for letter”. Scientists of the 1000 Genomes Project systematically investigated the genomes of 179 human individuals from different populations. In addition, the scientists also analysed the transcriptomes, i.e. protein-coding genes, of 697 people. Each DNA region was sequenced several times, rendering more than 4.5 terabases of DNA sequence (4.5 billion nucleotides). The map of human genetic variation prepared in the first 1000 Genomes Project phase contains 15 million single-letter changes, one million small deletions or insertions and 20,000 larger variants. More than 50% of the variants were observed for the first time. The project's database contains more than 95 percent of the currently measurable variants found in any individual. Future work will eventually identify more than 99 percent of human variants.

Looking at the individuals in the study, within some individuals there was very little genetic variation, maybe affecting only a few nucleotide exchanges. Between others there were more comprehensive ones, such as the duplication or rearrangement of entire chromosome regions.

Some differences are shared among many people, others only among a few. The improved map produced some surprises. For example, the researchers discovered that, on average, each person carries between 250 and 300 genetic changes that would cause a gene to stop working normally, and that each person also carries between 50 and 100 genetic variations that had previously been associated with an inherited disease. No human carries a perfect set of genes but because each person carries at least two copies of every gene, individuals are likely to remain healthy, even while carrying these defective genes, as long as the second copy functions normally.

Dr. Jan O. Korbel, Genome Biology Research Unit, EMBL © EMBL

In addition to looking at variants that are shared among many people, the researchers also investigated in detail the genomes of six people: two mother-father-daughter nuclear families. By finding new variants present in the daughter but not the parents, the team was able to observe the precise rate of mutations in humans, showing that each person has approximately 60 new mutations that are not found in either parent.

The pilot studies now enable the consortium scientists to create a comprehensive, publicly available map of genetic variation that will collect sequences from 2,500 people from 27 populations worldwide within the next two years. It is believed that more than 99 percent of human variants will have been identified by then. The international project is led by a 24-member steering committee, including Prof. Hans Lehrach, Director of the Max Planck Institute for Molecular Genetics. Dr. Jan Korbel, head of the Genome Biology Research Unit at the European Molecular Biology Laboratory in Heidelberg, and his team are also part of the project. Lehrach and Korbel's research groups are also involved in the International Network of Cancer Genome Projects (see BIOPRO article "Individual genome sequencing - for whom?"). The German institutions that are part of the 1000 Genomes Project receive funding from the German Federal Ministry of Education and Research under the Medical Genome Research NGFN-Plus programme.

Original publications:
The 1000 Genomes Project Consortium: A map of human genome variation from population scale sequencing. Nature 2010, DOI: 10.1038/nature09534

Stütz AM & Korbel JO: Potential and challenges of personalized genomics and the 1000 Genomes Project. Medizinische Genetik 22, 242-247 (2010)

Website address: https://www.gesundheitsindustrie-bw.de/en/article/press-release/most-detailed-map-of-human-genetic-variation