Molecular clocks: when times are a-changin'

The molecular clock has proved to be extremely valuable in placing timescales on evolutionary events that would otherwise be difficult to date. However, debate has arisen about the considerable disparities between molecular and palaeontological or archaeological dates, and about the remarkably high mutation rates inferred in pedigree studies. We argue that these debates can be largely resolved by reference to the "time dependency of molecular rates", a recent hypothesis positing that short-term mutation rates and long-term substitution rates are related by a monotonic decline from the former to the latter. Accordingly, the extrapolation of rates across different timescales will result in invalid date estimates. We examine the impact of this hypothesis with respect to various fields, including human evolution, animal domestication and conservation genetics. We conclude that many studies involving recent divergence events will need to be reconsidered.     

When clocks go bad: neurobehavioural consequences of disrupted circadian timing

Progress in unravelling the cellular and molecular basis of mammalian circadian regulation over the past decade has provided us with new avenues through which we can explore central nervous system disease. Deteriorations in measurable circadian output parameters, such as sleep/wake deficits and dysregulation of circulating hormone levels, are common features of most central nervous system disorders. At the core of the mammalian circadian system is a complex of molecular oscillations within the hypothalamic suprachiasmatic nucleus. These oscillations are modifiable by afferent signals from the environment, and integrated signals are subsequently conveyed to remote central neural circuits where specific output rhythms are regulated. Mutations in circadian genes in mice can disturb both molecular oscillations and measurable output rhythms. Moreover, systematic analysis of these mutants indicates that they can express an array of abnormal behavioural phenotypes that are intermediate signatures of central nervous system disorders. Furthermore, the response of these mutants to psychoactive drugs suggests that clock genes can modify a number of the brain’s critical neurotransmitter systems. This evidence has led to promising investigations into clock gene polymorphisms in psychiatric disease. Preliminary indications favour the systematic investigation of the contribution of circadian genes to central nervous system disease.     

Pathogen evolution: How good bacteria go bad

Recent findings suggest that dysentery-causing Shigella strains have arisen several times from Escherichia coli via plasmid acquisition and phenotypic convergence. Similarly, three Bacillus strains with distinct pathogenic properties are derivatives of a single species whose behavior is profoundly altered by acquired plasmids.     

Oogenesis: when most is good enough

In male meiosis an unaligned chromosome blocks meiotic progression. However, oocytes with one or more misaligned chromosomes can complete meiosis. This difference reflects a more permissive role of the spindle assembly checkpoint, rather than solely reflecting the ability of some univalents to adopt a meiosis II-like orientation on the spindle.     

Deciding group movements: Where and when to go

A group of animals can only move cohesively, if group members “somehow” reach a consensus about the timing (e.g., start) and the spatial direction/destination of the collective movement. Timing and spatial decisions usually differ with respect to the continuity of their cost/benefit distribution in such a way that, in principle, compromises are much more feasible in timing decision (e.g., median preferred time) than they are in spatial decisions. The consequence is that consensus costs connected to collective timing decisions are usually less skewed amongst group members than are consensus costs connected to spatial decisions. This, in turn, influences the evolution of decision sharing: sharing in timing decisions is most likely to evolve when conflicts are high relative to group cohesion benefits, while sharing in spatial decisions is most likely to evolve in the opposite situation. We discuss the implications of these differences for the study of collective movement decisions.     

When good organs go to bad people

A number of philosophers have argued that alcoholics should receive lower priority for liver transplantations because they are morally responsible for their medical conditions. In this paper, I argue that this conclusion is false. Moral responsibility should not be used as a criterion for the allocation of medical resources. The reason I advance goes further than the technical problem of assessing moral responsibility. The deeper problem is that using moral responsibility as an allocation criterion undermines the functioning of medicine.     

Circadian biology: clocks within clocks

A small cluster of approximately 20,000 neurons in the ventral hypothalamus provide the body with key time-keeping signals and drive circadian rhythms. This circadian clock exhibits surprisingly complex substructures, with inputs from the retina, and outputs to other brain structures. Rather little is known of the neurotransmitters involved, or their regulation.     

Blood loses it when nerves go bad

Myeloproliferative neoplasms are diseases that arise in the stem cells of the blood. In a recent paper published in Nature, Arranz et al. demonstrated that abrogation of sympathetic nerve fibers reduced bone marrow Nestin⁺ mesenchymal cells, which in turn led to an expansion of hematopoietic stem cells and progression of myeloproliferative neoplasms.The stromal cell compartment, or non-hematopoietic cells, of the bone marrow has emerged as an important driver of cell state in hematopoietic stem cells (HSCs) and hematopoietic stem/progenitor cells (HSPCs) in a non-autonomous manner. The HSC niche is not well defined and a number of studies suggest that there are specialized niches for the unique regulation of HSCs and HSPCs¹. Several studies suggest that HSCs reside in a perivascular niche in which a heterogenic population of perivascular mesenchymal stromal cells (MSCs) with overlapping expression of Nestin, LepR, Prx1, or Mx1 each synthesize multiple factors (e.g., CXCL12 and SCF) that promote maintenance and/or localization of HSCs^1,2. Endothelial cells (Tie2⁺)³, and MSCs (NG2⁺/LepR⁻) surrounding arterial vessels⁴, are other units of the niche reported to regulate HSC numbers and quiescence, respectively. Furthermore, osteoprogenitors lining the endosteal surface have a more indirect role in the regulation of HSCs⁶. Thus, it appears that hematopoietic regulation and differentiation in the bone marrow microenvironment is governed at multiple levels⁵.Increasing evidence suggests that dysregulation of the bone marrow microenvironment may participate in blood malignancies. For instance, perturbations of the miRNA processing or ribosomal components through Dicer1 deletion in immature osteolineage cells induced myelodysplasia in mice, followed by the rare emergence of acute myeloid leukemia (AML)⁶. Others reported that β-catenin stabilization in mature osteolineage cells resulted in Notch pathway activation, myelodysplastic syndrome, and highly penetrant AML in mice⁷. In humans, ∼5% of post-transplant AML patients relapse with a leukemia of donor cell origin, suggesting that some patients may have a microenvironmental driver of leukemogenesis⁸. Together, these studies are consistent with a role of the bone marrow microenvironment in maintaining the integrity of hematopoiesis and restricting oncogenesis. When the well-orchestrated regulation of hematopoiesis is disrupted, blood malignancies might occur.The study by Arranz et al.⁹ is a continuation of prior work identifying perivascular bone marrow Nestin⁺ MSCs affected by sympathetic nerve fibers to regulate HSCs¹⁰. Previous studies that a perturbed bone marrow microenvironment modulates myeloproliferative neoplasms (MPNs)^6,7 prompted the authors to further investigate the role of Nestin⁺ MSCs in MPN, specifically MPN associated with Janus kinase 2 (JAK2) mutations^11,12.The authors first analyzed Nestin expression in bone marrow samples from MPN patients and discovered that despite elevated blood-vessel density, Nestin⁺ cell numbers and mRNA expression were reduced. Similar findings were observed in genetically engineered mice that recapitulate human MPNs (e.g., Mx1-cre; JAK2^V617F), indicating that Nestin⁺ MSCs might play a role in MPN. Arranz et al. proceeded to investigate whether a selective depletion of Nestin⁺ MSCs mimics the MPN mouse model. Mice depleted of Nestin⁺ MSCs showed an expansion of HSCs, due to a drop in CXCL12 expression, accompanied by increased hematopoietic progenitors in bone marrow, peripheral blood and spleen, indicative of MPN. Extensive genome-wide RNA-sequencing studies revealed enrichment of Schwann cell- and neural-related genes in Nestin⁺ MSCs derived from MPN mice. This result prompted the authors to explore the role of sympathetic nerve fibers and nonmyelinating Schwann cells in MPN patients and the MPN mouse model. Strikingly, both MPN patients and MPN mice had reduced sympathetic nerve fibers and nonmyelinating Schwann cells adjacent to Nestin⁺ cells in the bone marrow. Multiplex ELISA experiments identified that mutant HSCs secrete IL-1β, which induced apoptosis in bone marrow Schwann cells by Caspase-1 activation followed by neuronal damage. Neural-glial damage in turn compromised Nestin⁺ MSCs survival and led to MPN. Finally, the authors rescued the MPN phenotype partially in MPN mice by treating the mutant mice with IL-1R antagonist, a neuroglial protection agent (4-methylcatechol), or a β3-adrenergic agonist (BRL37344) which compensated for deficient sympathetic stimulation. This treatment was selective against mutant hematopoietic progenitors and preserved normal HSCs, and this effect could only be observed in vivo. Therefore, the authors concluded that the effect was niche-dependent (Figure 1).Open in a separate windowFigure 1Bone marrow neuropathy leads to mutant HSC expansion in MPN. (1) IL-1β is released by mutant HSCs, which induces Caspase-1-dependent apoptosis in sympathetic nerve fibers, ensheathed by nonmyelinating Schwann cells. (2) Neural-glial damage leads to a reduced noradrenergic sympathetic stimulation of Nestin⁺ MSCs and loss of MSCs. (3) Aberrant neural regulation sensitizes Nestin⁺ MSCs to IL-1β-induced apoptosis with a subsequent drop in CXCL12 expression. (4) HSC and progenitor cell proliferation is increased, followed by MPN pathogenesis. (5) Nestin⁺ MSCs survival and function can be restored by the neuroglial protective agent 4-methylcatechol, the β3-adrenergic agonist BRL37344, or by blocking IL-1R. MPN, myeloproliferative neoplasm; HSC, hematopoietic stem cell; MSC, mesenchymal stem cell; NA, noradrenaline; AR, adrenergic receptor; IL, Interleukin; IL-1R, Interleukin-1 receptor.While the prevailing understanding of cancer as a disease in which changes in the cell of origin drive oncogenic transformation, these studies point to the potential for the microenvironment as a critical cooperator in the malignant process for at least some neoplasms. This study emphasizes that there may be a two-way perturbation process required for MPN. HSCs acquire a mutation (e.g., JAK2-V617F mutation) that leads to cell expansion and the mutant HSC perturbs the bone marrow niche, which further drive HSCs into neoplasia. Based on these findings, the authors postulated that neural-glial protective agents and β3-adrenergic agonists may subvert the process and be therapeutically useful. Therefore, this model provides insight into how the neural compartment of the bone marrow microenvironment can serve as a modulator of malignancy and offers a novel, testable approach for treating MPNs — by not only targeting the malignant cell, but also by selectively targeting the unhealthy niche.     

Hibernation in garter snakes (Thamnophis sirtalis parietalis): seasonal cycles of cold tolerance

1. The red-sided garter snake hibernates for about six months each year in Manitoba, Canada, where winter temperatures are often as low as -40 degrees C. Mammalian hibernators typically undergo profound changes in preparation for hibernation, but little is known about corresponding changes in reptiles. 2. We tested the importance of seasonal changes in the ability of red-sided garter snakes to hibernate successfully by exposing them to winter conditions at different times of year. 3. Animals that began hibernation in the fall were more likely to survive hibernation than animals that began hibernation in either early or late summer, despite the fact that the animals were kept on seasonally constant conditions prior to hibernation. 4. We suggest that these changes are derived from endogenous components of the yearly hibernation cycle of red-sided garter snakes but that only part of the cycle proceeds endogenously, i.e. it is not a completely endogenous circannual cycle.     

Inferring clocks when lacking rocks: the variable rates of molecular evolution in bacteria

Background  

Because bacteria do not have a robust fossil record, attempts to infer the timing of events in their evolutionary history requires comparisons of molecular sequences. This use of molecular clocks is based on the assumptions that substitution rates for homologous genes or sites are fairly constant through time and across taxa. Violation of these conditions can lead to erroneous inferences and result in estimates that are off by orders of magnitude. In this study, we examine the consistency of substitution rates among a set of conserved genes in diverse bacterial lineages, and address the questions regarding the validity of molecular dating.