Most complete overview of the human genome revealed

Synergistic evidence from two studies published in Nature this week have updated our understanding of the human genome.

Both studies were composed of international teams of scientists and led by researchers at the European Molecular Biology Lab (EMBL) in Heidelberg, Germany. One study focused on the structural variation of genomes in a 1019-person dataset, whereas the other study looked at a subset of 65 people to analyse their genomes more deeply to create more complete mapping of the human genome.

'One study uses less sequencing power, but a much larger cohort. The other uses a smaller cohort, but much more sequencing power per sample. This led to complementary conclusions,' said Professor Jan Korbel, interim head at EMBL Heilberg and co-senior author on both papers.

The Human Genome Project published the first rough draft of a human reference genome in 2000 (see BioNews 64) and a final draft in 2003, which was a blend of 13 people, mainly with European ancestry (see BioNews 204). Since then, scientists have been working to provide a more complete map of the global human genome (see BioNews 943, 1056, 1086, 1098, 1140 and 1147). The 1000 Genomes Project, which sought to provide a better understanding of the diversity within the genome from populations around the world, is one such endeavour (see BioNews 442, 564, 667 and 680). Both Nature studies replicated the diversity of the 1000 Genomes Project but used updated DNA mapping methods that were not available when the project began.

'The original 1000 Genomes Project created a map of genome locations that are variable in the human population, and this enabled us to systematically search for regions associated with common diseases,' said Sarah Hunt, the variation resources coordinator at EMBL's European Bioinformatics Institute. 'That first map was built from short variants, but we already know of cases where longer variants are associated with disease.'

When DNA is collected for sequencing it fragments into sections, which can either be short sequences or long sequences based on the preparation method. Sequencing long sequences relies on the accuracy of the base-pair reading technology, making it more technically challenging. When done accurately, long-read sequencing is better at creating maps of genomes. Both studies used this type of sequencing, with the larger cohort study relying on it as their primary method to update mapping of the human genome.

The larger cohort study focused on structural variations of DNA. These variations are anything that can lead to a change in the chromosome's structure, such as deletions and insertions of base pairs. They examined these structural changes in regard to population diversity. They found both common and rare variations and anticipate their data to be used to explore how these variations could lead to disease.

The smaller cohort study used multiple techniques to dive deeper into the human genome. After long-read sequencing, they examined inversions, duplications, and mobile elements that could be part of the genome. The genome is not in the same configuration in every cell, so these mutable elements can also shape disease. They additionally focused on centromeres and the Y chromosome, both of which have high levels of variability (see BioNews 943 and 1204).

'Through these studies, we have created a comprehensive and medically relevant resource that can now be used by researchers everywhere to better understand the origins of human genomic variation and see how it is affected by a plethora of different factors,' said Professor Tobias Marschall, director of the Institute for Medical Biometry and Bioinformatics at Heinrich Heine University Düsseldorf, Germany, and co-senior author on the two studies.

Production of data was the desired outcome in both studies. The results of both studies are hosted on the 1000 Genomes Project website and free for other researchers to download and use.