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BGI's Sequencing Projects Tackle Genetic Roots of Cancer and Disease, Reference Organism Assembly


By Monica Heger

BGI's 180 sequencers are churning out around 5 terabases of data per day on projects as diverse as cancer sequencing, exome sequencing of Mendelian disease, and whole-genome sequencing and de novo assembly of model plant and animal organisms, Joyce Peng, marketing director of BGI Americas reported at Cambridge Healthtech Institute's X-Gen Congress meeting in San Diego last week.

In an overview of the projects the institute is working on at its various facilities worldwide, Peng highlighted a few previously undisclosed projects and collaborations, as well as updates to other projects.

From Complex to Mendelian Disease

As China's representative in the International Cancer Genome Consortium, BGI is sequencing the exomes of 200 matched tumor/normal gastric cancer samples, as well as the whole genomes of a subset of those samples to a low depth in order to detect structural variation.

Preliminary sequence data from 10 primary tumors sequenced to 30-fold coverage revealed 6,615 novel coding SNVs, of which 3,643 were non-synonymous.

In addition, BGI researchers are sequencing a clear cell renal carcinoma tumor using a "multi-omics approach." BGI America's CEO Xun Xu told In Sequence that the team has sequenced the methylation profile, microRNAs, transcriptome, and the whole genome of one patient. The goal is to "mix all the evidence together to see the profile of renal cancer," Xu said.

Preliminary analysis has uncovered 43,428 SNVs, 168 of which are in coding regions, as well as 5,448 indels and 9,095 structural variations. The team also identified 24,187 differentially methylated regions and 8,416 differentially expressed RNAs. Looking at the pathways involved has implicated the MAPK signaling and focal adhesion pathway, as well as the IFI16 gene, which affects cell death and modulates the tumor suppressor p53.

BGI is also developing a method for single-cell sequencing, Xu said. It has so far sequenced 100 cells from one patient, and plans to publish the results soon. It is currently sequencing another 100 cells from a different patient, and plans to use the technique to study five cancer types: gastric, colon, renal, and two types of bladder cancer. While the sequencing of the first two patients were both internal projects, the institute is also collaborating with groups at Stanford University and academic institutions in the UK on single-cell sequencing projects.

BGI has also begun an effort called the 1,000 Mendelian Disorders project, for which it is currently seeking collaborators. Peng said that it has 100 ongoing collaborative projects under the initiative with 40 in validation stages, and has identified the disease genes in two disorders, including the neurodegenerative disease spinocerebellar ataxia.

As described in a paper published last year in the journal Brain, the BGI researchers sequenced the whole exomes of four patients in a four-generation Chinese spinocerebellar ataxia family and identified a missense mutation in the gene TGM6, as well as a separate mutation in the same gene in an additional family. Neither of the mutations were present in 500 normal individuals.

Peng also provided an update on BGI's collaboration with the LUCAMP consortium in Denmark to sequence the exomes of 2,000 individuals, including 1,000 obese and 1,000 healthy subjects (IS 11/9/2010).

The sequencing is complete, and resulted in 152,829 SNPs. The team is now in the process of genotyping around 20,000 of those SNPs in 17,000 additional individuals. So far, they have found that the majority of the SNPs in the obese individuals are rare — 66 percent of the SNPs have an allele frequency less than .05, while 41 percent have an allele frequency less than .01.

Additionally, BGI is conducting the sequencing for the Netherlands Genome Project, in which the whole genomes of 250 trios — parents and offspring — will be sequenced in order to map genetic variation in the Netherlands. The DNA samples will be provided from Dutch biobanks, which have more than 100,000 samples that have already been analyzed in genome-wide association studies.

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Pharma Collaborations

BGI also has several ongoing collaborations with pharmaceutical companies, including one with GlaxoSmithKline to sequence 200 genes from 15,000 people to identify drug targets for which GSK already has compounds in a range of diseases including cardiovascular, respiratory, psychological, immune, and neurodegenerative indications (IS 8/10/2010).

Peng said that so far BGI has completed the sequencing and analysis for 5,000 patients, uncovering around 7,000 unique non-synonymous SNPs.

Pfizer is also collaborating with BGI on several sequencing projects, including a project to sequence the exomes of 250 individuals in order to identify genes that are involved with pain sensitivity.

According to Brian Dougherty, a senior principal scientist at Pfizer who also presented at last week's meeting, the team, which includes collaborators from Kings College London and Pfizer UK, has so far sequenced and analyzed the exomes of 37 patients, 11 of whom are extremely sensitive to pain, 13 of whom feel no pain, and 13 controls.

They identified about 40,000 unique variants, but when looking at only the "top pain genes," were able to narrow that number down to 36 variants in 12 to 20 genes, said Dougherty.

The goal of the project is to identify new drug targets for the extreme ends of the pain sensitivity phenotype — those who are highly sensitive to pain as well as those highly insensitive to pain.

In a separate collaboration, BGI and Pfizer are conducting a targeted sequencing project of 120 genes implicated in schizophrenia. For the pilot phase, they are focused on 48 patients, and will then apply the approach to 500 cases of early-onset schizophrenia and 500 controls.

In addition, Dougherty said the partners have begun a small RNA sequencing project to see if next-gen sequencing can be used to monitor shRNA-delivered drugs, as well as a bacterial genome resequencing project to identify mechanisms of antibiotic resistance. Those projects are still in the very early stages.

Potatoes, Sheep, and Microbes, Oh My

Separately, BGI announced this week that it would participate in the Earth Microbiome Project, an international collaboration to determine the functional and evolutionary diversity of microbial communities across the globe including in samples from the soil, ocean, air, freshwater, and underground.

BGI will provide DNA extraction, amplification, sequence library construction, and sequencing for metagenomics projects and will also help develop a bioinformatics pipeline to help characterize 200,000 samples.

As part of the 1,000 Plant and Animal Genome Project, BGI researchers recently sequenced the genomes of the potato and sheep, bringing the project's completed genomes to 100. The project seeks to sequence the genomes of 1,000 important plant and animal reference species over the next two years.

Most of the projects are collaborations and involve academic researchers in China, Japan, Australia, US, and Europe. In May, the institute said it had sequenced around 50 genomes (IS 5/25/2010).

BGI is also a participant in the Genomes 10K project, an international effort that aims to assemble a "genomic zoo" from 10,000 vertebrate species, or one for each vertebrate genus, for which it said it would sequence and assemble the genomes of 100 vertebrates by 2012 (IS 5/18/2010). Xu said researchers have so far sequenced 50 vertebrate species, some of which overlap with the 1,000 Plant and Animal Genomes project.

Have topics you'd like to see covered in In Sequence? Contact the editor at mheger [at] genomeweb [.] com.

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