This week’s new papers

Here’s what we told the world’s journalists last week. You can use Google News to see what they made of our briefing.

Please cite Nature Genetics as the source of the following items. If publishing online, please carry a hyperlink to https://www.nature.com/naturegenetics.

Genetic variant associated with triglyceride levels

DOI:10.1038/ng1984

Scientists have identified a rare genetic variant that is associated with lower levels of triglycerides, according to a study to be published online this week in Nature Genetics. Triglycerides are the stored form of fat, and elevated levels have been linked to risk of coronary artery disease.

The genetic contribution to common diseases takes the form of common variants – those found at frequencies greater than 5% – and rare variants. One strategy to identify rare variants is to resequence candidate genes in a number of individuals. Jonathan Cohen and colleagues report the first application of this strategy in a large population. The authors studied more than 3,500 individuals from the Dallas Heart Study, whose lipid and glucose metabolism has been characterized in detail. They sequenced the gene ANGPTL4, which encodes a hormone involved in lipid metabolism, in each of these individuals. They found that those individuals with the lowest levels of triglycerides had more variation in ANGPTL4, and one variant in particular was associated with a 27% reduction in triglyceride levels, compared with individuals who lack the variant.

This association was confirmed in two other large population-based studies. Overall, this study confirms the value of the resequencing approach in identifying genetic variants that influence disease-related traits.

Genetic variant associated with protection against infectious diseases

DOI:10.1038/ng1976

A genetic variant associated with protection against four different infectious diseases is described in an online study this week in Nature Genetics. The variant, which is significantly more likely to be found in individuals who remain disease-free, is estimated to reduce the risk of disease by approximately half.

Proteins called ‘toll-like receptors’ (TLRs) are involved in the immune response to a variety of pathogens. Adrian Hill and colleagues reasoned that variation in a protein called Mal, which is a critical mediator of signaling by TLRs, might make certain individuals more or less susceptible to infectious disease. The authors determined the frequency of 33 single-nucleotide variants in the gene encoding Mal in more than 6,000 individuals from Gambia, Kenya, the UK and Vietnam with or without pneumococcal disease, bacteremia, malaria and tuberculosis – diseases that account for more than 5 million deaths each year in the developing world.

In the interests of giving credit to the resources geneticists find most useful, here are the the numbers of papers citing the most frequently cited links in Nature Genetics papers published in 2006 (volume 38). 108 of 184 papers cited links, totalling 531, with a mean of 2.9 per paper. The paper with the largest number of links was Park with 28.

Databases

9 NCBI Genbank which also has 261 linked nucleotide accessions (no repeat citations yet)

7 GEO with 25 microarray experiments and 5 microarray methods

4 ArrayExpress with 9 microarray experiments (one cited twice)

8 HapMap in Wu Rajewsky Hirschhorn Chakravarti Witt Yoshiura Daly Altshuler

5 dbSNP in Hirschhorn Georges Yoshiura Attie Flint

5 SeattleSNPs in Bhangale Zhang Lee Allikmets Stephens

3 PDB with 3 protein accessions

2 NCBI Trace Archive in Bhangale Stephens

2 RZPD in Timmerman Zeviani

2 GDB in Timmerman Stratakis

2 Cardiogenomics in Disteche Lee

Software

16 UCSC in Frazer Altshuler Wu Hirschhorn Ober Ranum Clark Hildebrandt Attie Harvey Ranum Petit Jackson Crow Chakravarti Radvanyi

6 Ensembl in Timmerman Zeviani Bamshad Mootha Stratakis Petit

5 R in de Laat Radvanyi van Steensel Doebley Weigel

4 ClustalW in Ranum Zeviani Zhang Timmerman

4 Broad in Altshuler Daly Oliver Rosenblatt

4 Haploview in Alarcón-Riquelme Chakravarti Yoshiura Daly

4 BLAST in Johnson Park Fuchs Jackson

3 Stephens lab in Legius Zhang Allikmets

2 CBS DTU in Zeviani Johnson

2 PAUP in Weigel Zhang

2 Clayton lab in Zhang Allikmets

Corporations

5 Affymetrix (you have to double click to come back from this link)

2 Softgenetics

2 Sapio

In the examples above, the citing paper is linked by first listed corresponding author for convenience rather than in accordance with journal policy (which is to cite First Author et. al. or Corresponding Author and colleagues). By following the link, the full authorship can be seen. It is clear that accessions mandated by the journal predominate, but ideally, all publicly deposited resources should be fully cited by authors, and properly logged and counted by the journals.

Thanks to Irina Nudelman for help with analysis, any errors are my own fault – Myles Axton.

19/02/2007

Dear Editor

As an autistic person and active advocate of “neurodiversity” I am more than a little concerned with the spin being given in the press following the publication of the latest research into the genetics of autism.

From the scientific viewpoint I am aware that this is only one more in a recent string of possibles, and that research is nowhere near a positive genetic test.

From my viewpoint I am already feeling threatened, in the way that people with Down’s syndrome are already threatened.

There has been so much negative and simply inaccurate publicity about autism that it has been hyped into a modern scourge like heart disease or cancer.

The fact that I am writing to you, that I am a post graduate student study at a leading University, and active at the highest levels in the largest organisation for autistic people in the UK shows that it is no such a thing.

Science fiction as usual has got there first, from Daniel Keyes story “Flowers for Algernon” through to Andrew Niccols movie “Gattica” and Elizabeth Moon’s novel “Speed of Dark”, the moral issues have been explored. Those very issues which the genetic scientists remote from the day to day experience of autism forget when they make their pronouncements about genetic screening and tailored drug treatments. It would be like a drug to cure homosexuality or left handedness, societies imposition on people who are different.

What is often also not realised when people like myself are responding to issues like this is that many of us were in our childhood a lot more “severe” than we appear now so the argument that high functioning and low functioning should be considered differently does not count for much amongst us, we will not be separated from solidarity with our less intellectual compatriots.

It concerns me that when the press responds to research such has been published in this journal, that the reaction of those researchers who are inevitably contacted by the press excludes the dark side of this research.

Science owes a responsibility to its subjects as Morton Anne Gernsbacher has recently written on our behalf in the APS Observer February 2000 Vol 20 number 2 that when we are so often talked about by the scientific establishment in terms that describe us as less than human the scientists should be brought to account.

Larry Arnold

Larry(at)larry-arnold.com

Here’s what we told the world’s journalists last week. You can use Google News to see what they made of our briefing.

Please cite Nature Genetics as the source of the following item. If publishing online, please carry a hyperlink to https://www.nature.com/naturegenetics.

Consortium tackles the genetic basis of autism

DOI: 10.1038/ng1985

The genomes of the largest collection of families with multiple cases of autism ever assembled have been scanned in a new study. The results provide new insights into the genetic basis of autism, according to a report published online this week in Nature Genetics.

Autism spectrum disorders (ASD) influence social interaction and communication and affect 6 out of every 1,000 children. The Autism Genome Project Consortium — comprising 50 centers in North America and Europe — collected DNA samples from nearly 1,500 families, each of which has more than two members with ASD.

The team carried out a two-fold analysis. First they assessed the frequency of alterations in copy number of different segments of the genome, finding an unexpectedly high percentage of the families — 7 to 12%, depending on how the analysis was done — in which all affected individuals share possibly detrimental chromosomal abnormalities. Two female siblings had deletions of the gene encoding the protein neurexin 1, which interacts with neuroligins — a family of proteins that have been implicated in some cases of autism. Finally, the authors carried out a ‘linkage’ analysis of these families, searching for regions of the genome that might be shared by the individuals with ASD. One particular region on chromosome 11 was identified, which has not previously been reported to harbour genes that affect risk of developing autism.

Some reactions to their own press releases put out last week were tracked by

Nancy Mendoza, Press Officer at The Science Media Centre

Scientists React To Autism Paper As Published In Nature Genetics

Professor John Burn, Medical Director & Head of Institute, Institute of Human Genetics, University of Newcastle, said:

“This is fantastic news. We have been waiting for the log jam to break on this for several years. There will almost certainly be an interaction between several genes so this one discovery doesn’t provide a complete answer and may not lead straight to a genetic test but it could be a key step in development for effective treatments as it provides a target for drug development.”

Dr Fred Kavalier of the British Society for Human Genetics said:

“Autism and related disorders affect up to 1 in 100 British children. There is not one specific gene that causes autism, but there a large number of genes that contribute to it. This new research has identified new genes that make up part of the complicated autism jigsaw. Further research will be needed to understand these genes better, in the hope that they will be useful in designing new treatments in the future. A cure for autism is a long way off, but this is one small step in the right direction.”

The Independent

Gene may hold key to understanding autism

REUTERS

International study finds new autism genetic links

BBC Online

Autism gene breakthrough hailed

Guardian

Global study of 1,200 families links new genes to autism

The Times

Tiny anomalies keep autism in the family

Dutch scientist Ronald Plasterk has been appointed Minister of Education, Culture & Science in Prime Minister Jan Peter Balkendende’s cabinet. Plasterk has been in the political world for some time. He will replace Maria van der Hoeven, whose proposals on intelligent design may have made her less than well suited to the post (van der Hoeven will now be Minister of Economic Affairs). Plasterk’s most recent published work in NG, using massively parallel sequencing to identify microRNAs in human and chimpanzee brain, can be found here. One wonders if a ministerial job in the Dutch cabinet is only a part time position.

Just to note one interesting example from the Question of the Year so far, David Goldstein suggests that

Before long, a global wealthy elite will not only stump up the $1,000 dollars but will also hire ’sequence consultants’ to advise them about what their complete sequence means for their health…

We all know what a difficult funding environment young scientists face these days, and many will be on the lookout for ‘alternative’ careers. I think Dr. Goldstein has hit on one that has yet to be fully explored (patent attorney and journal editor being old news by now). How long before a small group of enterprising postdocs puts together a sequence consulting firm? What you tell your clients may not even matter.

This is not the only opportunity out there for young scientists whose eyes are wandering from the lab bench. A report in the NY Times last September noted the attractiveness of real estate assets in biomedical hubs, which can results in a high rate of return to investors. The article, by Alison Gregor, notes that

Still, life sciences real estate is not something investors should dive into without doing their research…They need to know the science.

She goes on to quote Bruce Beal, chief executive of Beal Companies, a Boston developer:

There’s obviously a high failure rate when a company is doing this kind of testing, especially an embryonic company. So you want to be able to analyze the science of tenants you’re taking into a complex to make sure you’re getting a company founded on good research.

Let’s see. Why not a one-stop shop for genetics and life science consulting? You can offer an analysis of commercial biotech startups along Route 128, and throw in a little personal sequence consulting on the side, combining two of the hottest things going in today’s market.

Venture capitalists can reach me care of this blog.

Almost 15 years ago—April, 1992—Nature Genetics was launched as the first of the Nature research journals. Last year we were discussing ideas for commemorating this anniversary, following up on the ‘retrospective’ supplement that we published to celebrate ten years of NG (by the way, see here for an amusing take on the whole issue of anniversary issues). We decided on a more forward-looking theme this time, and stimulated by the brilliant annual questions that edge.org asks of its contributors and friends, we decided to launch our own ‘Question of the Year’. But what to ask? In the end, we decided on the topic of sequencing, given how much attention has been paid in recent months to technologies that may bring down the cost of sequencing substantially. What would geneticists actually do with all of this sequencing power? We’re asking this question to a select group, and the first 20 responses have been posted. An additional 5-10 replies will be posted every month until October, and we hope everyone finds them to be as provocative as we do.

My apologies for the nonexistent blogging over the past few months, owing to a large number of very interesting manuscripts and other responsbilities to deal with. That said, I will be making a renewed effort to start posting again on a regular basis. Our ‘Sunday Papers’ feature will be replaced by a posting of the press releases that we provide to registered journalists in advance of publication, as we thought it might be interesting to make these more widely available. Stay tuned also for a series of posts on editorial policies and day-to-day procedures at the journal.

Here’s what we told the world’s journalists last week. You can use Google News to see what they made of our briefing.

Please cite Nature Genetics as the source of the following items. if publishing online, please carry a hyperlink to https://www.nature.com/naturegenetics.

Large-scale survey of mutations in cancer

One of the largest surveys of mutations in human cancers is reported online this week in Nature Genetics. The study provides a preview of results that may be generated by even larger projects such as The Cancer Genome Atlas, set to begin soon.

Previous attempts at cataloguing mutations in different types of cancer have relied on DNA sequencing, which can be too expensive when applied to a large number of tumors. Levi Garraway and colleagues applied a previously developed technique called mass spectrometric genotyping to identify the frequency and distribution of 238 known mutations in 17 oncogenes in 1,000 tumors. The genotyping approach is more sensitive than the sequencing approach, identifying more mutations, and simultaneously detects mutations in multiple oncogenes in a cost-effective manner.

The authors report that mutations in three of the oncogenes were not found in any of the tumors, while mutations in the other genes were observed in only 30% of the tumors, indicating that many cancer-causing events remain to be discovered. There were relatively few examples where a specific mutation was found more than once, suggesting that mutations occurring at high frequency will be uncommon.

Common genetic variant protects against breast cancer

Scientists have confirmed that a common genetic variant — CASP8 — offers modest protection against breast cancer, according to a study to be published online this week in Nature Genetics. The report provides some of the strongest evidence so far that common variants affect the risk of developing breast cancer, and the size of the collaboration sets an important precedent for future studies.

Rare mutations in the genes BRCA1 and BRCA2 significantly raise an individual’s risk of breast cancer, but account for only a fraction of the overall variation in genetic risk. More common variants that have a smaller effect on individual risk have been difficult to find, largely due to the size of the studies needed to identify variants of small effect in a convincing manner.

The Breast Cancer Association Consortium, which comprises more than 20 collaborating research groups, examined 9 previously reported breast cancer susceptibility variants in at least 10,000 affected women and 10,000 disease-free women in a study led by Angela Cox. For 8 of the 9 genes, the Consortium reported either no association with breast cancer risk, or marginal evidence for an association. For a variant in the gene CASP8, however, they found a significant association. The particular variant assessed in the study is found in approximately 13% of women of European descent, and is protective, lowering the risk of breast cancer by approximately 10%.