Thursday, January 31, 2008

This Week's Citation Classic

DNA replication is amazingly accurate, but it's not perfect. And that's a good thing. If no errors were made during DNA replication, there would be no evolution. Ultimately mutation is the source of genetic variation, and genetic variation is the basis of evolutionary change: some mutants are more fit than others, and therefore are fruitful and multiply.

But what is the mutation rate? For a long time, this question was impossible to answer. While it was possible to estimate the deleterious mutation rate by observing phenotypic changes in offspring or changes in amino acid sequences, estimation of the genome-wide mutation rate had to await the advent of DNA sequencing.

When sequences finally started pouring in, estimates of genome-wide mutation rates varied wildly. One of the first studies to put this data in perspective was this week's citation classic:

JW Drake. 1991. A Constant Rate of Spontaneous Mutation in DNA-Based Microbes. PNAS 88: 7160-7164. doi:10.1073/pnas.88.16.7160

John Drake, the head of the Laboratory of Molecular Genetics at the National Institute of Environmental Health Sciences, compared the mutation rates for several microbial organisms, including yeast, bacteriophages, bacteria and filamentous fungi (i.e. those that had been sequenced at that time). He found a deep general trend. His abstract conveys the message much better than I could:

"Their average mutation rates per base pair vary by ~16,000-fold, whereas their mutation rates per genome vary by only ~2.5-fold, apparently randomly, around a mean value of 0.0033 per DNA replication. The average mutation rate per base pair is inversely proportional to genome size. Therefore, a nearly invariant microbial mutation rate appears to have evolved. Because this rate is uniform in such diverse organisms, it is likely to be determined by deep general forces, perhaps by a balance between the usually deleterious effects of mutation and the physiological costs of further reducing mutation rates."

Drake has made a career of estimating mutatation rates, and evolutionary biologists now have a stronger command of how variation is generated among organisms. It's such an important parameter in many evolutionary models.

How about humans? How many mutations do we have on average? Estimating mutation rates is not easy, as the methods section of Drake's paper should make clear. Different techniques, however, seem to consistently produce estimates of 1 to 6 point non-silent mutations in coding DNA per individual in humans. In a later paper, Drake gives ~64 as the total number of non-silent and silent point mutations per individual.

Photo: Replicating mtDNA.

Wednesday, January 30, 2008


A recent report in Genes and Development demonstrates how small variations in regulatory sequences can lead to large morphological variations. Researchers have generated mice with longer forelimbs by inserting into their genomes a piece of DNA that regulates wing development in the short-tailed fruit bat, Carollia perspicillata.

From the MS, "We replaced a limb-specific transcriptional enhancer of the mouse Prx1 locus with the orthologous sequence from a bat. Prx1 expression directed by the bat enhancer results in elevated transcript levels in developing forelimb bones and forelimbs that are significantly longer than controls."

In the photos, A & B are bat and mouse scaled for body length. C is the developmental stages of bat (top) and mouse (bottom) forelimbs. D is the same bat, but the mouse is now transgenic for the Prx1 regulatory region (scale similar to C).

The investigators conclude, "These findings suggest that mutations accumulating in pre-existing noncoding regulatory sequences within a population are a source of variation for the evolution of morphological differences between species and that cis-regulatory redundancy may facilitate accumulation of such mutations."

In other words, we are only a few steps away from winged mice.

Saturday, January 26, 2008

Viva la Evilucion!

ERV and I exchanged t-shirts. I got her one from the local evilution store and she got me one from cafe press.
I got a lot of comments on the shirt from co-workers and people on the street, most of it favorable.

Friday, January 25, 2008

A periodic table of microbes?

There's a great article from Melinda Wenner in this week's Nature News that expands on a theme I've been writing about lately: microbe and human interactions.

The article discusses recent results by Leonid Margolis. Margolis was attempting to grow HIV in some tonsil tissue infected with Human Herpes Virus 6 (HHV-6). In HIV patients, HHV-6 seems to hasten HIV progression, and no one knows why.

However in the tonsil tissue, Margolis and colleague, Jean-Charles Grivel, couldn't get the HIV to thrive. He repeated his experiments. Same result.

“We couldn't believe our eyes,” Margolis says. HHV-6, at least in this situation, seemed to protect against HIV.

Wenner writes, "Margolis uncovered why HHV-6 prevents HIV replication under certain conditions. A subtype of HIV, most often found in early infection, generally gains entry into the cell by binding the receptor CCR5. When HHV-6 infects first, however, it instigates production of an immune chemical that binds to CCR5 receptors, blocking HIV's access. HIV can develop resistance to this chemical over time and HHV-6 co-infection may exert selective pressure on HIV to become immune-resistant, or switch to a different co-receptor — a change accompanied by increased HIV virulence. This explains the often poor prognosis of patients infected by both viruses."

These results emphasize the importance of doing experiments under conditions that closely resemble real world cases, rather than in sterile lab cultures.

“If you study a pathogen such as HIV in a cell-culture model where there is no immune system, there is no effect from other microbes that are in the normal state in an infected human,” says Jack Stapleton, director of the University of Iowa's Helen C. Levitt Center for Viral Pathogenesis and Disease in Iowa City. “You're really missing important factors that will influence the pathogenesis.”

Margolis fantasizes about creating, "a table, not unlike Mendeleev's table of the elements, for infectious agents. Each cell in the table might feature the name of the microbe, the immune factors it affects, the receptors it uses and the signalling systems it incorporates. Just as the elemental version predicts how two substances react with one another, the periodic table of microbes would predict how two microbes interact in the human body."

Photo: HIV attacking CD4 cell from NIH.

Monday, January 21, 2008

This Week's Citation Classic

Ayala F J, Powell J R, Tracey M L, Mourao C A & Perez-Salas S. Enzyme variability in the Drosophila willistoni group. IV. Genic variation in natural populations of Drosophila willistoni. Genetics 70:113-39, 1972.

Francisco Ayala is an amazing scientist; his work includes more than 950 articles and 30 books. He has been President and Chairman of the Board of the American Association for the Advancement of Science, President of the Society for the Study of Evolution, a National Medal of Science winner and much more. He recieved his doctorate under the guidance of Theodosius Dobzhansky in 1964.

None of his work has received more citations (888 at last count) than the present article.

Ayala et al. took advantage of the newly discovered technology of gel electrophoresis. Lewontin and Hubby used gel electrophoresis to demonstrate the existence of high levels of genetic variation back in Drosopila pseudoobscura in 1966.

Ayala et al. took this a step further. Lewontin and Hubby used essentially lab strains (33 of 43 strains were reared in lab for 5+ years) . A criticism of Lewontin and Hubby was "Yeah, well you see lots of variation, but these strains have been in the lab for a long time. Maybe genetic changes are taking place in the lab and maybe there is less variation in the "wild" because of the effects of natural selection". To counter these arguments, Ayala et al. used strains much more recently caught from the wild.

Ayala writes, "It was, therefore, essential to collect wild flies and, indeed, most of the results concern wild flies. Collecting D. willistoni flies is, however, a pleasant task since the species lives in the forest of the American tropics. Several collecting trips to the Amazon basin and other regions of the American tropics were done."

Ayala et al. conclude that, "There is a great deal of variation —on the average, 58% of the loci are polymorphic and an individual fly is heterozygous at 18.4% of the loci."

Despite the variation, the pattern of allele frequencies was remarkably similar throughout the several million square mile area occupied by the species. This suggests the variation is maintained by balancing selection rather than being selectively neutral.

However, one of the interesting observations was that the D. willistoni did not form a single large panmixic population. There were found chromosomal polymorphisms that were very different from each other. This suggests that genetic mixing is rare among sub-populations and admits the possibility of speciation.

Not bad for an ex-priest! Yes, Francisco Ayala is a former priest of the Dominican order. An interview with Ayala can be found in the New York Times. Here he comments on religion and science, "Most mainstream theologians, and most people who have read the bible thoughtfully, realize that the Bible it is not an elementary book of biology, or an elementary book of cosmology or of physics. It amounts to blasphemy to try to understand the world of physics and biology by reading the Bible. That was not the purpose of the Bible....It is a travesty to interpret the Bible that way."

Another good article can be found here.

Sunday, January 20, 2008

Science Debate 2008

This year we, in the United States, will elect a new president. The future of this country, and the world, depends on the next president's actions during this critical period in human history. Most notable is the threat of global climate change, an issue that the current administration has failed to act upon. We cannot afford to lose another 4-8 years without addressing this issue. It is important for Americans to learn how the candidates stand on this and other science issues.

Support the Science Debate 2008

"Given the many urgent scientific and technological challenges facing America and the rest of the world, the increasing need for accurate scientific information in political decision making, and the vital role scientific innovation plays in spurring economic growth and competitiveness, we call for a public debate in which the U.S. presidential candidates share their views on the issues of The Environment, Health and Medicine, and Science and Technology Policy."

Some of the leading candidates have expressed anti-science views, particularly Mike Huckabee who has stated he does not believe in evolution.

A Science magazine press release documents the views of some of the candidates.
For those with access, Science also has an extended news focus on the candidates.
Wired has more here.

Friday, January 18, 2008

Origins of Syphilis

Carl Zimmer has an article on the Origins of Syphilis in this week's edition of Science.

The basic story is that Kristin Harper, a graduate student at Emory University "and colleagues used the variations in the Treponema DNA to draw an evolutionary tree, the deepest branches belonged to samples of yaws from the Old World. Newer forms of yawslike diseases emerged from the ancestral bacteria. The strange Treponema strain in Guyana sat on a relatively young branch, suggesting that yaws had been carried into the New World by the first immigrants some 12,000 years ago, and that the Guyana strain evolved there. It shares a close ancestry with all strains of syphilis. The relationship also suggests that the Guyana strain is a transitional form that had already acquired some of syphilis's traits, such as the open sores."

I usually refrain from mentioning articles in non-open access publications, but this article contains quotes from Science Blogger John Logsdon, so I include it here. The subject of the article is open-access from PLoS Neglected Tropical Diseases.

Microbes and Chronic Disease

In the US, most deaths are attributable to chronic afflictions, such as heart disease and cancer. Typically the medical community has attributed these diseases to accumulated damage, such as plaque formation in arteries or mutations in genes controlling cellular replication.

This view is changing.

Scientists are now beginning to recognize that many of these chronic illnesses are due to microbial infections. A recent report in the American Journal of Psychiatry suggests that schizophrenia, a mental illness leading to errors in perception, is associated with the pathogen, Toxoplasma gondii.

"Our findings reveal the strongest association we've seen yet between infection with this very common parasite and the subsequent development of schizophrenia," study investigator Dr. Robert Yolken of John Hopkins Children's Center in Baltimore said in a statement.

Toxoplasma gondii
, a parasitic protozoa usually carried by cats, is an interesting microbe, having been associated with behavioral changes in humans and rats.

Other diseases are also showing microbial connections. The most famous example is Helicobacter pylori, the unequivocal cause of peptic ulcers and suspected agent of gastric cancer. Human papillomavirus is associated with 90% of cervical cancers. Hepatitis B is linked with 60% of liver cancers.

Some diseases look suspiciously like infections, such as Hodgkin's disease, multiple sclerosis, juvenile onset diabetes and Crohn's disease.

In an evolutionary terms, these speculations make sense. Microbes exist to pass on their genes, and they may have evolved ways to "cryptic" rather than "conspicuous". Paul Ewald divides diseases into three categories: environmental, genetic and infectious. Environmental diseases are acquired from toxins such as those in cigarettes and pollution. Genetic diseases are those caused by errors in replication and development. Ewald reasons that, if diseases are too common to have arisen by random mutation and too ruinous to have survived natural selection, and if it is not environmental, then it must be infectious. By being cryptic, these infectious diseases enhance their spread by increasing the odds of transmission.

Toxoplasma is one of Carl Zimmer's favorite parasites.

Photo: Toxoplasma gondii from Wikicommons.

Friday, January 11, 2008

This Week's Citation Classic: Being Wrong

With my latest grant submission submitted, I can relax just a bit. I confess I am suffering separation anxiety though. There are still changes and additions I want to make, but it's gone out the door. Anyway, without further ado, this week's citation classic is:

Boyer, P. D. 1963. “Phosphohistidine.” Science 141: 1147–1153.

Adenosine triphosphate (ATP) is the prime driver of life. It provides the energy for most the energy-consuming reactions in the cell. Naturally scientists are interested in how it is made. When Paul Boyer published his one-word title Science paper, Phosphohistidine, he veritably turned the field of bioenergetics on its ear. For years, biochemists were trying to determine energy from the electron transport chain is coupled to ATP synthesis, and at last, a solution! Phosphohistidine was the high-energy intermediate of oxidative phosphorylation.

As Douglas Allchin writes, "Biochemists were primed to celebrate. One might well have imagined that the achievement here would surely garner Boyer a Nobel prize."

However, Boyer's triumph was short-lived. One of Boyer's grad students noticed that the results were sensitive to the concentration of succinate, a component of the Kreb's cycle. Further work, including the discovery of Phosphohistidine in E. coli (which have no mitochondria), put a damper on the claim.

In 1981, Boyer bluntly said, "I was wrong."

What happened? Boyer and his team missed a simple control. That is, they mistook other mitochondrial reactions for ATP synthethis. Phosphohistidine turned out to be important in the Kreb's cycle, but not for ATP synthesis.

"...Boyer did exhibit an important, perhaps under-appreciated element of scientific practice: finding the error and then recovering from it. Here, detection emerged from a combination of chance and effort to amplify the initial findings. Further interaction with the experimental system exposed an unusual aspect of the pattern they had already documented. Boyer perceived how all the results could fit another pattern, or explanatory scheme, and then collected additional data to show how the phenomenon fit one and not the other. He had to both recognize the oddity as significant and be able to imagine and appreciate an alternative explanation."

So these errors were quite informative for Boyer and pointed him in the right direction. Some 30+ years later, Boyer shared the 1997 Nobel Prize for in Chemistry with John Walker and Jens Skou "for their elucidation of the enzymatic mechanism underlying the synthesis of adenosine triphosphate (ATP)".

"Although errors entail further work, they do not necessarily become worthless scientific residue. When probed, errors can guide researchers to deeper knowledge. Errors may be a source of discovery."

Allchin, D. 2002. To Err and Win a Nobel Prize: Paul Boyer, ATP Synthase and the
Emergence of Bioenergetics. Journal of the History of Biology 35: 149–172.

Cartoon from the ATP synthase page.

Friday, January 4, 2008

Happy New Year!

Another year begins and the prospects for humans are still iffy. The threat of global nuclear Armageddon has hopefully receded somewhat, but we still face major global threats such as pollution and climate change.

This week's citation classic anticipates the problems with pumping CO2 into the atmosphere.
Hardin, G. 1968. The tragedy of the commons. Science 162: 1243-1248.

The tragedy of the commons is a conflict between individual interest and the common good. Hardin describes it here in the context of herdsmen grazing cattle on a pasture shared with his fellows:

"Picture a pasture open to all. It is expected that each herdsman will keep as many cattle as possible on the commons.... As a rational being, each herdsman seeks to maximize his gain. Explicitly or implicitly, more or less consciously he asks, 'What is the utility to me of adding one more animal to my herd?'"

The answer has a positive component and a negative component. For positive, the herdsman gains an additional cow and the proceeds that result from selling that cow later. For negative, overgrazing will reduce the proceeds gained from that cow. However, the positive outweighs the negative, so the herdsman always adds another cow... and another... and another.

This conclusion is reached by each herdsman sharing the commons.

"Therein is the tragedy. Each man is locked into a system that compels him to increase his herd without limit--in a world that is limited. Ruin is the destination towards which all men rush, each pursuing his own best interest in a society that believes in the freedom of the commons. Freedom of the commons brings ruin to all."

Producing carbon dioxide is something we all do, and it is precisely the type of desecration of the commons that Hardin is speaking of. However, as a global tragedy, it is precisely the most difficult one to solve. However, an appropriate start is for the United States and the global community to make a strong commitment to the Kyoto Protocol. Currently, of the 174 ratifying parties, no country has passed national legislation requiring compliance with their treaty obligation.

Science mag has collected the paper and some responses in a special issue.
The Garrett Harding Society can be accessed here.

Public Access Mandate Made Law

Over the holidays, President Bush has signed into law the Consolidated Appropriations Act of 2007 (H.R. 2764), which includes a provision directing the National Institutes of Health (NIH) to provide the public with open online access to findings from its funded research.

The law requires that NIH funded researchers upload e-copies of their published work to PubMed The full text of these publications will be available to all no later than 12 months following publication.

This is a big victory for open access.

“We welcome the NIH policy being made mandatory and thank Congress for backing this important step,” said Gary Ward, Treasurer of the American Society for Cell Biology (ASCB). “Free and timely public access to scientific literature is necessary to ensure that new discoveries are made as quickly as feasible. It’s the right thing to do, given that taxpayers fund this research.”

A full press release from the Alliance for Taxpayer Access is available here.