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Quirkology

There's an amusing article by Richard Wiseman over at New Scientist. I take most of the "studies" with a grain of salt, but its fun to read nonetheless. Here are some interesting "facts".

--[O]ne demographical group has come to stand out above all others as being most likely to push boundaries and break rules. These are not disaffected teenagers nor Italian football hooligans. They are women van drivers.

--[People] would rather have worn a sweater that had been dropped in dog faeces and not washed - raising genuine health concerns - than a laundered sweater that had been worn by a mass murderer.

--According to research carried out by Robert Sommer at the University of California, Davis, in 1988, lemons are seen as dislikable, onions are stupid, and mushrooms are social climbers.

How did these studies not win Ignoble Prizes?

This Week's Citation Classic

Sanger F, Nicklen S, Coulson AR. 1977. DNA sequencing with chain-terminating inhibitors. Proceedings of the National Academy of Sciences, U S A 74: 5463-7.

This paper describes the most important (IMHO) technical breakthrough in the biological sciences: DNA sequencing using a single-stranded DNA template, a DNA primer, a DNA polymerase, radioactively or fluorescently labeled nucleotides, and modified nucleotides that terminate DNA strand elongation.

Prior methods depended on partial hydrolysis and were painfully slow. It was a big deal when Gilbert and Maxam reported in 1973 the sequence of a whopping 24 basepairs using a method known as wandering-spot analysis. Contrast this to the ~3 billion base pair human genome. Clearly the process needed to be sped up in order to be useful.

The key innovation of the Sanger method was the use of dideoxynucleotides triphosphates (ddNTPs) as DNA chain terminators. The basic idea is that the florescently labeled ddNTPs will stop chain replication wherever they are incorporated into an elongating DNA strand. DNA fragments of various lengths are separated by electrophoresis and the fluorescent tags are "read" give the nucleotide sequence. The whole procedure relatively simple and is adequately described in wikipedia.

Sanger et al.'s technique was used to determine the sequence of the DNA bacteriophage PhiX174 which contains 5,386 nucleotides, the first DNA based organism ever to have its complete genome sequenced. (The first organism was MS2, an RNA bacteriophage).

It is true that the process was eventually sped up using thermally stable (e.g. Taq) DNA polymerases, capillary electrophoresis and dedicated thermal cyclers, but the basic technique is still used today.

Alas today, chain termination sequencing is being replaced by newer quicker methods, especially pyrosequencing. Chain termination methods are probably inadequate to compete for the Genomics X prize given to the first team build a device capable of sequencing 100 human genomes within 10 days or less with an accuracy of no more than 1 error in 100,000 base pairs, with sequences accurately covering at least 98% of the genome, and at a demonstrated cost of no more than $10,000 per genome.

Frederick Sanger was awarded his second Nobel Prize for this work in 1980.

Figure: a typical sequencing four-color chromatogram.

Why is there so much genetic variation?

One of the surprising discoveries when scientists first began looking at genetic variation was that there was a great deal more than expected by theory. In 1966, Richard Lewontin and Jack Hubby published a paper that revolutionized population genetics. They pioneered the use of protein gel electrophoresis to survey dozens of loci in the fruit fly, Drosophila pseudoobscura, and reported that a large fraction of the loci were polymorphic, and that at the average locus there was about a 15% chance that the individual was heterozygous. These results are surprising because it was expected that natural selection will reduce the amount of genetic variation in populations.

Forty years later evolutionary biologists still don't have many solid explanations for genetic variation in nature. However, a recent report in Nature by Fitzpatrick et al. shows that negative frequency dependent selection can maintain alternative feeding alleles in populations of fruit flies. Fruit fly larvae forage for food in two ways: by "roving" or "sitting". Rover larvae move around more than sitter larvae while feeding and they are also more likely to explore new food patches than sitters.

Fitzpatrick et al. discovered that each type was favored by natural selection when rare.

"If you're a rover surrounded by many sitters, then the sitters are going to use up that patch and you're going to do better by moving out into a new patch," says Marla Sokolowski, the PI on the research team. "So you'll have an advantage because you're not competing with the sitters who stay close to the initial resource. On the other hand, if you're a sitter and you're mostly with rovers, the rovers are going to move out and you'll be left on the patch to feed without competition."

Similar behaviors occur in C. elegans, which tend to clump or browse bacteria solitarily. I unsuccessfully looked for frequency and density dependent selection among these worms, but it is likely my assays weren't sensitive enough. The foraging gene is found in many animals, including honeybees, mice and humans. It is interesting to speculate on the roles that it plays in higher organisms, such as ourselves. Does it play any role in food-related behavioral disorders?

Marsupial Genome Sequenced

A report in Nature has announced that the first marsupial genome has been sequenced. Tarjei Mikkelsen of the Broad Institute in Cambridge, Mass and team sequenced the 3,475 megabase genome of the South American grey short-tailed opossum, Monodelphis domestica. The opossum genome appears to contain about 20,000 protein-coding genes, the authors found, and the vast majority of these are also found in placental mammals. Apparently most of the differences between marsupial and placental mammals comes from junk... ahem... non-coding sequences, not proteins. It provides more evidence the main difference between you and other animals is how your genes are regulated not the proteins you possess.

Oh and that isn't the only time I've seen 'possums in the news lately.

Apparently a homeless person seeking shelter from the rain in a trash bin was accidentally dumped into a garbage truck. Trapped in the garbage compactor, the man was able to avoid being crushed by grabbing a...

a) a steel pole
b) a brace
c) our marsupial cousin, Didelphis virginiana

If you picked, c, the Common Opossum, you get a medal.

Our friend Marko from Croatia writes "Are opossums that common?"
Yes, Marko, Common Opossums are in the International Union for the Conservation of Nature and Natural Resources' category of Least Concern.

Question of the Year

What would you do if you could sequence a genome for $1,000? In celebration of its upcoming 15th anniversary, Nature Genetics is asking prominent geneticists to weigh in on this question: what would you do if this sequencing capacity were available immediately? The responses are interesting.

Bruce Lahn would sequence "the genomes of a large number of cells from a single individual... to construct an ontogenetic tree of all the cells based on somatic point mutations."

Paul Nurse would sequence "a selected set of genes for as many species as possible... [and] bury the creationists and the intelligent designers under a mountain of base pairs."

Laurence Hurst would "love to know what underpins the heritable differences in musical ability."

Elaine Ostrander wonders "what are the genetic mechanisms that control the breed-specific behaviors of various domestic dog breeds?"

Francis Collins would determine where the soul is located. Wait, no, just kidding. He would use "genomic research to improve human health...for each of 30 common, complex diseases, such as asthma, arthritis, diabetes, various types of cancer, heart disease, stroke, Alzheimer's disease and depression."

What would you do?

Genes in Conflict

"The conflict between maternal and fetus genes is one of the weirdest ideas in the modern theory of evolution."* According to evolutionary logic, the fetus "wants" to milk the mother for all it can get; the mother "wants" to restrict the fetus to what it needs to survive and save something for future offspring. The reason is that the fetus benefits from every bit of help the mother gives, while the mother's return on her investment diminishes with increasing investment, (i.e. ever greater investment won't necessarily increase her fitness).

One example of this struggle is the regulation of the mother's blood sugar, which is much than normal higher during pregnancy. Well this makes sense, you might think, because the mother is now feeding a growing fetus. But look at the mother's insulin level, it also is much higher than normal, and insulin is used to down-regulate blood sugar levels. Huh, that's weird, she is secreting more insulin, yet her blood sugar level is ever higher. She must be responding less to insulin. Why should that be?

David Haig suggested that the fetus is trying to increase blood sugar levels by releasing human placental lactogen (hPL, a hormone that reduces the effects of insulin) into the mother's bloodstream and the mother is trying to reduce blood sugar levels by increasing more insulin. The amount of hPL in the mother's blood is astonishing, on the order of 1000-2000x the level of comparable hormones, and the amazing thing is that hPL is entirely unnecessary because babies with nonfunctional hPL genes are completely normal at birth. So the mother and fetus are battling over the allocation of resources by pumping out more and more hormones.

But wait that's not the weird part! The weird part is, strictly speaking, the conflict is not between mother and fetus, but rather between genes within the same individual. The fetus that contains a gene causing it to release more hPL will someday, provided it is a female, grow up to be a mother whose offspring may contain that very same gene and will be trying to suck every bit of nourishment out of her. The gene is then, within the very same individual, advantageous during fetus-hood and disadvantageous during mother-hood. The net result is that the fetus loses out by possessing the hPL gene, its lifetime reproductive output is reduced, but it doesn't matter. The gene spreads anyway because the gene increases its representation in the gene pool.

There is then an inherent inefficiency in life. The intragenomic conflict leads to reduced reproductive output, through less efficient use of resources and, more importantly, in the hPL case, through increases in the onset of diabetes. 10% of pregnancies result in gestational diabetes; and 50% of the cases of gestational diabetes results in full diabetes later on in life. Would that be object of an intelligent designer?

Photo by Street Cow.
*Ridley, M. 2001. The Cooperative Gene. The Free Press.