January 12, 2007
Vol. 11 - Number 2
Theories come and theories go. The frog remains.
-- Jean Rostand
MOLECULAR BIOLOGY: ON CHROMATIDS IN MITOSIS
The following points are made by Carmen Sapienza (Science 2007 315:46):
1) Eukaryotic diploid somatic cells reproduce by cell division (mitosis), in which each chromosome of a homologous pair (one from each parent) undergoes semiconservative DNA replication, producing a copy of each homolog. After replication and chromosome condensation, microtubules belonging to a structure called the mitotic spindle attach to opposite sides of each replicated homolog and pull one of the two copies (sister chromatids) to opposite poles. Barring uncorrected replication errors, the semiconservative nature of DNA replication ensures that each sister chromatid is identical and that each daughter cell will be genetically identical to the parent cell. Given this identity, most biologists believe that which chromatid segregates to which daughter cell is immaterial. However, having two copies of each homolog does bring up the potentially vexing issue of choice. Are both copies equally good? How is that decided? If they are not equally good, then what happens? New work (1) starts to address these questions, although which question is actually addressed is likely to be the subject of debate -- how chromatids are distinguished versus how they are segregated.
2) One can imagine situations in which the choice of which chromatid to segregate to which daughter cell might make a difference. Cairns (2) proposed that it would be advantageous to segregate the "oldest" DNA strands -- that is, the original DNA, as opposed to new DNA that is synthesized during replication -- to the stem cell daughter in any division that produced both a stem cell and a differentiated cell. Keeping the oldest strands in the stem cell would reduce the possibility that replication errors might affect the stem cell population and might reduce the risk of cancer. Another opportunity to put strand identity to good use has been envisioned by Klar (3), who argued that strand- specific imprinting and patterned segregation of DNA strands during mitosis could be the basis for forming the left-right body axis during development. In this model, nonrandom chromatid segregation arises when chromatids containing the old "Watson" (W) DNA strands segregate into one daughter cell while chromatids containing the old "Crick" (C) DNA strands segregate into the other daughter cell -- in other words, a WW:CC segregation pattern. In fact, this specific proposal by Klar, in combination with the results of earlier work (4), has led to the present report that identifies a factor involved in biased segregation of chromatids during mitosis.
3) Armakolas and Klar have used an established mouse cell culture system (5) in which it is possible to distinguish the segregation of sister chromatids of mouse chromosome 7. In this experimental system, a mitotic recombination event is induced that reconstitutes a drug resistance gene (Hprt) on only one of the two chromatids involved in the recombination event. Thus, drug selection produces cells that carry the Hprt-bearing recombinant chromatid from one homolog in all cases. To test whether segregation of chromatids is random or not, one need only determine which chromatid of the homologous chromosome 7 segregates to the drug-resistant cell -- the nonrecombinant chromatid (called an X segregation pattern) or the recombinant chromatid (a Z segregation pattern). These correspond to the WW:CC segregation pattern and the WC:WC pattern, respectively, in the model proposed by Armakolas and Klar.
4) In this experimental system, the prevailing view on the segregation of chromatids during mitosis is that the X mode (WW:CC) is predominant and results from physical constraints imposed on the mitotic chiasma (the physical point of crossover between two chromatids that facilitates exchange of pieces of chromatid) and by sister chromatid cohesion (5). That being said, "predominant" does not mean "exclusive," and herein lies the intellectual root of Armakolas and Klar's experiment. Liu et al. (5) and Armakolas and Klar (4) reported exclusive (100%) cosegregation of the reconstituted drug-resistance gene with the nonrecombinant chromatid from the homolog (X segregation) in a mouse embryonic stem cell system. Armakolas and Klar also described exclusive X and Z segregation in an endoderm and neuroectoderm cell line, respectively (4). They proposed that the exclusive segregation modes result from biased (nonrandom) segregation of DNA strands from each homolog to each daughter cell and that these patterns are cell-type specific (4).
5) Although well-reasoned objections have been raised to this explanation (the present results do not shed any direct light on this controversy), Armakolas and Klar carried their supposition one step further: If the factors that influence segregation of DNA strands are the same factors that influence left-right body axis formation, then how might a gene product that influences body axis formation influence the segregation of chromatids? They focused on the gene encoding the left-right dynein motor protein (LRD). Mutations in the mouse gene (Dnahc11) and the human homolog (DNAH11) encoding this motor protein cause left-right axis randomization of some internal organs. When Armakolas and Klar used the same Hprt-recombination experimental system, and reduced expression of the left-right dynein motor by RNA interference, chromatid segregation became nearly "random" in those cell lines in which it had been exclusively the X or Z type.
1. A. Armakolas, A. J. S. Klar, Science 315, 100 (2007).
2. J. Cairns, Nature 255, 197 (1975).
3. A. J. S. Klar, Trends Genet. 10, 392 (1994).
4. A. Armakolas, A. J. S. Klar, Science 311, 1146 (2006).
5. P. Liu, N. A. Jenkins, N. G. Copeland, Nat. Genet. 30, 66 (2002).
ECOLOGY: GLOBAL WARMING AND ANIMAL PHYSIOLOGY
The following points are made by T. Wang and J. Overgaard (Science 2007 315:49):
1) Climatic changes have been linked to altered geographical distributions of many organisms, including marine fish (1,2). Yet it remains difficult to distinguish direct causal relations between environmental temperature and species distribution patterns (3) from indirect effects through interactions with prey, predators, pathogens, or competitors (4). An ambitious goal of integrative biology is to understand how temperature affects physiological mechanisms at all levels of biological organization. This could allow predictions of how global warming affects animal performance and population dynamics. Animal physiologists commonly rely on laboratory studies to predict temperature tolerance of animals, but whole-animal performance in natural settings is rarely investigated. New work (5) provides compelling evidence that thermal constraints on oxygen transport are causing the population of a marine fish, the viviparous eelpout (Zoarces viviparus), to decline in the Wadden Sea.
2) Over the past decade, Pörtner and co-workers have studied various aspects of oxygen transport and metabolism in numerous animal species, including the viviparous eelpout. They have identified the pejus temperature (pejus means "turning worse"), beyond which the ability of animals to increase aerobic metabolism is reduced. This reduction is evident from the decline in aerobic scope, which is defined as the proportional difference between resting and maximal rates of oxygen consumption. The temperature range between the lower and higher pejus temperatures is much narrower than that between the critical temperatures (Tc), beyond which the animal only survives for short periods.
3) As in other animals, continued cardiac function is essential in fish, but coronary circulation is normally sparse. Thus oxygen to the fish heart is primarily provided by the venous blood returning from the body. The oxygen concentration of venous blood declines if cardiac output does not increase in proportion to the rise in metabolism that occurs with elevated temperature. These problems are exacerbated by the fact that the concentration of physically dissolved oxygen in the water declines progressively with increased temperature. As a result, the heart is likely to limit the aerobic scope, rendering the fish more vulnerable to predators and less effective as a forager.
4) The novel discovery of Pörtner and Kunst (5) is their observation of a strong negative correlation between estimated population sizes and summer temperatures over the past ~50 years. On a shorter time scale, the authors also found that warm summers strongly reduced population size the following year. It remains difficult to establish increased temperature as the mechanistic cause for the population decline, but the correlation to the pejus and critical threshold temperatures derived from laboratory data is persuasive.
1. G. R. Walther et al., Nature 416, 389 (2002).
2. A. L. Perry, P. J. Low, J. R. Ellis, J. D. Reynolds, Science 308, 1912 (2005).
3. M. N. Jensen, Science 299, 38 (2003).
4. A. J. Davis et al., Nature 391, 783 (1998).
5. H. O. Pörtner, R. Kunst, Science 315, 95 (2007).
EVOLUTIONARY BIOLOGY: OXYGEN AND CELL MEMBRANES
The following points are made by P. Baudouin-Cornu and D. Thomas (Nature 2007 445:35):
1) For many microorganisms, one cell is adequate; for some plants and animals, billions are scarcely enough. But whatever the number, the cell is the fundamental unit of living matter, and is invariably delineated by a membrane -- the plasma membrane -- that is a selective barrier separating the inside from the outside. Some cells may also contain compartments, which are bounded by further membranes. Communication between intracellular compartments, or between cells and their environment, relies on transmembrane proteins that span the entire biological membrane. Using the unfamiliar prism of atomic rather than amino-acid composition, Acquisti et al (1) show how their inspection of all the transmembrane proteins of 19 contemporary organisms tells us a lot about evolution.
2) Cells are divided into two large groups: eukaryotic, in which the DNA molecules are bounded by a nuclear membrane; and prokaryotic, which have no nuclear membrane. Prokaryotes are never found as complex, multicellular organisms. And whereas prokaryotes possess only simple intracellular compartments, or none at all, all eukaryotic cells contain compartments that are surrounded by two membranes. So understanding how and when compartmentalized cells appeared on Earth is one of the big questions in biology, as is understanding how and when multicellular eukaryotic organisms emerged millions of years later. Acquisti et al (1) provide novel evidence of the absolute requirement of atmospheric oxygen (O2) for these transitions to happen.
3) The "oxygen revolution" stems from the first appearance, 3 billion years ago, of organisms releasing O2 as a metabolic waste. This process led to a first great "oxygenation event", 800 million years later, with a second one occurring one billion years ago. This second event is believed to have eventually fuelled the appearance of complex life-forms during the Cambrian explosion about 543 million years ago (2). More recently, 425 million years ago, O2 levels were a major factor in the progressive adaptation of aquatic arthropods and vertebrates to terrestrial life (3). Accordingly, evolutionary analyses encompassing the past 2.3 billion years have revealed a correlation between increased organism complexity and the development of aerobic metabolism (4).
4) Two explanations have been given for this correlation, both invoking metabolic fitness. The first is that, compared with their anaerobic ancestors, oxygen-respiring cells are highly efficient energy-extracting machines: cells can use O2 as an electron acceptor in respiration processes, and because of its high reduction potential, the maximum energy can then be released from nutritional resources. A second, complementary explanation stems from the observation that O2 allows a thousand more metabolic reactions than can occur in anoxic conditions (5).
5) Acquisti et al (1) now propose a third explanation, this one based on functional constraints. They argue that in low O2 conditions it was impossible for cells to synthesize or maintain novel communication-related transmembrane proteins. Such proteins would be required for intracellular compartments to work together, a prerequisite to compartmentalization. Because evolution from unicellular to multicellular organisms requires efficient communication between cells, this evolutionary step was similarly hindered by insufficient levels of O2. Acquisti and colleagues' analyses suggest that the main distinctive feature of these novel transmembrane proteins is that they are enriched in oxygen atoms: in particular, their oxygen-rich external domains are longer than those of transmembrane proteins from uncompartmentalized cells.
1. Acquisti, C., Kleffe, J. & Collins, S. Nature 445, 47-52 (2007).
2. Knoll, A. H. Life on a Young Planet: The First Three Billion Years of Evolution on Earth (Princeton Univ. Press, 2003).
3. Ward, P., Labandeira, C., Laurin, M. & Berner, R. A. Proc. Natl Acad. Sci. USA 103, 16818-16822 (2006).
4. Hedges, S. B., Blair, J. E., Venturi, M. L. & Shoe, J. L. BMC Evol. Biol. 4, 2 (2004).
5. Raymond, J. & Segrè, D. Science 311, 1764-1767 (2006).
PLANETARY SCIENCE: METHANE LAKES ON TITAN
The following points are made by Christophe Sotin (Nature 2007 445:29)
1) The saturnian moon Titan is the second largest satellite in the Solar System, trumped only by Jupiter's Ganymede. It is the only Solar System satellite with a dense atmosphere, which produces a surface pressure 1.5 times that at Earth's surface. And it shares with Earth the peculiarity that nitrogen is the principal component of its atmosphere. The list of similarities does not end there, and, as Stofan et al (1), it has just been augmented by an account of what seem to be lakes at high northern latitudes on Titan.
2) The lakes are not formed of water, as they would be in earthly climes, but of the second most abundant component of Titan's atmosphere, methane (CH4). The bounteous presence of methane and aerosols in Titan's enveloping cloak hides the surface of the moon at visible wavelengths. For this reason, little was known about Titan's inner life before the arrival of the joint NASA/European Space Agency Cassini-Huygens mission in the Saturn system on 1 July 2004.
3) The lifetime of methane is short on geological timescales: the molecule lasts some tens of millions of years before it becomes dissociated by sunlight. Before the first results arrived from Cassini-Huygens, two hypotheses had been advanced to explain how, in the face of this slow depletion, Titan replenishes its atmospheric methane. First, that a methane-rich hydrocarbon ocean covers Titan's solid surface, and supplies the atmosphere in a cycle of evaporation and condensation (2). Alternatively, that underground methane reservoirs exist just below the surface or deep in Titan's interior, which deliver methane to the outside through "cryovolcanic" processes or when the surface is punctured by meteorite impacts. The first of these pictures was the more popular, and would have made Titan even more similar to Earth, with the extraordinary shared feature of a surface ocean. The Huygens probe, which was to be released by the Cassini spacecraft as it flew past Titan, was designed to survive for several minutes on reaching the assumed ocean's surface.
4) On 26 October 2004, a few months before it did release Huygens, Cassini performed its first close fly-by of Titan, skimming its atmosphere 1174 kilometres from the surface. Three remote-sensing instruments trained on the surface failed to detect a global ocean. What they detected instead was even more fascinating: impact craters, mountains, cryovolcanoes, dunes and river beds (3). The lack of a global ocean and the discovery of these surface features, together with characteristics of Titan's atmosphere such as its nitrogen and carbon isotopic ratios (4), strongly implied that the source of the atmospheric methane was internal. With Stofan and colleagues' discovery (1) of lakes at northern latitudes, the pendulum starts to swing the other way once more.(5)
1. Stofan, E. R. et al. Nature 445, 61-64 (2007).
2. Lunine, J. I., Stevenson, D. J. & Yung, Y. L. Science 222, 1229-1230 (1983).
3. Elachi, C. et al. Science 308, 970-974 (2005).
4. Niemann, H. et al. Nature 438, 779-784 (2005).
5. Tomasko, M. G. et al. Nature 438, 765-778 (2005).