What is it? An aid to calculation in population genetics, introduced by Sewall Wright. The rate of change of the genetic make-up of a population by genetic drift – fluctuations in allele frequencies caused by random sampling – is inversely related to the effective population size, Ne. Ne is measured with reference to an ideal ‘Wright–Fisher’ population. This has a fixed number of N diploid breeding individuals, with no distinction of sex. Each new generation is formed by sampling genes randomly from the parents of the previous generation. The rate at which selectively neutral variability is lost from the population is then equal to 1/(2N). In the messier real world, there may be two different sexes, population size may change, individuals may differ in their reproductive success and there may be overlapping generations. If you are clever enough, you can write down an expression for the rate of drift per generation in such cases. This is then equated to 1/(2Ne). Ne is usually substantially smaller than the census number of breeding individuals.Why is it useful? Genetic drift is a major factor in DNA sequence evolution. To make sense of the data, we need evolutionary models which include genetic drift. By plugging Ne into the relevant equations, we can write down general expressions, instead of having to work out new results for each type of population. For example, a favourable new mutation which increases the fitness of its carriers by a small amount s has a chance of spreading of 2(Ne/N)s in a population of size N and effective size Ne. Reducing Ne relative to N thus reduces the chance that a favourable mutation will spread.Similarly, the chance that a deleterious mutation can get fixed against selection is increased by a reduction in Ne, and approaches the value for a neutral mutation when |Nes|⪡1. The equilibrium level of within-population variability for neutral or nearly-neutral variants is controlled by the product of the mutation rate and Ne, so that Ne plays an important role in the interpretation of data on single nucleotide polymorphisms, a major focus of contemporary human genetics.What influences Ne? If population size changes, the long-term value of Ne, which controls the level of neutral variability, is the harmonic mean (reciprocal of the mean of the reciprocals) of the series of values for each generation. A population that has recently expanded, like our own, has a much smaller Ne than indicated by its current size. In the human case, levels of variability indicate that Ne is close to 10,000, reflecting the population size in the remote past. Ne is affected by mode of inheritance, so that X-linked, Y-linked and organelle genes each have their own Ne values, which differ from that for autosomal genes. Ne is also influenced by natural or artificial selection, which induce heritable variation in fitness. Selection at sites linked to a gene under study may greatly reduce its Ne value. This means that genomic regions with low levels of genetic recombination, where genes tend to be tightly linked to each other, may have lower than average levels of variability and adaptation.
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The intracellular movement of the bacterial pathogen Listeria monocytogenes has helped identify key molecular constituents of actin-based motility (recent reviews ). However, biophysical as well as biochemical data are required to understand how these molecules generate the forces that extrude eukaryotic membranes. For molecular motors and for muscle, force-velocity curves have provided key biophysical data to distinguish between mechanistic theories. Here we manipulate and measure the viscoelastic properties of tissue extracts to provide the first force-velocity curve for Listeria monocytogenes. We find that the force-velocity relationship is highly curved, almost biphasic, suggesting a high cooperativity between biochemical catalysis and force generation. Using high-resolution motion tracking in low-noise extracts, we find long trajectories composed exclusively of molecular-sized steps. Robust statistics from these trajectories show a correlation between the duration of steps and macroscopic Listeria speed, but not between average step size and speed. Collectively, our data indicate how the molecular properties of the Listeria polymerization engine regulate speed, and that regulation occurs during molecular-scale pauses.
Inositol 1,3,4,5-tetrakisphosphate (IP4), is a ubiquitous inositol phosphate that has been suggested to function as a second messenger. Recently, we purified and cloned a putative IP4 receptor, termed GAP1(IP4BP), which is also a member of the GAP1 family of GTPase-activating proteins for the Ras family of GTPases. A homologue of GAP1(IP4BP), called GAP1(m), has been identified  and here we describe the cloning of a GAP1(m) cDNA from a human circulating-blood cDNA library. We found that a deletion mutant of GAP1(m), in which the putative phospholipid-binding domains (C2A and C2B) have been removed, binds to IP4 with a similar affinity and specificity to that of the corresponding GAP1(IP4BP) mutant. Expression studies of the proteins in either COS-7 or HeLa cells showed that, whereas GAP1(IP4BP) is located solely at the plasma membrane, GAP1(m) seems to have a distinct perinuclear localisation. By mutational analysis, we have shown that the contrast in subcellular distribution of these two closely related proteins may be a function of their respective pleckstrin homology (PH) domains. This difference in localisation has fundamental significance for our understanding of the second messenger functions of IP4.
Ryanodine and inositol 1,4,5-trisphosphate (IP(3)) receptors - two related families of Ca(2+) channels responsible for release of Ca(2+) from intracellular stores  - are biphasically regulated by cytosolic Ca(2+)   . It is thought that the resulting positive feedback allows localised Ca(2+)-release events to propagate regeneratively, and that the negative feedback limits the amplitude of individual events  . Stimulation of IP(3) receptors by Ca(2+) occurs through a Ca(2+)-binding site that becomes exposed only after IP(3) has bound to its receptor  . Here, we report that rapid inhibition of IP(3) receptors by Ca(2+) occurs only if the receptor has not bound IP(3). The IP(3) therefore switches its receptor from a state in which only an inhibitory Ca(2+)-binding site is accessible to one in which only a stimulatory site is available. This regulation ensures that Ca(2+) released by an active IP(3) receptor may rapidly inhibit its unliganded neighbours, but it cannot terminate the activity of a receptor with IP(3) bound. Such lateral inhibition, which is a universal feature of sensory systems where it improves contrast and dynamic range, may fulfil similar roles in intracellular Ca(2+) signalling by providing increased sensitivity to IP(3) and allowing rapid graded recruitment of IP(3) receptors.
Polarized migration and spreading of epithelial sheets is important during many processes in vivo, including embryogenesis and wound healing. However, the signaling pathways that regulate epithelial migrations are poorly understood. To identify molecular components that regulate the spreading of epithelial sheets, we performed a screen for mutations that perturb epidermal cell migration during embryogenesis in Caenorhabditis elegans. We identified one mutant (jc5) as a weak mutation in itr-1, which encodes the single inositol 1,4,5-trisphosphate receptor (ITR) in C. elegans. During the migration of the embryonic epidermis, jc5 embryos display defects including misdirected migration or premature cessation of migration. Cells that halt their migration have disorganized F-actin and display reduced filopodial protrusive activity at their leading edge. Furthermore, some filopodia formed by epidermal cells in itr-1(jc5) embryos exhibit abnormally long lifetimes. Pharmacological studies with the inositol 1,4,5-trisphosphate antagonist xestospongin C phenocopy these defects, confirming that ITR function is important for proper epidermal migration. Our results provide the first molecular evidence that movements of embryonic epithelial cell sheets can be controlled by ITRs and suggest that such regulation may be a widespread mechanism for coordinating epithelial cell movements during embryogenesis.
Brain regions beyond visual cortex are thought to be responsible for attention-related modulation of visual processing 1 and 2, but most evidence is indirect. Here, we applied functional magnetic resonance imaging (fMRI), including retinotopic mapping of visual areas, to patients with focal right-parietal lesions and left spatial neglect 3 and 4. When attentional load at fixation was minimal, retinotopic areas in right visual cortex showed preserved responses to task-irrelevant checkerboards in the contralateral left hemifield, analogously to left visual cortex for right-hemifield checkerboards, indicating a “symmetric” pattern in both hemispheres with respect to contralateral stimulation under these conditions. But when attentional load at fixation was increased, a functional asymmetry emerged for visual cortex, with contralateral responses in right visual areas being pathologically reduced (even eliminated for right V4/TEO), whereas left visual areas showed no such reduction in their contralateral response. These results reveal attention-dependent abnormalities in visual cortex after lesions in distant (parietal) regions. This may explain otherwise puzzling aspects of neglect 5 and 6, as confirmed here by additional behavioral testing.
Condensin complexes organize chromosome structure and facilitate chromosome segregation. Higher eukaryotes have two complexes, condensin I and condensin II, each essential for chromosome segregation. The nematode Caenorhabditis elegans was considered an exception, because it has a mitotic condensin II complex but appeared to lack mitotic condensin I. Instead, its condensin I-like complex (here called condensin I(DC)) dampens gene expression along hermaphrodite X chromosomes during dosage compensation.
Here we report the discovery of a third condensin complex, condensin I, in C. elegans. We identify new condensin subunits and show that each complex has a conserved five-subunit composition. Condensin I differs from condensin I(DC) by only a single subunit. Yet condensin I binds to autosomes and X chromosomes in both sexes to promote chromosome segregation, whereas condensin I(DC) binds specifically to X chromosomes in hermaphrodites to regulate transcript levels. Both condensin I and II promote chromosome segregation, but associate with different chromosomal regions during mitosis and meiosis. Unexpectedly, condensin I also localizes to regions of cohesion between meiotic chromosomes before their segregation.
We demonstrate that condensin subunits in C. elegans form three complexes, one that functions in dosage compensation and two that function in mitosis and meiosis. These results highlight how the duplication and divergence of condensin subunits during evolution may facilitate their adaptation to specialized chromosomal roles and illustrate the versatility of condensins to function in both gene regulation and chromosome segregation.