If you ask me, or any of my editorial colleagues, what attracted us to this sort of work, one common answer you’d hear is that it exposes one to a very broad range of scientific activity. For at least some of us, this comes as a relief from the narrow view of the scientific enterprise that accompanies graduate and postdoctoral fellowships. On the other hand, sometimes you have to be careful what you wish for. You nurse a batch of papers on a host of different topics through the peer review process, some of them are published, and then the next batch comes along. This is never dull, but it does make it a challenge to have at your fingertips the kind of depth of knowledge in any given area that would be desirable. I often find myself wondering what the latest is in a given line of work that was published in the journal several months or years ago.

Occasionally, then, I’d like to highlight a new paper that amplifies and puts in a new light a previous publication in Nature Genetics. The paper by Anatoly Urisman and colleagues, just published in PLoS Pathogens, describes data that was presented at the February meeting of the American Society of Clinical Oncology, and covered in the press at that time. Urisman et al. report a novel gammaretrovirus in 8 out of 20 prostate cancers from individuals homozygous (QQ) for a common R462Q variant in RNase L, an enzyme that degrades viral and cellular single-stranded RNAs. Only one tumor out of 66 from individuals who did not have the QQ genotype harbored such a virus. Carl Zimmer has more on this paper here.

In 2002, Carpten et al. reported in Nature Genetics that the relevant variant underlying the familial prostate cancer susceptibility locus, HPC1, was the R462Q variant of RNASEL. Microdissected tumors with a germline mutation in RNASEL showed loss of heterozygosity, and had no detectable RNase L protein. Heterozygotes had lower RNase L activity than individuals with two copies of the wild-type allele. A subsequent study published in the journal by Casey et al. found at least one copy of the R462Q variant in 59% of the men studied, and implicated RNASEL in up to 13% of all prostate cancers. While this association has received some support, inevitably there have been failures to replicate the result.

Adding to concerns over RNASEL as a prostate cancer susceptibility gene was the nature of its function. If it has antiviral activity, then where was the relevant virus? Urisman et al. used the so-called ‘Virochip’, which is an array bearing the most conserved sequences of approximately 950 fully sequenced viral genomes, to search for viral sequences in prostate tumors. The virus they identified and fully sequenced, XMRV, probably provides the first documented case of human infection with a xenotropic retrovirus.

Urisman et al. raise a number of key issues in their paper. First, and most important, they emphasize that XMRV may in fact have no role in the etiology of prostate cancer. Second, if it does turn out to be important, it will be of great interest to determine if the R462Q variant affects acquisition of infection, or subsequent clearance. Third, XMRV infection seems to be targeted to stromal cells, implying an indirect (paracrine) effect (if any) on tumor growth. Finally, if XMRV is causally associated with prostate cancer, then a non-uniform prevalence of infection in different populations could explain the variability in the RNASEL genetic association studies. Regardless, the identification of XMRV is an exciting discovery, and should refocus efforts to show conclusively that the RNASEL R462Q variant is a risk factor for prostate cancer.

A bit belatedly, I’d like to point out that the winter issue of The Kenyon Review has a special section on ‘Literature and the Genome’. My colleague Myles Axton has an invited piece in the issue (“Midwife to the Wiring Diagram”), in which he describes his journey from Oxford to Nature Genetics, as well as some of his typically provocative views on the roles of editors and the state of the field.

The rest of the pieces in the issue are a mixed bag, but there is one that stands out as required reading. Clare Dunsford, Associate Dean at Boston College, has written a piece entitled “Base Pairs,” which chronicles the diagnosis of her son J.P. with fragile X syndrome, and the effect it has had on her and her family. Her essay movingly outlines her son’s health history, the devastating news that several of her nieces and nephews were also affected, as well as her own complex reaction to the news that her carrier status might—just might—explain certain aspects of her own behavior and personality (there is at least some published evidence that pre-mutation carriers have a higher frequency of depressive and anxiety disorders). She explains:

No sooner was the DNA test for Fragile X carriers discovered in 1991 than scientists were off and running to investigate whether these carriers showed differences from their “normal” peers, whether they were “affected,” a word I can never look at in the same way again after our diagnosis. And it was “our” diagnosis, not just J.P.’s, but his three cousins’—and yes, mine and my three sister’s and one of our parents’. That’s the peculiar heartbreak of the Fragile X diagnosis; it is not unique to the “proband,” as they call the first person to be investigated in the genetic study of a family. It’s contagious.

And later:

Do you know what it feels like to go all your life seeing yourself as a top student, the life of a party, the subject who views the world on the terms she sets, only to wake up one day to find yourself the object of a scientific gaze? This is different from being a patient, examined physically for an emergent medical problem. It is to rewrite your past and to cast a shadow over your present—to have your every behavior, your every mental process, scrutinized for pathology.

I can’t do justice to Dunsford’s eloquence and grim humor here, which are infused with a love of the poetry of Gerard Manley Hopkins and William Wordsworth. Fortunately, the full essay can be read here, free of charge. And there is news of a full-length book in progress, to be called Spelling Love with an X: A Mother, a Son, and the Gene that Binds Them.

The NHGRI has spent quite a lot of money in its ELSI program, collecting hard data on the potential impact of genetic diagnoses. All of it will no doubt be informative. But clearly there is a place for narratives like Dunsford’s. Better than any survey can, it tells of the complex reverberations of genetic illnesses in the lives of actual people, of the difficulty in telling ‘normal’ from not, and of a mother’s love.

Maley et al.

Genetic clonal diversity predicts progression to esophageal adenocarcinoma

Comments welcome.

Each week, the Nature Publishing Group puts out a press release announcing those papers that will be published the following week by Nature and the monthly Nature research journals. For most papers, this will simply be a title and a PDF—enough to allow an interested journalist to write something about the paper if he or she is inclined. For a few that are likely to be of particular interest to the general public, a summary of 200 words or so is included to highlight the work. We are not alone, of course. Universities and institutes have their own highly effective communications offices, which generate publicity for their scientists. By and large, this system works reasonably well to improve the quality of the stories that are written in the mainstream media.

But not always. Based on scans of recent stories relating to papers in NG, we have to give a thumbs-down to United Press International (UPI) for two cringe-worthy wire stories.

The first covers this week’s paper by Irwin McLean and colleagues reporting an association between a variant in the gene filaggrin and atopic dermatitis. It opens reasonably enough: “Scientists at Scotland’s University of Dundee have discovered a gene that may lead to finding a treatment for dry skin problems like eczema.” And it closes with a good quote from McLean: “We see this as a dawn of a new era in the understanding and treatment of eczema and the type of asthma that goes with eczema as well.” The headline?

New eczema treatment likely soon.

Ouch. This is the sort of claim that you’d think a wire service would ban as a matter of course, unless their definition of ‘soon’ is different from the one in my dictionary.

Going back a few weeks, NG published a paper from Michael Waters and colleagues at Cedars-Sinai Medical Center in Los Angeles, showing that mutations in the potassium channel KCNC3 underlie degenerative cell death in two families with ataxia. This result is particularly noteworthy because it provides the first evidence implicating defective potassium channels in neurodegeneration. The UPI story starts off inauspiciously, with the vague headline “Cell death tied to certain brain disorders”. The first sentence, however, is truly eye-catching:

An international research team has reportedly provided the first conclusive evidence that some disorders can be caused, at least in part, by gene defects.

Pauling and Ingram probably thought they covered this ground already.

The explanation for this oddity is revealed when you look at the Cedars-Sinai release, which was presumably the source for the UPI story. It uses the same wording, but rather than end with “gene defects” it tacks on the phrase “that interfere with the electrical impulses of rapid-firing brain nerve cells called bursting neurons”.

Should we care about errors like this? Well, we all make mistakes; it’s true. At the very least, however, the first example serves as a reminder to authors, editors and publicists to be careful in the language that is used to describe a breakthrough in basic science. Even if we are careful, as we were in this case, unwelcome hype is always a possibility. The second example shows that, in the absence of journalists with some relevant background in the subject, science news may be particularly vulnerable to error. One wonders if a similarly nonsensical truncation of the lead sentence in a political story would have seen the light of day, or remain uncorrected for three weeks (and counting)?

Nature Genetics was launched in 1992, just as the era of positional cloning was getting underway, and a large number of genes underlying single-gene human disorders were soon identified. Such a disease-gene identification is gratifying in and of itself, as it may lead to immediate help for those affected, and certainly tells us something new about the genetics of the human organism in general. The additional hope is that it will tell us something about more common (and complex) diseases that are related. This final hope has not often been borne out, which is why the example of filaggrin, and its role in atopic disease is worth celebrating. In the space of two months, Irwin McLean and his international team of collaborators have shown that mutations in the gene underlie ichthyosis vulgaris (itself a fairly common mendelian disorder of scaly skin), and now atopic dermatitis and associated asthma. Atopic disease affects about 20% of the population in the developed world.

Although filaggrin was a good candidate, and the mutant allele is quite common, this result was a long time coming. Irwin McLean explains why.

Irwin McLean writes:

In the outermost cells of the epidermis, a huge number of structural molecules are expressed which form a barrier largely impervious to external attack from pathogens, chemicals and allergens. This barrier also prevents water loss through the skin. Many genes encoding these late-differentiation proteins are located in a dense cluster on 1q21 known as the epidermal differentiation complex (EDC). Despite the high density of candidates on 1q21, surprisingly few genes for keratinizing disorders have emerged from the EDC. One exception is filaggrin, which has long been suspected of having a role in the most common keratinizing disorder, ichthyosis vulgaris, or common dry, scaly skin.

Upon terminal differentiation of epidermal keratinocytes, the 400 kDa profilaggrin is cleaved into 10-12 identical filaggrin peptides which aggregate and condense the keratin cytoskeleton. This protein-lipid matrix is then enzymatically cross-linked to form the skin barrier. From the late 1980s onwards, a number of biochemical, immunohistochemical and genetic linkage studies pointed to a possible filaggrin defect not only in IV, but also in an IV-like mouse mutant (flaky tail), and importantly, atopic dermatitis (“eczema”). However, filaggrin mutations have not been forthcoming.

The delay lies in the unusual structure of the FLG gene which consists of two small exons followed by a huge final exon encoding 10 or more tandemly repeated copies of the ~1 kb filaggrin sequence. Exon 3 varies also in size from 12-14 kb in the population and the repeats within it are incredibly similar in sequence at the DNA level, making it very difficult to amplify by PCR and even more difficult to sequence. For added fun, the very few specific bases that one finds within each filaggrin repeat often turn out to be polymorphic.

The problems of analyzing this type of exon were first encountered by Frances Smith and myself about 10 years ago when we undertook sequencing of the plectin gene (Smith FJD et al., Nat. Genet. 13, 450-457, 1996). Plectin’s final exon is about 7 kb in size and like filaggrin, consists of ~1 kb repeats. Part of the problem with this type of gene is knowing which repeat you have sequenced. It’s very easy to be fooled into thinking you have sequenced it all when in fact you’ve just sequenced one part of it multiple times. Basically our approach consisted of long-range PCR using various polymerase mixes and buffers, a great deal of staring at lengthy sequence alignments, and then making and testing a fairly frightening number of primers.

After plectin, we said “never again”, but following a conversation we had with our dermatology collaborator in Seattle, Phil Fleckman, whilst on a bus in Utah several months ago, Frances decided to take a shot at filaggrin. We were suspicious when realized the first IV samples we got had previously been in a number of different labs in the USA and Europe who had given up on filaggrin. Undeterred, Frances applied her strategy and after considerable effort, found the R501X mutation. By analyzing a number of key families identified by Alan Irvine in Dublin, the semi-dominant inheritance in IV became apparent. Finding a second loss-of-function mutation explained most of our IV families.

We were excited to find the cause of a really common monogenic defect carried by 9-10% of European people but filaggrin had a further reward in store for our efforts (and primer bills). From a published genome scan for atopic dermatitis (AD) susceptibility genes, the EDC locus had shown linkage. Many IV patients also have AD and in our IV families, the filaggrin variants gave a significant lod score as a second trait. To investigate further, we teamed up with Somnath Mukhopadhyay and Colin Palmer in Dundee, Hans Bisgaard in Copenhagen, and Alan Irvine to analyze a number of patient cohorts. Quickly screening thousands of people for the filaggrin variants was no picnic and involved most of the lab in an incredibly intense team effort but in every case, we found an extremely significant association of these mutations both with AD, and to a lesser extent, with the form of asthma that occurs with AD.

We hypothesize that the key early event in AD is an impairment of skin barrier function, as suggested previously by Bill Cookson and others. This leads to increased epidermal water loss, leading to the dry skin seen in IV and AD. Importantly, the defective barrier may well allow continual presentation of antigens and allergens to the immune system via the skin. This leads to AD and in some cases, AD with asthma. Further work with animal models should shed further light on these pathomechanisms and provide the means to test new therapies or preventative measures.

So, have we had enough of big repetitive genes? “Never again” is what we swore, the time before.

Palmer et al.

Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis

Coucke et al.

Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome

Kassen & Bataillon

Distribution of fitness effects among beneficial mutations before selection in experimental populations of bacteria

Kissler et al.

In vivo RNA interference demonstrates a role for Nramp1 in modifying susceptibility to type 1 diabetes

Yeh et al.

Functional classification of drugs by properties of their pairwise interactions

Comments welcome.

Richard Dawkins’ The Selfish Gene is 30 years old this year. It remains a seminal argument for the gene as the fundamental unit of selection, and the evolutionary implications that follow from this. But it also seems to have gained a reputation as the book to turn to if you want to disabuse yourself of the notion that life is worth living. The Sunday Times has published an edited extract of the foreword that Dawkins has written for the 30th-anniversary edition, in which he writes about the anniversary and the reaction to the book. Here’s an example of one reader’s despair:

On one level, I can share in the sense of wonder Dawkins so evidently sees in the workings-out of such complex processes…But at the same time, I largely blame The Selfish Gene for a series of bouts of depression I suffered from for more than a decade…Never sure of my spiritual outlook on life, but trying to find something deeper—trying to believe, but not quite being able to—I found that this book just about blew away any vague ideas I had along these lines, and prevented them from coalescing any further. This created quite a strong personal crisis for me some years ago.

Now there’s a book with impact.

Dawkins responds:

Presumably there is indeed no purpose in the ultimate fate of the cosmos, but do any of us really tie our life’s hopes to the ultimate fate of the cosmos anyway? Of course we don’t; not if we are sane. Our lives are ruled by all sorts of closer, warmer, human ambitions and perceptions. To accuse science of robbing life of the warmth that makes it worth living is so preposterously mistaken, so diametrically opposed to my own feelings and those of most working scientists, I am almost driven to the despair of which I am wrongly suspected.

The Onion rings the alarm.

Carlborg et al.

Epistasis and the release of genetic variation during long-term selection

Jiang et al.

Calcium oxalate urolithiasis in mice lacking anion transporter Slc26a6

Comments welcome.

Just to follow up on this morning’s post about the HPV vaccine, the bloggers at the American Journal of Bioethics point out that there is a relevant new blog started by the Ethics of Vaccines Project at the University of Pennsylvania Center for Bioethics. Today’s post has more information about the HPV controversy, and links to this article published last year in Fortune that fills in more of the details.