Genomes Unzipped

Report on clinical genome sequencing

25/10/2011
Categories: Journal Club
Written by Caroline Wright

The PHG Foundation, an independent genomics think-tank, has launched a new report on next generation sequencing and its impact on health and health systems. The Report, Next steps in the sequence: the implications of whole genome sequencing for health in the UK can be freely downloaded and aims to provide a comprehensive overview of the many and varied issues relating to clinical genome sequencing.

When planning the work, we were motivated by the astonishingly rapid development of fast, affordable whole genome sequencing (WGS) technologies, which are set to change many aspects of health care. The sheer quantity and complexity of the information generated by genome sequencing, along with ever-changing understanding of the function of genomes in health and disease, presents new challenges for health systems.

The Report reviews the technologies, informatics pipeline and key clinical applications of WGS, and as well as the economic, ethical, legal and social implications and organisational challenges of offering WGS within the UK NHS. The final two policy chapters outline different scenarios for testing, storing and returning results, and contains 10 key recommendations reached with the help of several expert stakeholder workshops.

Continue reading ‘Report on clinical genome sequencing’

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Debating the future of genome sequencing in medicine

21/10/2011
Categories: ELSI
Written by Luke Jostins

This is a cross-post from my more technical blog, Genetic Inference. However, I thought that it might be of interest to non-specialists who like to keep up with the ongoing debates about the role of genomics in health and medicine.

Last week many of us at Genomes Unzipped (along with over 7000 other geneticists) were at the International Congress of Human Genetics in Montreal. A highlight of the meeting was a large debate entitled “Current and Emerging Sequencing Technologies: Changing the Practice of Medical Genetics”. The panel and the audience were both packed with research scientists, clinicians and industry researchers (you can see the full list of panel participants here), and as you’d expect the discussion was at times pretty lively.

Different perspectives

Joris Veltman described his exome sequencing of 500 individuals with intractable disease, and noted that there has been much success, and very little evidence of harm. Ségolène Aymé mentioned NIH targts that hope to see almost all genetic diseases diagnosed by 2020, and new treatments for rare diseases to be developed simultaneously. There seemed to be a solid consensus across the panel that sequencing should be rolled out as a standard tool in the diagnosis of genetic diseases, provided that the approach is a targeted one, restricted to finding the pathogenic mutation(s) causing the disease.

More controversial was the role of sequencing of healthy individuals, and the general return of data to patients or doctors for any reason other than directly diagnosing a genetic disease. Rade Drmanac, chief scientific officer of Complete Genomics, was obviously strongly in favour of everyone having their genome sequenced, and made it clear that Complete Genomics intends to start offering sequencing to doctors in the future. In his vision, genomes are sequenced at birth, and an initial analysis of immediately actionable results (e.g. potential genetic diseases) is passed to the doctor and patient, with further analyses being carried out if and when they are required.

Michael Hayden immediately dismissed this as hype. He pointed out how unable the US is to handle medical sequencing, with no good systems of reimbursement, a massive shortage of genetic councilors, and a general lack of training in the medical profession.While more positive in general, Louanne Hudgins also expressed worries about the lack of knowledge of genetics among doctors, with some truly scary examples of MDs failing to understanding even the most basic concepts in genetics.

Continue reading ‘Debating the future of genome sequencing in medicine’

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Revisiting RNA-DNA sequence differences

12/10/2011
Categories: Journal Club
Written by Joe Pickrell

A few months ago, I discussed a paper by Li and colleagues reporting a large number of sequence differences between mRNA and DNA from the same individual [1]. While some such differences are expected due to known mechanisms of RNA editing (e.g. A->I editing, see [2]), Li et al. reported an astonishingly high number of them, including thousands of events inconsistent with any known regulatory mechanism. These results implied at least one, and probably many, new mechanisms of gene regulation, and called into question some basic assumptions in molecular biology.

An alternative explanation for the observations of Li et al. is less exciting–imagine two genes with similar (but not identical) sequences, which produce similar (but not identical) mRNAs. If you accidentally attributed both mRNA sequences to the same gene, you could erroneously conclude that one of the two sequences arose via RNA editing of the other. According to a new paper in by Schrider and colleagues [3], this banal artifact accounts for the majority of the reported RNA-DNA sequence differences in Li et al.

Schrider et al. show that RNA-DNA mismatches are enriched in genes with close paralogs or copy number variants, both of which are consistent with the technical artifact mentioned above. However, their most striking result is that, at many of the putative RNA editing sites, the “edited” base from the mRNA is actually present in genomic DNA. To show this, Schrider et al. took advantage of the fact that low-coverage DNA sequencing data is available for the individuals used in the Li et al. study. They searched through these data to find genomic sequences matching the “edited” mRNA form. If these sites were truly due to RNA editing, they shouldn’t find any. Instead, at ~75% of the tested sites, they could find a genomic match to the “edit” in at least one individual. There are some potential complications with the interpretation of this number (as they note, the genomic data could include sequencing errors that happen to be the same base as the “edit”), but this observation strongly suggests that a majority of the sites identified by Li et al. are false positives due to this single technical issue.

—
[1] Li et al. (2011) Widespread RNA and DNA Sequence Differences in the Human Transcriptome. Science. doi: 10.1126/science.1207018

[2] Levanon et al. (2004) Systematic identification of abundant A-to-I editing sites in the human transcriptome. Nature Biotechnology. doi:10.1038/nbt996

[3] Schrider et al. (2011) Very Few RNA and DNA Sequence Differences in the Human Transcriptome. PLoS One. doi:10.1371/journal.pone.0025842

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Friday Links: Studying association studies, and success at last in psychiatric genetics

07/10/2011
Categories: Friday Links
Written by Luke Jostins

In PLoS Genetics this week there is a viewpoint article on data sharing in disease genetics. The authors systematically looked at 643 genome-wide association studies published between 2002 and 2010, to see how easily available the results of the studies are now. They found that the availability of full study results has gone down over time, and many groups that do share data have put more restrictions in place on its use. They put this down to fears over the privacy of research subjects, and in particular to the Homer et al study. The Homer et al result is somewhat complicated, but in essence it says that if you have stolen someone’s genotype data, you can use it to figure out if they have participated in any given research study by looking at the full results of the study.

It certainly seems possible that worries about privacy are reducing the free flow of information within the research community. However, whether on balance the decrease in information flow is worth the increase in security is an open question. For my own view, I feel that having the genome-wide results of genome-wide association studies freely available is very important to the field, and is more important than the the rather esoteric risk of someone stealing someone’s DNA and using it to figure out that they once took part in a research study of inflammatory bowel disease. [LJ]

Genome-wide association studies have been hugely successful in identifying dozens of common genetic risk factors for a large number of common diseases. However, one area that GWAS has not had much success in is the field of psychiatric illness, where finding common risk factors that replicate across studies has been consistently difficult. However, it looks like this is starting to change. The current issue of Nature Genetics has two papers from the Psychiatric GWAS Consortium, detailing some of the largest meta-analyses of schizophrenia and bipolar disease ever published.

The schizophrenia study robustly replicated two previously implicated variants, and discovered five new ones, and the bipolar disease study replicated one and discovered a new one. The new variants give us some pretty startling insights into the genetics of the diseases, in particular revealing the importance of a non-coding gene micro-RNA 137 in regulating a wide range of genes expressed in neurons. As always, these variants explain only a small proportion of the total genetic effect, but they show that psychiatric genetics has now truly entered the GWAS arena, with all the scientific benefits that this can bring to medical research. [LJ]

The images above, in order, are taken from the paper Temporal Trends in Results Availability from Genome-Wide Association Studies, and from Wikimedia Commons.

Tags: bipolar disease, data sharing, GWAS, open access, privacy, psychiatric genetics, schizophrenia.
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Results of Nature poll on personal genetic analysis by scientists

05/10/2011
Categories: Quick Link
Written by Daniel MacArthur

Last month we pointed to a poll over at Nature looking primarily at the use of personal genetic tests among scientists (Nature‘s Brendan Maher was kind enough to consult us when designing the poll, so we were able to pass on some of the lessons we learned when doing our own reader survey last year). The results are now in, and Brendan has a brief article taking a look at the results.

Firstly, there was a fantastic response to the survey – nearly 1,600 participants. Of those, 289 (18%) had taken some kind of genetic test; interestingly, a further 54% said they’d be interested in doing so if given the opportunity. The vast majority of genetic tests done were genome scans (50% 23andMe). The motivations of those who had tests done were very similar to those from our readers – intellectual curiosity ranked at the top, with interest in health, genealogy and ancestry ranking lower.

Brendan’s piece has some nice vignettes from survey respondents. He was also kind enough to pass on the raw (anonymised) data to us for further analysis, and we’ll be poking around in there over the next week or so. Some immediately interesting results emerge from the comparison of the results from participants who fell into the “biology” vs “medicine” discipline: of those who had taken genetic tests, biologists were far more likely to have been tested by 23andMe (73.3% vs 47.2%) and were more likely to have cited “intellectual curiosity” as a major factor in their decision (71.1% vs 42.6%), whereas “medicine” respondents were more likely to cite a specific health risk as a major factor (34.4% vs 18.7%), were more likely to have consulted a clinician beforehand (23.0% vs 7.8%) and were more likely to report negative outcomes to testing (8.2% vs 4.8%). Of those who hadn’t yet had a genetic test done, biologists were more likely to be interested in doing so if given the opportunity (74.4% vs 67.6%). Nothing terribly shocking, but some useful insight into the basis of the “culture war” between basic and medical researchers over the issues surrounding personal genomics.

Anyway, kudos to Brendan and the Nature team – and to their readers, of course – for generating such an interesting data-set. No doubt you’ll be hearing more about the results of this survey soon.

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The week that I worried I had a rare genetic disease

15/09/2011
Categories: Disease Risk
Written by Joe Pickrell

I recently had a series of moderately unpleasant health problems, which eventually led to my being tested for a rare, and potentially very serious, genetic disease (for worried parties: the test was negative). I thought I would share this anecdote because, first, it’s the only time I’ve wished I had more genetic information about myself in a medical setting, and second, because it illustrates the sorts of gaps in medical knowledge that could be aided by routine genome sequencing.

Continue reading ‘The week that I worried I had a rare genetic disease’

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Complete Genomics to sequence 1500 whole genomes for pre-term birth study

15/09/2011
Categories: In The News
Written by Daniel MacArthur

Genome sequencing provider Complete Genomics has announced a deal with the non-profit Inova Translational Medicine Institute, under which the company would sequence 1,500 complete human genomes to help explore the genetic basis of premature birth.

The Inova collaboration is one of many large-scale genome sequencing studies currently being planned and performed around the world. In some respects the study is actually quite a small one – only 250 “cases” (i.e. premature babies) are being sequenced, along with 250 normal-term control babies, which means the researchers will have low statistical power by the standards of modern genomics. However, sequencing this number of complete genomes to high depth is (as far as I know) unprecedented, and the inclusion of the parents of all of the children in the study will provide the team with the ability to do some very interesting analyses – for instance, looking at “de novo” mutations that arise in the babies but weren’t present in either parent, as well as exploring potential effects of the maternal genome. Maternal genetics are known to be important in determining the risk of premature birth: girls born prematurely have a higher risk of delivering a pre-term baby themselves (with twin studies suggesting between 15 and 40% of the risk is heritable), while paternal genes seem to have almost no effect.
Continue reading ‘Complete Genomics to sequence 1500 whole genomes for pre-term birth study’

Tags: Complete Genomics, sequencing, whole-genome sequencing.
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Nature poll for scientists on personal genomic analysis

14/09/2011
Categories: Quick Link
Written by Daniel MacArthur

Brendan Maher from Nature has alerted us to a new poll that may well be of interest to many of our readers – an investigation of the attitudes of researchers towards personal genetic testing. Here’s the summary:

We aim to get a sense of how many researchers are actually peering into their own genomes. The responses will be analysed in aggregate to aid in a news story, and no identifying individual information will be used unless you agree to be contacted by a reporter. At the end of the survey you will have the chance to enter our prize draw to win a £100/$150 Amazon gift card.

You can fill in the survey here.

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Direct-to-consumer genetic test results in a clinical setting: a case report

02/09/2011
Categories: Guest Posts
Written by Daniel MacArthur and Guest Author

Dr Neeta Tailor is an anaesthetist working at the Royal Gwent Hospital in Wales. Dr Tailor recently treated a friend of Genomes Unzipped members (referred to here as Patient X) who required emergency surgery following some unusual and fairly horrible complications (believe me, I’ve seen the photos!) from wisdom tooth removal. The remarkable thing about this case: prior to surgery the patient volunteered information about her potential drug responses based on her 23andMe profile, including variation in one gene that could have had a profound effect on her response to a standard muscle relaxant. Dr Tailor kindly agreed to write up her experience in this guest post.

For those interested in the genetic details: Patient X’s 23andMe results suggest she is heterozygous for the rs1799807 SNP, which induces an aspartate to glycine change in the BCHE gene and is associated with a substantially prolonged apnea (loss of breathing) following administration of succinylcholine. This is one of three separate mutations in the BCHE gene tested by 23andMe. Although in this case the clinicians had already decided independently to avoid the use of succinylcholine, it’s intriguing to think about how rapidly this type of information could become useful to clinicians – and what steps will need to be taken to ensure DTC genetic testing results are trustworthy enough to justify their consideration in this kind of emergency setting. [DM]

Anaesthesia is classically described as the pharmacologically induced triad of amnesia (memory loss), analgesia (pain reduction) and the loss of muscle reflexes. Patients usually come across anaesthetists during their pre-operative anaesthetic assessment; we are the ones telling you that our job is to pop you off to sleep, although it is usually more complicated than that!

The patient described below works in the world of genetics and invited me to describe her case in order to illustrate how pharmacogenomics and person specific genetic characteristics may affect the choice of general anaesthesia.

A 37 year old woman (Patient X) was booked onto the emergency theatre list on a Sunday morning. The planned operation was incision and drainage of an infected haematoma in the cheek, an unusual complication which had developed quickly over 48 hours following the extraction of a wisdom tooth by her own dentist. By the time she was admitted to hospital, she had extensive facial swelling, not just of her gum, but also the whole of the left side of her face from her forehead to her neck. In addition, she had reduced jaw movement, as well as limited mouth opening of less than one finger breadth. She was also feeling quite unwell having vomited during the night and her blood tests showed raised markers of infection. She was in pain requiring several different types of analgesia.

This presentation in itself poses some difficulty. One of our jobs as anaesthetists involves administering drugs to cause unconsciousness which subsequently requires maintenance of a patent airway using either a mask, an airway device that sits above the vocal cords, or by a tube in the trachea. We usually then maintain unconsciousness using an inhaled volatile anaesthetic via the chosen device.

During this operation we knew we were going to need to share the airway with our maxillo-facial surgery colleagues performing the procedure. To ensure the optimal outcome for all (an anaesthetised patient for us and access to the mouth for the maxfax team), a tube in the trachea was the most ideal option. However, to get to the trachea, we have to get in the mouth and get a good view of the vocal cords and this is where the potential problem could arise.
Continue reading ‘Direct-to-consumer genetic test results in a clinical setting: a case report’

Tags: 23andme, clinical applications, guest post, neeta tailor, personal genomics.
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Heritability and twins, yet again

26/08/2011
Categories: Uncategorized
Written by Daniel MacArthur

Slate’s Brian Palmer has written an astonishingly ignorant critique of the use of twin studies to estimate the heritability of complex traits. Razib has a pithy response, in which he refers to the Slate piece as “a sloppy mishmash”: there’s just so much wrong with the piece (beginning with its first sentence: “One of the main messages of science over the last couple of decades is that genes are destiny”) that it’s hard to know where to start pulling it apart.

Fortunately there’s no need for a point-by-point response here: Luke wrote a lengthy response to another ignorant critique of twin studies late last year, and his cautious defense of the methodology is just as pertinent here. In addition, it’s been reassuring to see that the comments thread at Slate has been almost universally negative.

As Luke noted last year, there are some valid criticisms that can be pointed at twin studies, although none of these fundamentally undermine the value of these studies for understanding human genetics. It’s a shame that Palmer chose to ignore these substantive criticisms in favour of sweeping dismissals and eugenic slurs.

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Report on clinical genome sequencing

Debating the future of genome sequencing in medicine

Different perspectives

Revisiting RNA-DNA sequence differences

Results of Nature poll on personal genetic analysis by scientists

The week that I worried I had a rare genetic disease

Complete Genomics to sequence 1500 whole genomes for pre-term birth study

Nature poll for scientists on personal genomic analysis

Direct-to-consumer genetic test results in a clinical setting: a case report

Heritability and twins, yet again

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