For our final post of 2005, I’d like to highlight an important anniversary that seems to have been overlooked. Twenty-five years ago (on October 30, 1980, to be exact), Nature published a report by Christiane Nusslein-Volhard and Eric Weischaus, entitled “Mutations Affecting Segment Number and Polarity in Drosophila. The abstract:

In systematic searches for embryonic lethal mutants of Drosophila melanogaster we have identified 15 loci which when mutated alter the segmental pattern of the larva. These loci probably represent the majority of such genes in Drosophila. The phenotypes of the mutant embryos indicate that the process of segmentation involves at least three levels of spatial organization: the entire egg as developmental unit, a repeat unit with the length of two segments, and the individual segment.

Thus was a revolution in developmental genetics born.

And what a moment it must have been—if it was a single moment—when this massive and risky screen started to yield mutant phenotypes that, remarkably, could be neatly placed into only three categories.

The loci identified were cubitus interruptus, wingless, gooseberry, hedgehog, fused, patch, paired, even-skipped, odd-skipped, barrel, runt, engrailed, Kruppel, knirps, and hunchback. Think of the avalanche of work that was set off by the identification of every one of these genes, in fields such as developmental biology, molecular biology, cell biology, cancer, and others.

Perhaps the more interesting thing to think about, however, is the philosophical shift in science, and why it is that such a seminal experiment wasn’t done until the late 1970s, when the technical advances made by Nusslein-Volhard and Weischaus were really rather modest. Some of this is discussed in various sources, including a reprint of the paper published in the July 1994 issue of the Journal of NIH Research, accompanied by revealing interviews of both authors and Matthew Scott (I’m looking at a print copy ripped from the original journal, but the online version of this journal—now defunct—is sadly nowhere to be found on the web). Perhaps the best discussion of this work is an overview written by David States and Fotis Kafatos, and posted on the EMBL website (EMBL being justifiably proud of having provided the setting for the work, and thoughtfully providing a view of the ‘Bierhelderhoff’ restaurant—shown below—which, in this story, is apparently Heidelberg’s version of ‘The Eagle,’ Watson and Crick’s Cambridge haunt).

States and Kafatos insightfully outline the state of the field in the mid-1970s, Nusslein-Volhard and Wieschaus’s meeting in the Basel laboratory of Walter Gehring, their shared lab at EMBL-Heidelberg, the concept of the saturation screen for zygotically active mutants in Drosophila, the essential new method to make the embryos transparent, the equally essentially dual microscope, and the ultimate realization in the mid-1980s that these segmentation genes are conserved across 600 million years of evolution. The Nobel lectures of each author (Nusslein-Volhard and Wieschaus) also reward reading.

The concept of the genetic screen that their work exemplifies is an interesting subject in its own right. A few years ago, our colleagues at Nature Reviews Genetics had the clever idea to commission a series of reviews under the heading, “The Art and Design of Genetic Screens”. Links to these reviews can be found for each of the major model organisms, including D. melanogaster, C. elegans, A. thaliana, mammalian cells, filamentous fungi, E. coli, mouse, D. rerio, and yeast.

To close in the present day, Peter Robin Hiesinger and Bassem Hassan recently wrote the following in Cell:

It seems that, by mistaking the “omics” wave for the systems approach itself, we are forgetting some of the most influential systems approaches of the past: when Christiane Nusslein-Volhard and Eric Wieschaus targeted the whole Drosophila genome using random mutagenesis to unravel the riddle of embryonic pattern formation, they were doing systems biology.

And so they were.

I’m often asked if I miss benchwork. On balance, the answer is usually no. Working as an editor allows one to come to grips with a wide range of fascinating science without the daily disappointments of actually doing the experiments. Of course, you also miss out on the thrill of a new discovery. If I had it do over again, I think the burgeoning intersection of genetics and evolution would be an area that might have held my interest for the longest period of time as an experimentalist. The ability to apply molecular genetic tools to organisms with interesting evolutionary histories, such as the cichlid and the stickleback (see here, here, and here, for example) seems like a uniquely appealing interdisciplinary development (for some of this year’s standout findings, see Science’s breakthrough of the year special). That fundamental new insights into the genetic basis of evolution are occurring against the backdrop of the unfortunately resilient distraction known as ‘intelligent design’ is one of the great ironies of our time (see the full text of the recent Kitzmiller decision, however, for good news on this front). This is all by way of introducing the second in our series of ‘Paper Trail’ reports from authors of NG papers. First author Meredith Protas explains the origins of her work generating a linkage map of the cavefish Astyanas mexicanus, and its application to the evolution of albinism, as reported in the journal.

Meredith Protas writes:

During my first year in graduate school, one of my professors mentioned that Dr. Cliff Tabin was starting to work on the genetic basis of beak size variation in the Galapagos finches. I was amazed that it was possible to look at the genetics behind classical systems in evolutionary biology and joined Cliff’s lab to work on this project. Eventually, this particular project became impossible to do, but after seeing the amazing variation in beak size and shape between the different Galapagos finch species I still wanted to pursue the genetic basis of morphological diversity. We searched for another system in which these types of questions would be possible to address. At this time, there were QTL analyses being performed on cichlids and sticklebacks, which already had provided interesting and useful information about how certain morphologies evolved. For many of the same reasons that cichlids and sticklebacks were chosen for QTL analyses, as well as many additional unique features, we were drawn to the system of Astyanax mexicanus, the Mexican cave tetra. We then set up a collaboration with Dr. Richard Borowsky at NYU, who was working with this species (see also here).

Cave animals are a fascinating group. Two very common characteristics in obligate subterranean species (ranging from salamanders to shrimp) are loss of eyes and loss of pigment. Because similar light-less environments cause or allow these same phenotypes to occur over and over again in vastly different organisms, it is a system well suited to the study of parallel evolution. Looking at fish alone, there are 86 known species of obligate cave dwelling fish that have some degree of eye and pigment loss. The mystery behind cave animals is why are eye size and pigmentation reduced? There are three main theories; the first is that eye size and pigment loss is advantageous in cave animals because of energy conservation. The second is that eye and pigment loss is advantageous in cave animals because the genetic changes that cause eye and pigment loss also cause adaptive changes that allow the animals to be better suited to life in the cave. The final theory is that neutral mutation causes regression of the eye development and pigmentation pathways because there is no selective advantage to maintaining these systems in the dark environment.

Continue reading →

Oh et al.

Identification of direct targets of DAF-16 that control life span, fat storage and diapause by chromatin immunoprecipitation

Koshiba-Takeuchi et al.

Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart

Chen et al.

The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation

Drake et al.

Conserved noncoding sequences are selectively constrained and not mutation cold spots

Yu et al.

A unified mixed-model method for association mapping that accounts for multiple levels of relatedness

Gilbert et al.

Trak1 mutation disrupts GABAA receptor homeostasis in hypertonic mice

Comments welcome.

Apologies for the light blogging of late. I’ve done a bit of traveling (visiting labs in North Carolina, about which you can read either here or in the print journal in the near future). This was followed closely by a move of our office to a new location in downtown Manhattan, hard by the Holland Tunnel. For those of you who are interested, Nature Genetics shares office space with several other Nature journals, including Nature Medicine, Nature Neuroscience, Nature Immunology, Nature Structural & Molecular Biology, Nature Biotechnology, and Nature Methods. Together with staff for some of the academic journals that Nature Publishing Group turns out, we’re now a pretty sizable operation. Nature Cell Biology, Nature Materials, Nature Physics, and (soon) Nature Nanotechnology are based in London, as are the Nature Review titles, and Nature itself, which also has editors based in Washington, D.C., San Francisco, and Boston. Our colleagues at Nature Chemical Biology are based in Boston as well. In any case, our move was more or less complete when we were hit by the New York City transit strike. Thankfully, the strike is now over, and life is back to normal (or as normal as it gets in NYC).

We’ll post a few things next week, including a very interesting set of author comments on the recent cavefish paper published in the journal, and then resume regular posting in the New Year.

Rovelet-Lecrux et al.

APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy

Chan et al.

Homozygous L-SIGN (CLEC4M) plays a protective role in SARS coronavirus infection

Ræder et al.

Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction

Li et al.

Genome-wide transcription analyses in rice using tiling microarrays

Takahashi et al.

Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor

Comments welcome.

Fischer et al.

Defective planar cell polarity in polycystic kidney disease

Nguyen & Disteche

Dosage compensation of the active X chromosome in mammals

Ono et al.

Deletion of Peg10, an imprinted gene acquired from a retrotransposon, causes early embryonic lethality

Protas et al.

Genetic analysis of cavefish reveals molecular convergence in the evolution of albinism

Comments welcome.

My colleague Myles Axton has issued the following challenge:

I’d be interested to compile a list of papers that are relatively poorly cited for the reason that they answer a question so comprehensively that nobody subsequently works on that problem. If anyone can come up with any, these could be tagged in Connotea as “category killers” to receive their rightful place in the history of genetics.

Gene Expression has a thoughtful interview with Armand Leroi, author of Mutants, a wonderful synthesis of history, human teratology, and developmental genetics. Leroi comments on the beauty of C. elegans, the best way for a science writer to land an agent, recent controversies over race and genetics, the scientific cultures on different sides of the Atlantic, and the relative roles of mutations of large and weak effect in evolution. He also discusses the concepts of hybrid vigor and ‘hybrid breakdown’ by way of commenting on the recent NG paper by Helgadottir et al., which identifies a haplotype conferring particularly high risk of myocardial infarction in African Americans. Speaking of which, wouldn’t it be interesting to consider the protective effect of a variant in MMP3 in Europeans in this context?

Conrad et al.

A high-resolution survey of deletion polymorphism in the human genome

Hinds et al.

Common deletions and SNPs are in linkage disequilibrium in the human genome

McCarroll et al.

Common deletion polymorphisms in the human genome

Comments welcome.

One of the most enjoyable parts of being an editor is the opportunity to travel to conferences, meetings, and to visit those kind enough to invite us into their laboratories. This gives us a chance to get to know the community we work with better and to hear about the latest happenings in different fields. As you can imagine this is not only enjoyable, but helps editors understand how the journal can best serve our core scientific communities.

I will take this opportunity of our new Nature Genetics blog to share with you some of my recent scientific travels.

This month I attended the 3rd Seattle Biostatistics Symposium, focused on statistical genetics.

[Third Seattle Symposium in Biostatistics: Statistical Genetics and Genomics ]

The symposium was co-sponsored by Rosetta/Merck, University of Washington, and Fred Hutchinson Cancer Research Center, and featured an impressive lineup of speakers that included many of the leaders in statistical genetics. This effort was spearheaded by co-chairs Eric Schadt (of Rosetta, a fully owned subsidiary of Merck) and John Storey (of the biostatistics department of University of Washington), who began two years ago to assemble this program. The organizing committee also included Bob Waterston (chair of Genome Sciences at University of Washington), Thomas Flemming (current Chair of Biostatistics, University of Washington), and Bruce Weir (who is in the process of moving to Seattle to assume his new post as Chair of the University Washington Biostatistics department). Over 400 participants joined the engaging lectures and discussions of the symposium, that included sessions on population based analyses, family based analyses, and analyses of microarrays and functional genomic data. About 100 also attended the pre-symposium workshops on design and analysis of microarray experiments (taught by John Storey and Katie Kerr of UW) and on analysis of population genetic data (taught by Matthew Stephens of UW and Jonathan Pritchard of University of Chicago).

Although the Seattle biostatistics symposium has been far from annual (so far it has been every 5 years), a few of the participants have presented in both of the previous symposiums. Although for reasons of confidentiality I will not include their names, looking back over the proceedings of these previous symposiums does afford a look at the nature and changing interests within biostatistics and the UW department, over the course of the past 10 years. The first symposium, held in 1995, covered ‘Survival Analysis’. The second symposium, held in 2000, focused on ‘Analysis of Correlated Data’. The proceedings of the previous symposiums have been published by Springer, and are of course available on amazon.com. The current symposium, focused on statistical genetics with an empahsis on human genetic data analyses and characterizing human genetic variation, seemed to reflect the general interest in several overlapping communities. This was also reflected by the appointment of Bruce Weir as new Chair of Biostatistics at UW, who hopes to emphasize statistical genetics, and strengthen ties with the department of Genome Sciences.