Moseley et al.

Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8

Weisenberger et al.

CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer

Sebaihia et al.

The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome

Delmaghani et al.

Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy

Comments welcome.

I recently came across an article on Craig Venter in The Daily Telegraph, posted on Edge. It seems that the publication of the complete sequence of Venter’s genome is imminent, in an “as-yet-unnamed journal”. This is far from the first profile on Venter, but they’re always worth reading because inevitably you get this sort of thing:

Though current understanding is primitive, Venter’s DNA will eventually reveal the genes that act with education and upbringing to shape his health, outlook, and even personality. Perhaps there are clues to explain why he left home at 17 to surf. There may be glimpses of why he tried to drown himself after witnessing the Vietnam war, only to return home determined to restart his life. Perhaps his DNA will reveal how an obscure scientist who has rebelled against authority all his life became a major figure in biology who likes to boast that he took on the British and American governments and won.

Perhaps they’ll even have to update the genetic code:

UUU=Phe

UUC=Phe

UUA=Leu

UUG=Leu

CUU=Surf

CUC=Surf

CUA=Leu

CUG=Leu

You get the idea.

If the author really wants to know the most important risk factor for leaving home at 17 to surf, here it is: being 17 in California, a few minutes from the Pacific Ocean, the year the Beach Boys released the album Surfin’ USA.

Anyway, how much of this does the author believe? Later in the article, we read this:

So what does his code tell him, other than that he does indeed have blue eyes? For one thing, he is now taking a statin drug, after finding a variant of a gene that puts him at risk of heart disease. But the big picture is mind-bogglingly complex. ‘There are more than 300 genes that contribute to blood pressure regulation alone,’ Venter tells me. ‘People say there are things like “colon cancer genes”. There are not. We all have the same genes, but with variation in their spelling.’ As he puts it, ‘It is perfectly clear that it is not clear.’ And even if we understood it all, he admits, there is still the influence of the environment to reckon with. ‘I don’t worry about what people will find in my genome because it is so hard to interpret’. What we really need to do to dis-entangle nature and nurture is to sequence the genomes of millions of people as they go about the business of living and dying; only then will we see which bits of DNA really count.

I recognize that it’s common practice in magazine journalism to set up a strawman at the beginning of your piece, and then knock it down at the end. But I worry (as I’ve noted before) that all anyone will remember will be the strawman, which gets repeated endlessly. While finding the right balance between justified excitement and skepticism can be a difficult thing, a little better effort in some quarters would help.

In 2004, Francis Collins made the case in Nature for a large prospective cohort study of genes and the environment in the United States. The Secretary’s Advisory Committee on Genetics, Health, and Society, an advisory panel in the Department of Health & Human Services, was asked to gather information on the issues involved in embarking on such a project. Their report can be found here, and they have now asked for public input and comment. As much as $3 billion (or more) could be devoted to such a project, if the decision is made to go forward. The comment period is open until 31 July.

It would be difficult to do a bad interview with David Botstein (your recorder would have to break), but Jane Gitschier has a particularly good one over at PLoS Genetics. Much of it deals with his ongoing experiment in undergraduate education at Princeton, some of which we wrote about in our own piece on Botstein.

If you’re looking for some good lines, you won’t be disappointed:

What happens to students who come to college wanting to learn biochemistry? They find themselves first in a chemistry class with a hundred students with absolutely no interest in chemistry. All of those students drill a hole in the head of the instructors and each other to get the best possible grade because all they want is the grade. You teach these people later, and you realize that they are unteachable, to a first approximation. I have never failed as a teacher, except when trying to teach genetics to medical students.

Good thing Princeton doesn’t have a medical school.

And this, commenting on the revelation that ultimately led to the 1980 paper on generating linkage maps via RFLPs:

So finally I say something like, “Look there is nothing special about HLA. What’s good about HLA is that it has many alleles, and because it has many alleles, you can tell if you have linkage, and if you have many multiallelic markers all over the genome, you can map anything!” And as soon as the words were out of my mouth, I look at Davis, Davis looks at me, and we both understand that of course there are such markers, and we could make a map of the human genome tomorrow.

However:

What was really noticeable at the time was that the human geneticists didn’t get it. At all. At all, at all, at all. It took a really long time. Skolnick was beating the drum. In 1983, I went to the ASHG meeting, and I gave this long discussion of how it would all work, and I had to explain Southern blot and this and that. I went to NIH and tried to get money, and Ruth Kirschstein looked at me and said, “We don’t do things like that.”

But the rest of the interview delves into his personal history, much of which was unknown to me. Born in Switzerland in 1942, he came to the United States at the age of seven with his family. His mother, Anne Botstein (née Ania Wyszewianska), was Guido Fanconi’s chief resident (of Fanconi anemia fame). David Botstein himself has published on Fanconi anemia. He points out that Fanconi was also the discoverer of cystic fibrosis, and notes that his mother (a pediatrician) was the first to show that cystic fibrosis is inherited (a family study in Switzerland during the war). Add in his father Charles Botstein, a well-known physician and professor at Einstein who pioneered the use of radiotherapy in the treatment of uterine cancer, his brother Leon, a well-known college president and conductor, his sister Eva, a cardiologist, and you have quite a talented family.

In fact, there might be a pretty good book in all of this. Dr. Botstein: get thee a publisher.

Morgan et al.

PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron

Rollmann et al.

Pleiotropic fitness effects of the Tre1–Gr5a region in Drosophila melanogaster

Tirosh et al.

A genetic signature of interspecies variations in gene expression

Hollanda et al.

An inherited mutation leading to production of only the short isoform of GATA-1 is associated with impaired erythropoiesis

Comments welcome.

General Wesley Clark, former four-star general and NATO’s Supreme Allied Commander, Europe, talked at the recent YearlyKos blog-fest about his early interest in science:

I was in the ninth grade in the Little Rock Public School System, and they, one of our- I guess I got a note from my homeroom teacher. I’d been selected to participate in the Federal Radiation Project. So, there was four or five of us from Pulaski Heights and four or five from Forest Heights, and we were taken across town at 3:30 in the afternoon, after school, a couple three days a week. And we met with Mr. Barihugh, who was the tenth grade, he was the Biology teacher at Hall High School, and we were only in ninth grade, but this was to give us a jump on those Soviets’ kids who were learning things. And so, what we were taught about, we were taught about – and here’s how smart it was. The one thing the Soviets couldn’t quite handle was genetics, Mendelian genetics, because if you understand genetics with dominant and recessive genes, then you have to question whether you can, by the environment alone, create a new form of man. And so, in the Federal Radiation Project, they talked to us and they taught us about genetics with the, the species was Drosophila melanogaster, which is the common fruit fly. And the medium was, was spoiled bananas. So, Mr. Barihugh would go to the, the Krogers, and he’d buy the oldest bananas he could find, and he’d come back and they’d mash them up in a test tube. And we would, we would look at these Drosophila melanogasters under a microscope, well actually under a big magnifying glass, and you could see the colors of their eyes and the numbers of wings. And then you’d stuff them into the, and let them feed on the banana stuff, and then you’d- He’d take them over to the University of Arkansas Medical center and give them, you know, thousands of roentgens, rads. He, he irradiated them, thank goodness not us. The radiation was on the fruit flies. And the idea was could you mutate the fruit flies – could you convert yellow eyes into, into, into red eyes? And so, we spent about six weeks on this, and I don’t know if we ever produced a new modern fruit fly. I think we produced a lot of sterile fruit flies.But it was a very fertile period for those of us who were engaged in the research, and it really opened our eyes to science.

I’m not exactly sure how this experiment would have fired up the patriotism of a bunch of fifteen-year-olds to go out and win the Cold War, but it’s a charming anecdote nonetheless.

You can read the full transcript of his remarks here.

Now that the finished sequences of all of the human chromosomes have been published, Nature has put together the Human Genome Collection, an online focus including commentaries (old and new), video interviews, and of course the sequences themselves. Of particular interest is that each chromosome is ‘annotated’ with papers published in NPG journals (a number from Nature Genetics) that specifically pertain to that chromosome. This sequence papers themselves are freely available.

A couple of weeks ago I spent a few days at the 71st Cold Spring Harbor symposium, this one on regulatory RNAs. I don’t have to tell this audience that the emergence in the last few years of a remarkable diversity of functions for small RNAs is one of the most exciting developments in contemporary genetics and molecular biology. If anything, the results presented at the symposium will only serve to heighten enthusiasm for the importance of this incredibly flexible molecule. In regard to microRNAs, David Bartel probably said it best when he noted:

When considering the widespread conserved targeting and targeting avoidance, together with species-specific targeting, it is hard to escape the conclusion that microRNAs are influencing the expression and/or evolution of most mammalian protein-coding genes.

A few other thoughts from the meeting:

The first task is obviously to identify the small RNAome (forgive me), and in that regard it’s clear that several groups are proceeding with deep 454-based sequencing in order to do this.

You can tell that an area of research is beginning to mature when good old-fashioned genetics is consistently being applied to it, and that’s the case with many aspects of the small RNA world. Large-scale genetic screens are being carried out to identify all of the RNA and protein components that regulate several features of small RNA metabolism.

A debate is emerging as to whether microRNAs largely act by fine-tuning gene expression, or whether they may have central roles in cellular differentiation events. Early data suggest some of both, but it’s too early to say whether one role will dominate.

The bulk of the ENCODE data will soon see the light of day in formal publications, and a preview given by Tom Gingeras was rather remarkable. There may be as many as 450,000 small RNAs transcribed in the human genome, and the overall complexity of the genome is much deeper than had been anticipated. It’s also clear that the exact number of protein-coding genes is irrelevant as a metric for complexity. Alternative splicing, overlapping sense-antisense transcripts, small RNAs, and exon-exon fusions mean that the genome’s functional output is truly staggering.

You can listen to interviews with leading scientists working on small RNAs here.

I also must mention our new supplement on microRNAs, which is freely available, and contains perspectives and reviews on miRNAs covering discovery, target prediction, miRNA function, their roles in development, viral miRNAs, and roles in plants. It’s all freely available. Enjoy.

We recently ran a Touching Base article explaining how to make publication quality figures from electropherograms using commercial viewer and graphics software.

Can anyone explain to readers how to make good sequence figures from ABI or Geospiza Finch trace viewer software or from widely used free or open source sequence viewing software? What graphics program do you use?

Zhang

Parallel adaptive origins of digestive RNases in Asian and African leaf monkeys

O’Neill et al.

Epigenetic characterization of the early embryo with a chromatin immunoprecipitation protocol applicable to small cell populations

Horvath et al.

A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia

Vithana et al.

Mutations in sodium-borate cotransporter SLC4A11 cause recessive congenital hereditary endothelial dystrophy (CHED2)

Comments welcome.