Archive for the 'Friday Links' Category

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Friday Links

Clinician Jacob M. Appel has a refreshing take on direct-to-consumer genetic testing – unlike many of his stethoscope-wielding brethren he rails against the idea that members of the public shouldn’t have access to their genetic information without the supervision of a medical professional:

The underlying belief of DTC opponents is that laymen are incapable of handling their own genetic information without the assistance of physicians. As a physician myself, I cannot help but fear that this approach smacks of the worst aspects of medical paternalism. We may soon find ourselves living behind a genetic Iron Curtain whose drawstrings are held by a cadre of white-coated Platonic guardians. Despite the public triumphs of the genetic revolution, our genetic liberties are slowly and silently slipping away.

Let’s hope this attitude catches on. [DM]

SNPedia’s Mike Cariaso discusses the present and future of personal genomics in a brief op-ed piece in Bio-IT World, which ends on an optimistic note:

While there is considerable trepidation at the marketing of genomes, I’ve been pleasantly surprised by the nearly universal consensus that you have a fundamental right to your genome. The biggest reluctance comes from those who want you to have the data, but only after they tell you what it means for a reasonable fee. But the head of the NIH, Francis Collins, has said, “free and open access to genome data has had a profoundly positive effect on progress.” FDA regulations may curtail the marketing, but it seems increasingly unlikely to limit the fundamental availability of personal genomes for the masses. The learning curve is still steep and much uncertain remains, but the path seems safe with no fundamental barriers to continued progress in all directions. [DM]

23andMe’s Joanna Mountain has a great post summarising the key messages for personal genomics from the presentations at the recent American Society of Human Genetics meeting. [DM]

Genetics chairs across the US read this Nature news piece carefully, which outlines new strategic directions for NHGRI.  We should expect that 15-20% of the current budget for large scale sequencing centers will be reallocated to three areas in the next funding cycle: analysis of Mendelian disease, clinical use of sequencing to guide treatment of difficult cases, and development of more user-friendly software for analysis of next-gen data. The clinical emphasis of these new priorities echoes other exciting developments for sequencing centers in other countries, such as the Wellcome Trust Sanger Institute’s DDD project. [DC]

Over at Genomics Law Report, Unzipper Dan Vorhaus reports from the recent Partners Healthcare Personalized Medicine Conference. The conference included real-time polling of the audience on various topics, including this highlight:

46% of the audience said they would wait until the price of whole-genome sequencing (WGS) dropped to $100 before taking the plunge. 30% would be buyers at $1,000, 9% thought $0 sounded more reasonable and a full 15% answered that they weren’t interested in a whole-genome sequence at any price. Panelist Mark Boguski (Beth Israel Deaconess Medical Center) joked that the audience was “cheap” but, given the rapid decline in the cost of WGS, “patient” may be a better adjective. By way of comparison, at last year’s conference 59% answered that $100 was their preferred price point, with only 10% declining WGS no matter what the price. Is it possible that some people are are getting cold feet as the prospect of actually having their own genome sequenced becomes more realistic? [DM]

Friday Links

We’ve been pretty quiet here at Genomes Unzipped for the last couple of weeks, while many of us prepared for and attended the American Society of Human Genetics meeting in Washington DC last week. The meeting was (as usual) an exhausting barrage of presentations on human genetics; you can get a flavour of the new results presented either by scrolling back through the Twitter coverage, or reading the summary posts by Luke Jostins (who found himself explaining why Eric Lander was wrong about epistasis and missing heritability) and Larry Parnell. Shirley Wu also has an excellent recap of the meeting, including an analysis of the Twitter coverage.

My overall impression of the meeting – and this was a view shared by many other attendees I’ve spoken to – was  that 2010 was a year of transition. The numbers were impressive: Stacy Gabriel at the Broad Institute blithely reported that their pipeline is now theoretically capable of sequencing up to 800 exomes (complete sequence of the protein-coding regions of the genome) per week, and the 1000 Genomes Project has now completed sequencing of over 1,000 whole genomes at low coverage. Projects that would have seemed mind-blowing even a year ago seem almost mundane now, an indication of just how fast sequencing technology has moved in the last twelve months.
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Friday Links

At long last, the 1000 Genomes Project pilot paper has been published this week in Nature. The paper describes the whole-genome sequencing of 179 individuals from 4 populations, and two mother-father-child trios, looking at the whole range of genomic variation, including SNPs, small indels and larger structural variants. A total of 15m variants were called, about 8 million of which were never seen before (shown in the Venn-diagram to the right), and all the data generated (including sequence, site locations and genotypes) has been released online for anyone to use.

GNZ authors feature pretty heavily in the paper’s author list. Daniel looked for loss-of-function mutations (variants that entirely break a gene), and found about 2000. Don looked at calling de-novo mutations (mutations that occur between parent and child) from the trios, and found around 100 total, which gives a mutation rate of about 10^-8 per base per generation, or around 60 new mutations for every baby born. Luke called 2,780 variants on the Y chromosome, and put together a new Y haplogroup tree (with branch lengths!), and Jeff was involved in the validation effort.

This paper only describes the pilot phase of the 1000 Genomes Project. There is a lot more to come yet, including extending the sample size and introducing new variant calling methods. The project is going to cross the 1000th genome sequenced any day now, and eventually thousands of individuals from dozens of populations will be included.[LJ]

Saturday Links

Due to a communication breakdown, no-one wrote a Friday Links post yesterday, so today we have a Saturday Links to make up for it.

Steve Hsu has a very appropriately named post, News from the future, about the Beijing Genomics Institute. The BGI is the largest genome sequencing center in China, and one of the largest in the world, and is growing faster than any other, and loading up on a shedload of high-tech HiSeq machines.

Steve reports that the BGI are claiming that their sequencing rate will soon be at 1000 genomes per day, with a cost of about $5k (£3.2k) each. To put a slight downer on these amazing numbers, he clarifies that this might be referring to 10X genomes, which would realistically mean ~300 high quality genomes a day, at $15k (£9.6). Either way, if you want to keep an eye on how fast whole-genome sequencing is progressing, perhaps with an eye to when you’re ready to shell out to get your own done.

A question for the comments: how cheap would a whole-genome sequence have to get before you’d order one?

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Friday Links

This will be somewhat of an introspective Friday Links, looking at what other people have had to say about our recent announcement. We’ll resume our regular programming next week.

It’s been a big week here at Genomes Unzipped, with the announcement that all of the group members have released their genetic data publicly. The announcement was accompanied by a story by Mark Henderson in The Times (subscription only, unfortunately, but also syndicated here) along with commentary from Misha Angrist, Linda Avey and Christine Patch.

You can also listen to Daniel talk about the project on the BBC World Service (starts 19m30s), and Carl on BBC Radio Scotland (starts 38m). Finally, Luke and Daniel were on CBC Radio’s The Current today.

Continue reading ‘Friday Links’

Friday Links

The Genomes Unzipped team has been quiet for the last few weeks as we prepare for a major announcement – stay tuned next week to find out more. In the meantime, here are a few things we found around the web this week.

China’s sequencing powerhouse BGI collaborated with Danish researchers to analyse the exomes (the sequences of all protein-coding genes) of 200 individuals from Denmark, in a study published in Nature Genetics. The researchers took an approach similar to that adopted by the 1000 Genomes Project, sequencing each of the individuals at fairly low depth (with each base in the exome being covered on average by 12 sequencing reads, as compared to at least 30 for a “high quality” genome), but then using a statistical approach to identify variants and infer their frequency within the population. The headline finding was that the sequenced individuals carry more rare protein-altering polymorphisms than expected; the authors conclude:

Based on our findings, we support the idea that much of the heritable variation affecting fitness is caused by low-frequency mutations, which are often overlooked in studies based on genotyping rather than resequencing.

The conclusion that much of the “missing heritability” for disease is driven by rare protein-altering mutations is plausible, but this study in and of itself doesn’t provide compelling evidence in support of it. Fortunately, more definitive studies are underway: as tens of thousands of exomes from disease patients and controls accumulate over the next two years, the contribution of rare protein-coding variants to disease (or surprising lack thereof) will soon be fairly definitively established. [DM]

Bio-IT World has an excellent special issue on “The Road to the $1000 Genome”, highlights include an article pondering the often underestimated costs of analysis of genome sequences, and an update on Hugh Reinhoff’s personal quest to find the mutation underlying his daughter’s genetic disease. The issue coincides with the launch of editor Kevin Davies’ new book The $1000 Genome, which was favourably reviewed this week at 23andMe’s blog The Spittoon. [DM]

In Science this week, John Travis takes a look at the technically and ethically challenging world of Native American genetics, focusing on the effort to sequence the nuclear genome of Lakota warrior Sitting Bull from snippets allegedly taken from the man’s hair. The story includes the unusual method by which the main researcher in the project gained approval to study the Native American’s remains:

LaPointe said the basement ceremony was required to get permission from Sitting Bull himself, who was killed in 1890. Willerslev says something odd happened at the ceremony, recalling a blue-green light that ran across his body and into his mouth. LaPointe says the spirit of Sitting Bull tested the geneticist and approved. As a result, LaPointe allowed Willerslev to cut a short section from a long braid of Sitting Bull’s still-shiny black hair and fly it back to the University of Copenhagen for analysis.

If only all ethics committee meetings were livened up by pyrotechnics… [DM]

A piece in Fortune tells the remarkable story of Hugh Martin, CEO of the massively-funded third-generation sequencing startup Pacific Biosciences, who has battled openly with cancer while guiding the company through funding rounds and towards a public share offering. [DM]

Friday Links

The largest genome-wide association study ever undertaken was published in Nature this week. The appropriately named Genetic Investigation of ANthropocentric Traits (GIANT) consortium combined data from 183,727 individuals and identified around 180 loci influencing human height. The loci were enriched with genes underlying skeletal growth and other relevant biological pathways. Interestingly, these 180 loci are estimated to only account for 10% of the phenotypic variation in height (or around 12.5% of the heritability). [CAA]

Christophe Lambert from Golden Helix has an excellent, thorough post looking at the importance of careful experimental design in large-scale genetic association studies. In particular, Lambert focuses on the need for randomising samples across experimental batches: if you have some batches containing entirely cases and others entirely controls, then the all-too-pervasive spectre of batch effects can easily create false positive associations. In many cases batch effects can be recognised and corrected for post hoc (Lambert cites a good example from the original WTCCC study), but in other cases a failure to perform the right quality controls can have devastating consequences (Lambert cites the recent longevity GWAS paper in Science). I’d be interested to hear from my more GWAS-savvy colleagues (Carl, Jeff) whether randomisation is standard procedure in most large GWAS now. [DM]

We managed to miss this out last week, but the current issue of Nature Genetics has a strange and wonderful paper on breast cancer genetics. The study looked at 2838 individuals with BRCA1 mutations that strongly predispose to breast cancer, and looked for non-BRCA1 variants associations with breast cancer in this group. They found an associated variant of chromosome 19, and replicated it in another 5986 BRCA1 carriers (where do they find this many BRCA1 carriers?). To top it all off, they looked at this variant in another 6800 breast cancer patients without BRCA1 mutations, and found no association. However, when they stratified their samples into ER+ and ER- associations, they found associations in both, but going in opposite directions! The variant predisposes people to ER- cancer, but is protective against ER+, and taken together they pretty much perfectly balance out. [LJ]

Friday Links

Over at 23andMe’s blog The Spittoon, Stanford genetics professor Uta Francke has a great point-by-point dissection of the new policy statement of the European Society of Human Genetics on direct-to-consumer genetic testing. Francke doesn’t shirk from explaining that this statement should be seen in the context of an ongoing turf war between traditional geneticists and DTC upstarts:

For example, organizations like ESHG, the American Society of Human Genetics (ASHG), and the American College of Medical Genetics (ACMG) were created to represent the interests of their professional membership, similar to the American Medical Associations (AMA) for physicians. Any claims to act in the public interest by protecting people from potentially damaging genetic information may reflect a fear of the new consumer-driven healthcare system that, as in the case of DTC genetic testing, may circumvent the professional establishment. Insisting on individual professional counseling in the pre-testing and post-testing phase can be interpreted as an attempt to ensure continued involvement of board-certified genetics professionals. [DM]

In PLoS Genetics, researchers report that a SNP associated with risk for colorectal cancer likely exerts its effect by modifying the expression level of a nearby gene. Previous studies on a different region associated with both prostate and colorectal cancer revealed a similar mechanism (see here, for example). This contributes to growing molecular evidence that SNPs with long-range regulatory effects might be generally important in disease. [JP]

Kevin Davies’ superb new book The $1000 Genome is now available on Amazon. Keith Robison has already posted his review, and I’ll have my full thoughts here on Genomes Unzipped soon – but for now I’ll just say that Davies’ long and extensive experience working the genomics beat really pays off, with both a wealth of inside information and juicy anecdotes about the key players in the field. Well worth a read for anyone interested in modern genomics (i.e. everyone reading this post). [DM]

Dan Koboldt of MassGenomics has a useful review of the recent Cold Spring Harbor Personal Genomes meeting. He pulls out four key themes emerging from the conference: new estimates of human mutation rates, more sequencing of cancer genomes, studies of genome regulation and epigenetics, and an explosion of exome sequencing in both severe and common diseases. [DM]

Our own Dan Vorhaus reports on the utterly bizarre decision by Health and Human Services (HHS) Secretary Kathleen Sebelius and NIH Director Francis Collins to discontinue the Secretary’s Advisory Committee on Genetics, Health, & Society (SACGHS). Inexplicably, Sebelius and Collins argued that “the major topics related to genetic and genomic technologies had been successfully addressed by the committee through its comprehensive reports and recommendations over the years”. Vorhaus notes diplomatically that “it is clear that even those issues SACGHS investigated in detail have not been resolved with any meaningful degree of finality”. [DM]

Friday Links

Over at Your Genetic Genealogist, CeCe Moore talks about investigating evidence of low-level Ashkenazi Jewish descent in her 23andMe data. What I like about this story is how much digging CeCe did; after one tool threw up a “14% Ashkenazi” result, she looked for similar evidence in 23andMe’s tool. She then did the same analysis on her mother’s DNA, finding no apparant Ashkenazi heritage, and to top it all off got her paternal uncle genotyped, which showed even greater Ashkenazi similarity. [LJ]

A paper out in PLoS Medicine looks at the interaction between genetics and physical activity in obesity. The take-home message is pretty well summarized in the figure to the left; genetic predispositions are less important in determining BMI for those who do frequency physical excercise than for those who remain inactive. This illustrates the importance of including non-genetic risk factors in disease prediction; not only because they are very important in their own right (the paper demonstrates that physical activity is about as predictive of BMI as known genetic factors), but also because information on environmental influences allows better calibration of genetic risk. [LJ]

Trends in Genetics have published an opinion piece in their most recent issue outlining the types of genetic variants we might expect to see for common human diseases (defined by allele frequency and risk), and how exome and whole-genome sequencing could be used to find them.  They give a brief, relatively jargon-free, overview of gene-mapping techniques that have been previously used, and discuss how sequencing can take this research further, particularly for the previously less tractable category of low-frequency variants that confer a moderate level of disease risk. [KIM]

More Sanger shout outs this week; Sanger Institute postdoc Liz Murchison, along with the rest of the Cancer Genome Project, have announced the sequencing of the Tasmanian Devil genome. The CGP is interested in the Tasmanian Devil due to a rare, odd and nasty facial cancer, which is passed from Devil to Devil by biting. In fact, all the tumours are descended from the tumour of one individual; 20 years or so on, and 80% of the Devil population has been wiped out by the disease. As well as a healthy genome, the team also sequenced two tumour genomes, in the hope of learning more about what mutations made the cells go tumours, and what makes the cancer so unique.

I have to say, this isn’t going to be an easy job; assembling a high-quality reference genome of an under-studied organism is a lot of work, especially using Illumina’s short read technology, and identifying and making sense of tumour mutations is equally difficult. Add to this the fact that the tumour genome is from a different individual to the healthy individual, this all adds up to a project of unprecedented scope. On the other hand, the key to saving a species from extinction could rest on this sticky bioinformatics problem, and if anyone is in the position to deal with it, it’s the Cancer Genome Project. [LJ]

Tasmanian Devil image from Wikimedia Commons.

Friday Links

A lot of the Genomes Unzipped crew seem to be away on holiday at the moment, so today’s Links post may lack the the authorial diversity that you’re accustomed to.

I just got around to reading the August addition of PLoS Genetics, and found a valuable study from the Keck School of Medicine in California. They authors looked at the effect of known common variants in five American ethnic groups (European, African, Hawaiian, Latino and Japanese Americans), to assess how similar or different the effects sizes were across the groups.

The authors calculated odds ratios for each variant in each ethnic group, and looked for evidence of heterogeneity in odds ratios. They find that, in general, the odds ratios tend to show surprisingly little variation between ethnic groups; the direction of risk was the same in almost all cases, and the mean odds ratio was roughly equal across populations (the authors note that this pretty effectively shoots down David Goldstein’s “synthetic association” theory of common variation). One interesting exception was that the effect size of the known T2D variants was significantly larger in Japanese Americans, who had a mean odds ratio of 1.20, compared to 1.08-1.13 for other ethnic groups. The graph to the left shows the distribution of odds ratios in European and Japanese Americans.

These sorts of datasets will be very useful for personal genomics in the future, as a decade of European-centered genetics research has left non-Europeans somewhat in the lurch with regards to disease risk predictions. However, the problem with the approach in this paper is that even this in large a study (6k cases, 7k controls) the error bounds on the odds ratios within each group are still pretty large. [LJ]

Over at the Guardian Science Blog, Dorothy Bishop explains the difference between learning that a trait is heritable (e.g. from twin studies), and mapping a specific gene “for” a trait (e.g. via GWAS). Her conclusion is worth repeating:

The main message is that we need to be aware of the small effect of most individual genes on human traits. The idea that we can test for a single gene that causes musical talent, optimism or intelligence is just plain wrong. Even where reliable associations are found, they don’t correspond to the kind of major influences that we learned about in school biology. And we need to realise that twin studies, which consider the total effect of a person’s genetic makeup on a trait, often give very different results from molecular studies of individual genes.

There are also interesting questions to be asked about why there is such a gap between heritabilities estimated by twin studies, and the heritability that can be explained by GWAS results. That is, however, is a question for another day. [LJ]

Another article just released in PLoS Genetics provides a powerful illustration of just how routine whole-genome sequencing is now becoming for researchers: the authors report on complete, high-coverage genome sequence data for twenty individuals. The samples included 10 haemophilia patients and 10 controls, taken as part of a larger study looking at the genetic factors underlying resistance to HIV infection. While this is still a small sample size by the standards of modern genomics, there are a few interesting insights that can be gleaned from the data: for instance, the researchers argue from their data that each individual has complete inactivation of 165 protein-coding genes due to genetic variants predicted to disrupt gene function. I’ll be following up on this claim in a future post. [DM]

Finally, a quick shout-out to our fellow Sanger researchers, including Verneri Anttila and Aarno Palotie, along with everyone else in the International Headache Genetics Consortium, for finding the first robust genetic association to migrane. They looked at 3,279 cases and >10k controls (and another 3,202 cases to check their results), and found that the variant rs1835740 was significantly associated with the disease.

To tie in with the above story, in the region of 40-65% of variation in migraine is heritable, but only about 2% of this was explained by the rs1835740 variant. However, explaining heritability isn’t the main point of GWAS studies: a little follow-up found that rs1835740 was correlated with expression of the gene MTDH, which in turn suggests a defect in glutamate transport; hopefully this new discovery will help shed some light on the etiology of the disease. [LJ]

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