PHG Foundation | Comparison of twenty human genomes - proof of concept?

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Comparison of twenty human genomes - proof of concept?
20 September 2010 | By Simon Leese | Research article

A study published in PLoS Genetics has employed next-generation sequencing to compare twenty human genomes in order to evaluate the potential of this technique to identify the genetic cause of disease [Pelak et al. PLoS Genet (2010) doi:/10.1371/journal.pgen.1001111].

The team of researchers sequenced ten genomes from individuals with haemophilia A and ten non-haemophiliac genomes as controls, and compared them for a range of genetic variants using a variety of software tools. Haemophilia A was chosen for this study because it is a highly penetrant Mendelian disorder caused by mutations in the F8 gene, which codes for the blood clotting factor VIII.

The authors found that the cause of haemophilia A was ‘easily recognisable’ from the comparative data; the F8 gene standing out as the one containing the greatest number of functional variants in the haemophiliacs, versus none in the controls, which they conclude is proof of concept that this technique is able to pinpoint the genetic variations responsible for a Mendelian disease. The researchers also found that all twenty of the genomes contained many genes that are not expressed, suggesting the future possibility of a human ‘knock-out’ database – whereby an individual’s non-expressed genes are correlated with their phenotype – which they say could become a critical tool in human functional genetics.

Comment: This study is an early demonstration of the potential for next-generation sequencing technologies and attendant analytic software to improve our ability to identify the genetic basis of disease. However, it also highlights some of the current limitations of these techniques. The study was able to identify the causal variant for haemophilia in only six out the ten genomes of those with the disorder, due to the difficulty in detecting some types of functional variants such as indels. The study authors’ suggestion of the future development of a large human knock-out database is interesting, but would present a great many obstacles to overcome in practice, including difficulties in assigning phenotypes and establishing the criteria for control subjects, as well as the non-trivial considerations of ethics and protocol
PHG Foundation | Comparison of twenty human genomes - proof of concept?