16 November 2008
Two new papers in the journal Nature have reported complete human diploid genome sequences, both male, from anonymous individuals of African and Asian ancestry. The African genome is that of a man from the Yoruba ethnic group in Nigeria, West Africa, and the Asian that of a man of Han Chinese descent. The original (haploid) human genome sequence was produced from a composite sample of DNA from several anonymous donors and completed in 2003. The first genome sequences from individuals were released in 2007, those of scientists Jim Watson (see previous news) and Craig Venter (see previous news), both of European descent. The Beijing Genomics Institute (BGI) in China announced completion of the first complete diploid genome sequence of a Chinese individual shortly afterwards (see previous news), but it has only now been published. The first individual female genome sequence has been hailed rather for its significance as the first genome from a cancer patient (see previous news).
Determining the genome sequences of individuals with different ethnic ancestry is of interest to allow comparison; in particular, to identify common variations that may confer susceptibility or resistance to diseases and occur at very different frequencies in different populations. Work began earlier this year on an international ‘1000 Genomes Project’ to sequence genomes from at least 1000 individuals, to create a valuable (and publicly accessible) database for analysis (see previous news).
The African genome sequence is the work of an international consortium including researchers at the Wellcome Trust Sanger Institute near Cambridge. They report on their use of a technique termed reversible terminator chemistry, whereby DNA molecules are amplified in situ on a solid platform before being used as templates for re-sequencing of the genome using fluorescently labelled reversible chain-terminating deoxyribonucleotides [Bentley DR et al. (2008) Nature 456(7218):53-9]. This system reportedly allows massively high-throughput sequencing at low cost, with the complete genome sequence generated in just eight weeks using six machines, at a cost of US $250,000. The sequence reportedly covered 99.9% of the reference human genome sequence, with high-quality coverage of 93%. In addition to the genome sequence, they report characterization of 4 million single nucleotide polymorphisms (SNPs) and 400,000 structural variants. They were able to compare their results with those from previous work analyzing the same genome and reported good concordance between the different sets of data. Of note, the West African genome was found to contain a significantly greater amount of polymorphism than that of a Northern European sequence
The Asian genome sequence by researchers from the Beijing Genomics Institute was produced using a commercial parallel sequencing approach similar to that reported by the African genome team, using Illumina Genome Analyzer machines. They report sequence representing high-quality coverage of 92% of the genome, and identification of around 3 million SNPs [Wang J et al. (2008) Nature 456(7218):60-5]. Comparison with the Venter and Watson genomes revealed that 1.2 million of these SNPs were common to all three genome sequences. The sequences were produced in “1-2 months” with five machines and a reported cost of under US$500,000. Analysis of SNPs identified a mutation in the GJB2 gene associated with a form of recessive deafness, and common variants associated with increased susceptibility to tobacco addiction and Alzheimer’s disease; the anonymous donor is reportedly a heavy smoker, but no data was available to show any family history of Alzheimer’s disease; however, individual alleles associated with susceptibility or resistance to complex conditions and diseases would not have a very significant effect and so the statistical relevance of such information would be highly limited.
Comment: Both papers predict the application of advancing sequencing technology for a boom in personal genome sequencing and application of this information for personalized medicine, to improve the prediction, prevention and treatment of disease. Their postulated timescale for such developments differ, however, with the Asian genome team referring to ‘ultimately’ and ‘eventually’ whilst the African genome team talks rather of the ‘near future’. An editorial accompanying the papers notes that the “age of personal genomes is here” and comments on how far developments have fulfilled the original predictions for this milestone [Nature 2008, 456(7218):1]. Broadly, the message is that whilst these achievements are highly significant, in fact much more work will be required to make sense of the bewildering complexity that is the human genome in health and disease, and that meanwhile attention could usefully be devoted to considering associated issues.