With at least the provisional success of genome-wide association studies to identify common disease-related variants now apparent, and highly significant P values floating up out of figures looking like nothing so much as a series of champagne flutes full to the brim, it’s interesting to take a look back at a paper that arguably provided the key impetus for the field. In their 1996 Science paper “The Future of Genetic Studies of Complex Human Diseases” (cited 2,231 times as of this writing), Neil Risch and Kathleen Merikangas asked:

“Has the genetic study of complex disorders reached its limits?”

Remarkably, this was the key question only 11 years ago. Of course, Risch & Merikangas were referring to the specific question of whether linkage studies would be adequate to detect variants of modest effect in the realm of complex disease. In his address upon receiving the Curt Stern award at the 2004 meeting of the American Society of Human Genetics, Risch described how the article came about:

“One colleague I worked with extensively, both in teaching and research, was Kathleen Merikangas, a psychiatric epidemiologist with interests in genetics. We spoke frequently about the state of the field of genetic epidemiology and where it was and should be going. We continued these discussions even after my move to Stanford in 1995. We began to develop an awareness that the linkage approach, although having some modest success in complex diseases, was unlikely to identify the large majority of genes. We were influenced by a news item that appeared in Science on July 14, 1995, entitled “Epidemiology Faces Its Limits”….Although the article did not discuss human genetics or genetic epidemiology, we realized that many of the comments could apply to the developing situation in human genetics as well”.

Interestingly, the author of that Science news article, Gary Taubes, is back in The New York Times magazine, with another piece pouring cold water on the field of epidemiology.

In any case, after penning a draft entitled “Human Genetics Facing Its Limits”, they realized that a more optimistic slant would be required, preferably one that offered an alternative approach. Again, from the Stern address:

“If we could have any tool to use for mapping disease genes, we wondered what would it be? Again, on the basis of my experience with HLA-associated diseases and my knowledge about disease associations with other blood-group systems, I knew that many of these associations, although highly significant statistically, would not produce substantial or robust linkage signals. Therefore, why not reverse the process of positional cloning? Instead of searching randomly through the genome by location, why not start with genetic variants and test them directly as candidates? The problem with candidate-gene association studies had been the limited number of candidates and, therefore, the low prior probability of a ‘hit’. But what if we could compile a list of all polymorphisms in the human genome?”

You know the rest. What’s remarkable about the Risch & Merikangas paper, beyond the power calculations showing that the relative gain in power for association studies as opposed to linkage, was the authors’ prescience in outlining the key issues. They noted the stringent genome-wide significance level that would be required for testing on the order of 1 million variants, while also pointing out the likelihood that linkage disequilibrium would allow this number to be reduced substantially. They also implored investigators to preserve all of their samples for future large-scale testing, and it could be argued that the collection of samples is now the rate-limiting step in association studies. Concluding, they wrote:

“Thus, the primary limitation of genome-wide association tests is not a statistical one but a technological one. A large number of genes (up to 100,000) and polymorphisms…must first be identified, and an extremely large number of polymorphisms will need to be tested”.

And finally:

“The human genome project can have more than one reward. In addition to sequencing the entire human genome, it can lead to identification of polymorphisms for all the genes in the human genome and the diseases to which they contribute”.

This is a reminder to those of us who, in the wake of so many robust associations, thought this was considered to be the reward from the very beginning. It wasn’t always obvious, it seems.

This week’s new papers

Here’s what we told the world’s journalists last week. Please cite Nature Genetics as the source of the following items. If publishing online, please carry a hyperlink to https://www.nature.com/naturegenetics.

Mitochondrial point mutations do not limit lifespan

DOI: 10.1038/ng1988

A large number of point mutations in mitochondria — the energy-producing units of the cell — do not have a direct link to the ageing process in mice, according to a study to be published online this week in Nature Genetics. While such mutations have been shown to accumulate during ageing in mice and humans, this result contradicts the notion that such mutations are causal factors in the aging process.

The widely debated mitochondrial theory of ageing postulates that the lifelong accumulation of mitochondrial DNA mutations contributes to the decline of tissue function observed in ageing. Lawrence Loeb and colleagues used a new, highly sensitive approach to determine the rate of single base-pair mutations in mitochondrial DNA in normal ageing mice, and in so-called ‘mitochondrial mutator mice’, which have a 500-fold greater mutation burden than normal mice. While the authors found that normal mice have an 11-fold increase in mitochondrial point mutations with age, the mutator mice did not have any obvious features of accelerated ageing, suggesting that the more modest mutation burden in normal mice is not likely to be contributing to the ageing process. It is important to note that this study does not exclude the possibility that large deletions of mitochondrial DNA contribute to ageing. For example, large deletions in mitochondrial DNA have been correlated with the impairment of certain neurons in aged individuals and in individuals with Parkinson disease.

A follow-up story in The Scientist can be found here.

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.

Bergamaschi et al.

iASPP preferentially binds p53 proline-rich region and modulates apoptotic function of codon 72–polymorphic p53

Lalioti et al.

Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule

Ioshikhes et al.

Nucleosome positions predicted through comparative genomics

Ramirez et al.

Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase

Comments welcome.

Padiath et al.

Lamin B1 duplications cause autosomal dominant leukodystrophy

Zara et al.

Deficiency of hyccin, a newly identified membrane protein, causes hypomyelination and congenital cataract

Manak et al.

Biological function of unannotated transcription during the early development of Drosophila melanogaster

Lee et al.

Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus

Chan et al.

Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer

Comments welcome.

Maller et al.

Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration

Li et al.

CFH haplotypes without the Y402H coding variant show strong association with susceptibility to age-related macular degeneration

Ramsey et al.

Dual feedback loops in the GAL regulon suppress cellular heterogeneity in yeast

Comments welcome.

Knight et al.

Unraveling adaptive evolution: how a single point mutation affects the protein coregulation network

Carter et al.

A signature of chromosomal instability inferred from gene expression profiles predicts clinical outcome in multiple human cancers

Burdick et al.

In silico method for determining genotypes in pedigrees

Comments welcome.