As advances in technology, namely the ease with which genes can now be sequenced, cast gene patents in an ever more anomalous light, Genome Biology and our sister journal Genome Medicine tackled the issue from a number of angles. You might even say that we brought a myriad of views to the debate…

Do-it-yourself

Back in 2010, regular Genome Biology contributor Steven Salzberg published a

Read more]]> Many years of legal argument culminated this week in a landmark ruling by the US Supreme Court. In Association for Molecular Pathology vs Myriad Genetics, the SCOTUS judges ruled – unanimously – that isolated human genes are a product of nature and, as such, are not eligible for patent protection.

As advances in technology, namely the ease with which genes can now be sequenced, cast gene patents in an ever more anomalous light, Genome Biology and our sister journal Genome Medicine tackled the issue from a number of angles. You might even say that we brought a myriad of views to the debate…

Salzberg

Do-it-yourself

Back in 2010, regular Genome Biology contributor Steven Salzberg published a Correspondence laying out a method for DIY genetic testing of Myriad's patented BRCA genes. In some eyes, Salzberg's proposal skirted close to the fringes of what might pique the interest of Myriad's lawyers, or at least would have done if carried out for profit.

Science vs law

The following year, we reported from the 12th International Congress of Human Genetics (or, more familiarly, ASHG), where a debate on gene patents formed a key part of the program at what is the world's premier human genetics conference. Panel member Judge Sweet, who had ruled on one of the Myriad case’s many iterations, made clear that asking lawyers not trained in the sciences to rule on complex patent arguments is a far from ideal process.

Judge Sweet

Indeed, as Salzberg points out on his Forbes blog, the SCOTUS ruling is riddled with basic biological inaccuracies. Moreover, many scientists will be puzzled by the distinction the lawyers-cum-judges of SCOTUS make between 'isolated DNA' and cDNA. A separate, but concurring, Opinion by Justice Scalia was not only honest enough to admit his ignorance of genetics and molecular biology but even declared an open hostility to the very science on which he was ruling: "I am unable to affirm those details on my own knowledge or even my own belief."

When a Court decides matters on which it is – by its own admission – ignorant, one has to wonder if a better solution might be for Congress to pick up the slack with legislation. As put by Allison Dobson and Jim Evans in a Genome Biology Opinion (which dissects the issues surrounding gene patents): "History is full of examples in which existing law could not keep up with what was happening on the ground."

Open questions: cDNA and gene fragments

As touched upon above, one unresolved area that future courts or legislatures might seek to address is the question of cDNA patent eligibility. SCOTUS ruled that cDNA should be considered as a natural product for the purposes of patent law, although care was taken to express no opinion on patent eligibility on other grounds. Therefore, although Myriad's key patents on isolated BRCA genes have been struck down, its patents on BRCA cDNA still stand.

One of the claims within Myriad's cDNA patents, as with its isolated DNA patents and the gene patents filed by many other biotech companies, is that the protection extends not just to the sequence as a whole, but also to short fragments of a gene. Put simply, the patents cover any 15 base-pair sequence found within the thousands of base pairs that make up BRCA cDNA.

Our Twitter chat preempts SCOTUS

Chris Mason and Jeffrey Rosenfeld showed in a Genome Medicine Correspondence article that the 15 base-pair clause lays claim to sequences in many hundreds of genes; in fact, a similar claim for one particular bovine gene covers 85% of genes in the human genome. The many questions raised by the startling figures in Mason and Rosenfeld's article were the subject of a Twitter chat, with participants including Mason himself and 23andme co-founder Linda Avey.

A new era

To many observers, including Evans, the SCOTUS ruling of 'no' to isolated DNA and 'yes' to cDNA was entirely unsurprising. Indeed, many expert observers had publicly expected this verdict based on the discourse of the SCOTUS hearing (although fewer had predicted the unanimity of the judges). So why is the judgment a big deal?

Well, change is already happening. What was for years hypothetical arguments about baseball bats is suddenly real world impact. Within hours of SCOTUS holding that "a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated", multiple competitors had announced cut-price genetic tests for BRCA genes.

We have transitioned to a new phase of personal genomics and moved on from lawyers entangling themselves with what might be construed as unhelpful, irrelevant and unsupported analogies about randomly selected inanimate objects.

In the words of Stanford Law Professor Hank Greely: "Price hemorrhaging begins!"

Human genomics is mostly correlative: a genetic variant is seen to be associated with a given phenotype. In some cases, the association might be strong enough to infer a cause, but as everyone knows, correlation is no proof of causation. Unfortunately, the sort of confirmatory functional work that might be possible in laboratory animals is usually frowned upon by pesky ethics committees if you propose ...

Read more]]> To mark the passing of the sun into Gemini, this month Genome Biology has published a special issue on twin studies. Not really: we just had a lot of twin studies and they all fortuitously ended up being published in May. But they’re good studies, so we thought it was worth highlighting them here.

Human genomics is mostly correlative: a genetic variant is seen to be associated with a given phenotype. In some cases, the association might be strong enough to infer a cause, but as everyone knows, correlation is no proof of causation. Unfortunately, the sort of confirmatory functional work that might be possible in laboratory animals is usually frowned upon by pesky ethics committees if you propose it in humans. Fortunately, monozygotic twins can be very useful from this point of view, as they are a sort of biological replicate for your experiment. They are particularly useful for epigenetic studies, because with essentially identical genomes, any differences in epigenetic factors must be environmentally determined (or stochastic variation).

This is perhaps best exemplified by the study by Jörn Walter and colleagues. These researchers took 17 pairs of adult identical twins in which the two twins in each pair had been born with different weights. Since the twins had identical genomes, the weight differences must be environmentally determined. Walter’s team wanted to know if this would have had any effect on DNA methylation in the twins. As it happens, it seems that it did not. The co-twins showed very similar genome-wide DNA methylation profiles, with most observed differences being attributed to the cellular composition of the samples profiled. This would seem to imply that the major component contributing to methylation is genetic, and at least in the case of discordant birth weights, environmental factors have little impact.

In contrast, Jeffrey Craig and colleagues found that there must be at least some non-genetic factor in DNA methylation. The focus of their study was how methylation changes over time. They took ten pairs of identical twins and five pairs of fraternal twins and measured DNA methylation status at birth and then 18 months later. They found that, in general, methylation increases over time. They also found that pairs of twins tended to show differing changes in methylation. Thus, changes in methylation over time must have a large environmental or stochastic component, rather than being genetically determined.

Vardhman Rakyan and colleagues also found loci with differing methylation status between co-twins in their study of 33 pairs of monozygotic twins. Interestingly, these differences were found to be stable over time, at least in the small subset of subjects where this was tested. The genes where these differences were found tended to be those with little or no expression in the cell types studied.

The somewhat contrasting findings of these three studies – that twins may or may not have similar methylation profiles, and that any differences may or may not be stable over time – could be explained by a number of factors. Perhaps the choice of cell type studied makes a difference, or maybe even the definitions of ‘similar’ or ‘different’. Also, when a field is in its infancy it is not uncommon for apparently conflicting studies to be published until the field settles down and the conflicts are resolved. Whatever the final answer turns out to be on whether methylation status is largely genetically or environmentally determined, it is clear that twin studies are going to have a large part to play in sorting out this exciting field.

In other words, DNA methylomics has become a convenient tool. Whenever some more or less inexplicable changes in the cell occur, you can say: look, DNA methylation is affected too! And it almost invariably will be. Which is why the rare studies demonstrating otherwise are so important: reminding us that in biology ...

Read more]]> That DNA methylation studies change the way we perceive genetic regulation should be clear to anyone who has read last year’s Genome Biology special issue on epigenomics (if you haven’t yet – you definitely should!). Changes in DNA methylation have been associated with cancer, neurodevelopmental diseases and all sorts of metabolic disorders. The role of DNA methylation in cell differentiation and reprogramming has also been previously described.

In other words, DNA methylomics has become a convenient tool. Whenever some more or less inexplicable changes in the cell occur, you can say: look, DNA methylation is affected too! And it almost invariably will be. Which is why the rare studies demonstrating otherwise are so important: reminding us that in biology nothing ever follows just one obvious path. In this month’s issue of Genome Biology, we publish two such studies.

In the first of them, Rene Ketting and colleagues look at DNA methylation changes during the differentiation of intestinal cells in mice. They study these changes genome-wide and with an impressive single-base resolution, which is still quite a rarity in methylome studies, and monitor them across the transition from embryonic stem cells to terminally differentiated villus cells. And they find that, quite surprisingly, differential methylation throughout this process is very limited. This study comes hot on the heels of similar work from Alex Meissner’s lab, and is one of the very first to report such an unusual methylation dynamics during stem cell differentiation.

Most famous American twins. /source: wiki (fair use)

In our epigenomics issue, Jordana Bell and Tim Spector discussed an experimental setup in which differential DNA methylation is studied in monozygotic twins. Disease-discordant twin studies have so far proven to be an incredibly popular approach to epigenome-wide association studies, with recent publications on twins discordant for obesity, autism, breast cancer, diabetes, psioraris, and so on. Many, if not most, of these studies show that some differential DNA methylation can usually be observed. Enter Joern Walter and colleagues – authors of another article published in the May issue.

Walter and colleagues looked at DNA methylation in monozygotic twins discordant for birth weight. Hard as they tried, however, they did not manage to find any differences in DNA methylation above what would be expected from technical noise. Of note is the method the authors use to correct for saliva sample heterogeneity; and there is a cautionary tale hidden here: although a number of studies have recently reported that saliva can be used as a surrogate for other tissue types, not many of them acknowledged the uneven cell type composition of this source.

As it happens, we also publish two more twin-based studies in this issue. The story behind all our twin articles (sprinkled with twin-Gemini references) is described in another Genome Biology blog.

Some of the proposed solutions, including CGAL, are based on assembly likelihoods. Others use modified N50 metrics. But they are all lacking in one respect: ease of use. And this should be a priority: with gargantuan genome sequencing projects, aiming to complete not just one genome but as many as thousands ...

Read more]]> In January we published CGAL  – a new metric for the evaluation of genome assembly quality. This article was a result of a fairly recent revelation in the field that the traditionally defined N50 metric is not sufficient enough and new approaches are needed. It shouldn’t come as a surprise then that the CGAL article was not the only one trying to address this issue in recent months.

Some of the proposed solutions, including CGAL, are based on assembly likelihoods. Others use modified N50 metrics. But they are all lacking in one respect: ease of use. And this should be a priority: with gargantuan genome sequencing projects, aiming to complete not just one genome but as many as thousands of them, proliferating like rabbits, the ability to just sit down and use a tool that is easy to apply and that gives useful output has never been more important.

wiki; public domain

And this is exactly what REAPR, a new software tool published this week in Genome Biology, is trying to achieve. The article’s Sanger Institute-based authors, Dr Otto and colleagues, provide us with a tool that can identify errors in genome assemblies without the need for a reference sequence.

Although primarily validated on bacterial, Plasmodium and C.elegans sequences, REAPR easily scales up all the way to mammalian, including human, genomes. The authors demonstrate how REAPR can also be used for progress-monitoring in ongoing sequencing projects. Combine all that with an implementation for Windows and Mac operating systems, as well as clear and thorough documentation, and you end up with a tool that simply cuts to the chase.

RNA binding proteins and their recognition elements within the transcriptome
The issue will focus on RNA binding proteins (RBPs), and the RNA molecules and motifs to which they bind: it is this RNA landscape, sculpted by RBPs, that we believe to be a particularly exciting and fast-moving area of research at the present time.

Read more]]> Genome Biology is very pleased to announce the Guest Editors of our special issue on the RBPome as John Rinn and Jernej Ule. The issue will be published in late 2013.

RNA binding proteins and their recognition elements within the transcriptome
The issue will focus on RNA binding proteins (RBPs), and the RNA molecules and motifs to which they bind: it is this RNA landscape, sculpted by RBPs, that we believe to be a particularly exciting and fast-moving area of research at the present time.

John Rinn

Jernej Ule

Now, recombination hotspots are a bit of an enigma themselves: for a long time no one could put their finger on how these hotspots are defined – or chosen. But, as it ...

Read more]]> Taking into account the importance of the role that genetic recombination plays in evolution, adaptation, survival, and – perhaps most importantly – sex, we know surprisingly little about the molecular foundations of this phenomenon. What we do know is that genetic recombination is not a completely random process; that it follows a pattern. Some chromosomal regions are more, and some less, likely to be affected by double-stranded breaks – and the recombination events that follow. Areas with a high frequency of recombination have been appropriately dubbed ‘recombination hotspots’.

Now, recombination hotspots are a bit of an enigma themselves: for a long time no one could put their finger on how these hotspots are defined – or chosen. But, as it happens, something else’s fingers are involved: those of the zinc finger protein PRDM9. The mystery slowly started to unveil in 2010 when three articles in Science identified PRDM9 as a key player in the process of recombination hotspot determination.

DNA being repaired after recombination

Thanks to those papers and subsequent work, we know that PRDM9 binds to specific DNA sequences, activating chromatin and guiding the generation of double-stranded breakpoints. But there is still some confusion regarding the make-up of these DNA sequences, and this is the problem that Petkov and colleagues address in an article published in Genome Biology last week.

In the article, Petkov and colleagues take two variants of mouse PRDM9, express them in E. coli and then assess which sequences in four known hotspots the protein binds to, and how. As it turns out, for the same variant of PRDM9 there is very little sequence similarity between the different binding sites, and the specificity of each of the protein’s dozen zinc fingers seems to be context-dependent. As part of this survey, the authors also identify the shortest DNA sequence required to bind PRDM9.

The data collected by Petkov and colleagues represents one of the most detailed and comprehensive PRDM9 DNA-binding maps described to date. Their work, however, raises more questions than it answers: instead of one consensus sequence, the article identifies a whole collection; instead of defining a set of rules for PRDM9 interactions with DNA, Petkov and colleagues suggest that its zinc fingers are quite fickle in this regard. And this is all already apparent in an in vitro study – PRDM9 behavior may be revealed as even more complex when we move to in vivo studies of this capricious protein, and to human-dedicated models.

Life's secret
For this reason, when I look at one of the beautiful X-ray diffraction photos taken by Rosalind Franklin and her PhD student Ray Gosling in the early 1950s, from painstaking work performed on calf thymus samples in gloomy ...

Read more]]> One of the most wonderful things about science, to my mind, is the way its fundamental principles are simultaneously both universal and personal. Quantum physics helps to explain the nature of grandiose concepts such as time and space, but it also applies to the insignificant particles that make up my own cells. Equally, within these very cells, at any moment, biological processes newly reported in the literature are taking place, as are those that have yet to be discovered.

Diamond in the rough: an early X-ray diffraction image of crystalline DNA

Life's secret
For this reason, when I look at one of the beautiful X-ray diffraction photos taken by Rosalind Franklin and her PhD student Ray Gosling in the early 1950s, from painstaking work performed on calf thymus samples in gloomy basements by the banks of the River Thames, I know that my own DNA could produce just such an image: the stark, spotty diamond patterns that told the secret of the double helix – and, with it, the secret of life itself.

Today is DNA60, the 60th anniversary of the three seminal Nature papers that first described DNA's double helical nature. Watson and Crick's paper – the best known of the three – presented the double helix model of DNA’s structure, astounding in its simplicity and elegance. Most of all, the paper was shocking because the structure itself revealed the mode of genetic replication, and in doing so proved beyond doubt that DNA was the stuff of genes, the chemical of genetic inheritance. Nature is rarely so kind in its revelations, and seldom so memorable.

Rosalind Franklin, Ray Gosling and the King's version of the double helix story
Also remarkable in Watson and Crick's paper was the total absence of experimental data; instead, they had used X-ray diffraction data generated by Franklin and Gosling as the basis for their model. These data were published in an accompanying paper, and so acquired parity of sorts in the literature, but Watson and Crick had very much won the race to the double helix.

It's often said that, well – to the victor the spoils! And so it was with DNA: Watson wrote a book that become the best known account of the double helix's discovery. Many years later, however, a different perspective, by Rosalind Franklin's biographer, attracted some attention and, as a result, more emphasis is now placed on the role of Franklin and her colleagues at King's College London.

Ray Gosling

On this, the 60th anniversary, Genome Biology publishes yet another account of the story, that of Ray Gosling, Franklin's PhD student. Gosling describes how he was the first person to crystallize DNA, before Franklin was even involved in the project. What had been fuzzy patterns were suddenly dazzling diamonds, and it's an image that leaves Gosling in awe to this day.

Over at Biome, you can listen to an audio excerpt of our interview with Gosling, in which he describes – with some amusement – a trip made by the King's DNA team to Cambridge, where they viewed Watson and Crick's lesser known first model. As Franklin was very quick to point out, this beginner's attempt contained a number of major errors.

DNA: past, present and future
As a further celebration of DNA60, we canvassed our Editorial Board members for their most memorable moments in the field of genome biology since the double helix. The clear emergence of introns as a favorite discovery will no doubt be pleasing to those nostalgic for the pre-omics days of classical biology, and you can read a free excerpt of this section of the article at Biome.

Outside of introns, selections included the human and mouse genome projects and sequencing technologies. Recent improvements in the sensitivity of the latter of these has of course brought about the era of the data deluge and a high demand for bioinformaticians. So how better to round off our honoring of DNA Day than with a 5-step DNA60IFX Bioinformatics Challenge?

Update: The winners of our DNA60IFX Bioinformatics Challenge were announced at 8 pm Eagle Time, DNA Day. Although the challenge has now concluded, we've left the puzzles open for anyone who would like to try them out for fun. For more info, please see the Challenge homepage.

See also: We reviewed the Wellcome Trust's special DNA60 conference, 'Genomic Disorders 2013: From 60 years of DNA to human genomes in the clinic', here.

Read more]]> This year's Abcam conference on 'non-coding RNAs, epigenetics and transgenerational inheritance' had a distinct Lamarckian flavor with conference Chair and 2013 Hooke medal recipient, Eric Miska, recommending Arthur Koestler's 'The case of the midwife toad' as extracurricular reading. In addition to his literary recommendations Miska discussed his recently published observations on the ability of piRNA phenotypes to be inherited through generations in C. elegans. The nematode and RNAi theme was continued in Scott Kennedy's talk, which focused on his recently published work on identifying genes required for RNAi inheritance in C. elegans. He identified such genes through screening for mutants defective in transmitting RNAi phenotypes to the next generation, but which are still able to perform RNAi themselves. This has led to the identification of the nuclear argonaute protein HRDE-1, which directs silencing in germlines. Interestingly, hdre-1 deficient worms exhibit mortal germlines, which through successive generations ultimately leads to sterility.

Peter Sarkies, a Post-doc in the Miska lab, shared his exciting work on understanding the function of the RNAi pathway in nematodes, which clearly hasn't arisen purely for the benefit of molecular biologists. Oded Rechavi continued this theme with a discussion on the function of trangenerational RNAi. His work, published in Cell 2011, has identified the trangenerational inheritance of virus-derived siRNAs, suggesting that this mechanism may be involved in providing protection to offspring. However, to date only one C. elegans-infecting virus has been identified.

Transgenerational epigenetic inheritance was examined not only in nematodes but also in mouse models, including a presentation of ongoing work by Erica Watson on the analysis of transgenerational epigenetic effects due to abnormal folate metabolism using a mouse model deficient in a key folate metabolism enzyme. Anne Ferguson-Smith discussed recent work that follows on from previous publications on a mouse model of intergenerational epigenetic inheritance. This model is concerned with the effects of severe maternal caloric restriction, which leads to low birth weight offspring – a characteristic that is known to be associated with increased risk of obesity, diabetes and cardiovascular disease later in adult life. This effect is transmitted over at least two generations and her talk focused on understanding the underlying epigenetic modifications responsible for this phenotype.

Investigation of transgenerational epigenetic inheritance in plants was also discussed, including a delightful presentation by Genome Biology Editorial Board Member David Baulcombe on generating transgenic plants. As previously shown by Baulcombe, sRNAs can move through the plant to distant locations, including across the grafted region of two plants. Baulcombe's recent work has shown that this phenomena can be exploited in order to generate (epi)genetically modified plants.

While transgenerational inheritance and small RNAs appeared to dominate the talks, long non-coding RNAs were not forgotten with a truly absorbing talk by Genome Biology Editorial Board Member John Rinn on his recent work into understanding the functional of individual lncRNAs.

This two-day conference highlighted some of the major areas of investigation in this relatively young field, in particular the observance that acquired traits, mediated through epigenetic effects, can be passed onto offspring in a rather Lamarckian fashion.

Recently, we excited informatics enthusiasts with the prospect of a special Genome Biology Bioinformatics Challenge in honor of DNA60, but we were lamentably low on the detail. Here, we are putting that right.

So what is this Challenge all about then?
DNA60 celebrates the sixtieth anniversary of the publication of Watson and Crick's Double Helix, and Genome Biology will be marking the occasion, April 25th, with some special content. But we also wanted to have some fun, and to give away some prizes, so we decided to ...

Read more]]> Stand by for an important update on Genome Biology's highly anticipated, ultra-tricky, ultra-cool, *supreme* DNA60 Bioinformatics Challenge with a truly amazing prize…

Recently, we excited informatics enthusiasts with the prospect of a special Genome Biology Bioinformatics Challenge in honor of DNA60, but we were lamentably low on the detail. Here, we are putting that right.

So what is this Challenge all about then?
DNA60 celebrates the sixtieth anniversary of the publication of Watson and Crick's Double Helix, and Genome Biology will be marking the occasion, April 25th, with some special content. But we also wanted to have some fun, and to give away some prizes, so we decided to augment our coverage in the journal with a special Bioinformatics Challenge (we usually run these at our Beyond The Genome conferences).

The challenge will comprise five steps, and will begin 7 am ET on Monday April 22nd. The final step will be on DNA Day itself, Thursday April 25th.

Mike Schatz (l); James Taylor (r)

The prizes
Winner – the first correct answer receives a brand new, shimmeringly shiny iPad

2x runners-up - your choice of either free registration to Beyond The Genome or one-year subscription to Genome Biology

The plan
Each step of the Challenge will require you to use all the bioinformatics wherewithal that you can muster in order to identify a hidden sequence within a dataset.

Keep an eye on this blog and Twitter (@GenomeBiology and #DNA60IFX) for a link to the Challenge start-page. For subsequent steps, your previous answer will be the key to the URL with the instructions for the next step.

Questions and queries
If you have found this blog post to be irritating and/or confusing, then you can get in touch with the questions you want answered in the comments below, or through Twitter (@GenomeBiology or #DNA60IFX)

Update: The Challenge is now live. The homepage has full details, including a schedule of the steps. Good luck!

So it was not entirely out of keeping with expectations when philosopher (and former candidate for Slovene of the year) Renata Salecl stepped onto the podium and asked:

'Should I kill myself, or have ...

Read more]]> It is not unusual per se for Nobel laureates to be quoted at genomics conferences, but it is perhaps a little out of the ordinary when the Nobel Prize in question is for Literature. But, then again, the Wellcome Trust's 'Genomic Disorders 2013: From 60 years of DNA to human genomes in the clinic' was not your run-of-the-mill conference; instead, a mesh of current research and historical (and futuristic) perspective paid tribute to the 60th anniversary of Watson and Crick's discovery of the double helix.

So it was not entirely out of keeping with expectations when philosopher (and former candidate for Slovene of the year) Renata Salecl stepped onto the podium and asked:

'Should I kill myself, or have a cup of coffee?'

For those unfamiliar with mid-20th Century Absurdist literature, these are the (translated) words of French-Algerian faux existentialist Albert Camus, taken from the pages of his 1942 novel L'Étranger. Salecl chose the quote as an illustration of the anxiety surrounding ambiguous data generated by modern genetic techniques. Camus' protagonist, Meursault, bumbled through life making choices where the options were clear-cut: with genetic data, we are faced with unknowns, risk factors and grey areas.

Absurd genomics
Meursault ultimately ended up on death row after committing murder, so maybe we should not let him inform the debate too strongly. Salecl reminded us, however, that a real problem of unwarranted certainty exists when handling forensic genetic data in legal cases. And such miscalculations may also result in death row, but for innocent victims of judicial inadequacies.

Salecl offered examples of incompetence and compromised integrity on the part of forensic scientists, and even suggested that a malevolent individual, in the mold of Harold Shipman, might deliberately falsify forensic reports as a form of sadistic power trip. Suffice it to say that the prospect of incompetence is worrisome enough, especially when one considers the number of forensic scientists who put their name to a recently published paper purporting to report the 'Bigfoot' genome sequence.

Genomes2people – but which bits and which people?
A more practical assessment of genetic uncertainty was put forward by Robert Green, of Genomes2People. Together with colleagues, Green has developed a set of recommendations for the reporting of incidental findings in genomic data, one of the main headaches of the personal genomes era that is opening up before us. He discussed studies into how people respond to such findings, and the general trend is an encouraging one: more exercise, more insurance take-up, and so on. Of concern, however, was the large number of people who are unable to accurately describe the risk factor reported to them, even when they can remember the details of what was said.

When experts were canvassed as to which type of incidental finding should be reported, taking into account disease type and the known risk of the variant, very little by way of consensus emerged. Perhaps there really is no right or wrong answer, but this is not an issue with room for neutrality – each finding is either reported or it isn't, and either way you are taking a point of view. Green and his colleagues have at least managed to arrive at a minimal list – encompassing 57 genes in 24 conditions – of risk variants that they recommend should be reported as incidental findings. But they also suggest each clinician should apply personal judgement to individual cases.

Variant-based therapeutics
Green made the point that incidental findings in genetics data seem to be held to a different standard to those derived from imaging data or physical examinations. Perhaps this is because many genetic findings are today not actionable. By conventional approaches (find a druggable target, and then a safe and specific drug for the target), patients have little hope of a successful remedy in the near future.

But Tamar Grossman, of ISIS pharmaceuticals, explained how therapeutic antisense oligos (ASOs) offer a whole new paradigm for rational drug design. One of the exciting features of ASOs is that they not only avoid the need to discover a druggable site (and then a small molecule of high affinity and specificity), but can also target the large number of genes for which no readily druggable site is discoverable.

ASOs can operate by a number of mechanisms, one of which is masking aberrant splice sites, as shown by Jennifer Lentz (Louisiana State University). In a recently published study, Lentz applied ASOs to a mouse model of Acadian-type Usher syndrome, which involves a specific mutation that promotes an inappropriate splicing event.

Lentz is able to prevent onset of the deafness and vestibular symptoms of Usher syndrome mice, although has not yet established whether this is also true of the blindness phenotype. Interestingly, Usher syndrome patients have expressed interest in translating these ASOs to the clinic, but only if it means prevention of blindness. Deafness, on the other hand, is viewed as natural variation – not a 'condition' that clinicians should seek to correct in utero.

DNA60
Rounding off the meeting with ASOs was fitting, given that they function through complementary base-pairing – the heart of Watson and Crick's double helix discovery, sixty years earlier, in the very same Cambridge streets now playing host to the conference in its honor. The progress made in genetics during these sixty years is really something to behold, and was fully on show at the meeting.

On the anniversary itself, 25th April, Genome Biology will publish some special content celebrating sixty years of the double helix, so please do look out for that. We are also hosting a special commemorative bioinformatics challenge, beginning a few days earlier and culminating on DNA day, of which you can read more here.