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PubMed1977

Epigenetic variation of cultured somatic cells: evidence for gradual changes in the requirement for factors promoting cell division.

Cells of higher plant species in culture sometimes lose their requirement for an exogenous supply of a cell division factor that, thereafter, they are able to produce. This heritable change, known as cytokinin habituation, appears to be an epigenetic one rather than a classical mutation because it is directed, potentially reversible, leaves the cell totipotent, and involves the expression of a latent differentiated function. By using cloned cell lines derived from pith parenchyma of tobacco, we have obtained evidence that the habituation process is gradual rather than all-or-none and leads to progressively more autotrophic tissues. Cells in culture show reversible shifts among a range of habituated states but remain totipotent and can be induced to regain their requirement for a cell division factor. Thus, it appears that habituation involves epigenetic changes in a quantitative cellular phenotype. Our findings support the hypothesis that tumor progression in crown gall, a neoplastic disease of higher plants, can be accounted for by heritable changes in the pattern of gene expression.

Cell Differentiation↗

PubMed1975

A study of hypothalmic neurosecretory cells of bullfrogs in vitro.

Neurosecretory cells of preoptic nuclei of bullfrogs were studied in isolated hypothalamo-hypophysial preparations under constant perfusion with oxygenated Ringer solution at 15-17 degress C. Antidromic potentials were recorded following stimuli applied to the posterior lobe of the pituitary or the stalk. 2. Intracellularly and extracellularly recorded potentials resembled those obtained in vivo from neurosecretory cells of the mammalian hypothalamus. They were unique in that the antidromic potential had a long duration (10-20 msec) and a distinct notch on the rising phase (between A and B spikes). The conduction velocity of the stalk fibres in vitro at this temperature was 0-1--0-2 m/sec. 3. When two successive stimuli were given to the posterior lobe or to the stalk separated by intervals of between 30 and 65 msec, the test (second) response showed a longer delay of the B spike. This delay between the A and B components was as long as 10 msec. Further shortening of stimulus intervals produced block of B spikes in the test response. A complete separation of A and B spikes occur spontaneously in a few instances. 4. Evidence indicated that inhibitory recurrent axon collaterals play a role in the control of bullfrog neurosecretory cells. Antidromic potentials were inhibited by a 'conditioning' stimulus for as long as 300-400 msec, even when the stimulus did not evoke an antidromic potential. 5. It was found that in addition to the inhibitory interaction there is a facilitatory recurrent axon collateral system which operates within the nuclei. The evidence for this is: (1) stimulation of the posterior lobe, with single subthreshold pulses evoked an action potential if preceded by another stimulus of subthreshold or just threshold intensity. The durations of such facilitatory effects were found to be 20--400 msec; (2) a single pulse given to the posterior lobe did occasionally evoke two spikes from neurosecretory cells; the second spike which occurred 15-30 msec after the first had the characteristics of a trans-synaptically produced potential; (3) gradual changes in the intensity of stimuli applied to the neural lobe produced a sudden shift in latencies ranging between 15 and 30 msec. The potentials having long latency also showed characteristics of those transsynaptically excited. In addition, an increase in excitability of neurosecretory cells by antidromic stimulation was confirmed by using orthodromically induced action potentials in in vivo studies. Possible functional significance of inhibitory and excitatory recurrent collateral system in neurosecretory cells was discussed. 6. Two to threefold increase in NaCl concentration of a perfusate slightly increased the latency and refractory period of antidromic potential but not the shape of the potential. Norepinephrine added to a perfusate (1 mug/ml). augmented the separation of A and B spikes of the antidromic potential. Acetylcholine at a concentration of 1 mug/ml. did not have an appreciable effect on the antidromic potential.

Acetylcholine↗

PubMed1977

Osmotic adaptation to rigid contact lenses.

Using a precision thermocouple hygrometer, requiring just 5 microliters of sample, the tear osmotic pressures of 6 subjects were monitored throughout their adaptation to rigid contact lenses. Relative to the prefitting baselines established for each previous to this study, these subjects showed a range of hypotonic shifts on initially receiving their lenses, but this imbalance was rectified by the end of the first wearing week and a new relatively hypertonic level of tear osmotic pressure was commonly established. This new baseline was reflected in the pre-insertion samples of several of the subjects as well once adaptation was advanced.

Adaptation, Physiological↗

PubMed1979

[Relationship between the minute superslow oscillations and the level of energy supply in brain tissue].

In animals, an increase in glycolysis intensity and processes of oxidative phosphorylation in the brain correlated with the steady potential shifts within the range of 0--1.0 Hz in the neocortex, dorsal hippocampus, and thalamic nuclei. The neurotropic drug ethymizol revealed two effects depending on the initial functional state of the rabbit: 2.5 mg/kg of the drug enhanced the amplitude of the minute waves in the frontal neocortex and dorsal hippocampus, increasing the metabolic rate in the unsteady period of conditioning, whereas after the fast conditioning the drug rendered background values to the minute oscillations and elongated the extinction of conditioned reflexes. The ethymizol appears to be an unspecific connector.

Animals↗

PubMed1979

Carcinogenesis in tissue culture 30: malignant transformation of normal rat liver cells treated with diethylnitrosamine in tissue culture with special reference to the differential effects of cytochalasin B on various cells with and without tumorigenicity.

Liver tissue of a suckling rat was cultured. After 3 weeks of cultivation, the cultures consisting of epithelial cells were treated with 50 micrograms/ml or 100 micrograms/ml DEN for 7 days. 5 months after the treatment, the mode of chromosome number was found decreased from 42 to 40 in the 100 micrograms/ml DEN-treated group and shifted to triploid range after 21 months. The mode in the 50 micrograms/ml DEN-treated group maintained the diploid number until the 5th month but was found reduced to 40 in 21 months. On subcutaneous backtransplantation into young rats at the 22nd month, the treated cells produced tumors at the site inoculated in all the rats. Metastatic foci were also detected in lungs. These tumors were histologically diagnosed as hepatomas. Untreated control cells did not produce tumors. The differential effects of cytochalasine B on the cells with and without tumorigenicity were examined by the use of these cells and other cells, and it revealed that the capacity of multinucleated cell-formation by cytochalasin B fairly corresponds with the backtransplantability of the cells. Binucleated cell formation, not more than 2 nuclei, in the culture of normal cells was found by time-lapse cinemicrography to be not due to the non-capacity of multinucleation but to the destruction of multinucleated cells.

Animals↗

PubMed1977

[Further fields of application of the infrared false colour film in ophthalmological photography (author's transl)].

Aside from the distinction between old hemorrhages and pigmented changes of the ocular fundus, the use of metaspectrophotography of the eye with the Kodak Ektrachrome Infrared Film IE 135-20 can be extended successfully to other fields of ophthalmological photography. By shifting the spectral range used for photography towards near infrared and cutting off the short wavelenght part by a yellow filter, spoiling scattering is avoided up to 98 percent. Thus clear goniophotography is rendered possible even with higher magnification. Better pictures are achieved in photography of the periphery of the ocular fundus, of the fundus of eyes with moderate opacity of the cristalline lens, of juvenile macular degeneration, and of pigmented areas of the iris suspected to be tumorous.

Eye Diseases↗

PubMed1976

DNA "melting" proteins. III. Fluorescence "mapping" of the nucleic acid binding site of bacteriophage T4 gene 32-protein.

The intrinsic tryptophan fluorescence of bacteriophage T4-coded gene 32-protein is found to be partially quenched on binding a variety of mono-, oligo-, and polynucleotides. This phenomenon is exploited to partially "map" the nucleic acid binding site of the protein. The intrinsic fluorescence spectrum of the protein peaks at about 347 nm, compared to 359 nm for the fully solvated model fluorophore, N-acetyl-L-tryptophanamide. Nucleotide binding, or collisional quenching by iodide ion, reduces the intensity of the fluorescence, with little or no peak shift. Small ligands, ranging in size from ribose- and deoxyribose-phosphate to tetranucleotides, quench the fluorescence by 2 to 6%; larger ligands quench from 20 to 35% of the intrinsic protein fluorescence. Iodide quenching experiments subjected to Stern-Vollmer analysis suggest that the binding of short nucleotide-containing ligands brings about a conformational change in the protein, fully exposing a tryptophan side chain to the solvent environment. The fluorescence of this tryptophan is fully quenched by the binding of d(Ap)2, but is largely unaffected by the binding of d(ApA) or d(pA)2, indicating both that this (tryptophan) "reporter" residue is located in the nucleic acid binding site and that binding is polar, i.e. polynucleotide chains of only one orientation are complexed. Long oligonucleotides fully quench the fluorescence of this binding site tryptophan. At high salt concentration (2 M NaCl), gene 32-protein forms self-limited dimers (Carroll, R.B., Neet, K.E., and Goldthwait, D.A. (1972) Proc. Natl, Acad. Sci. U.S.A. 69, 2741-2744; (1975) J. Mol. Biol. 91, 275-291). These dimers, in either high salt or in low salt after cross-linking, fail to bind nucleotides, suggesting that dimer formation partially occludes the nucleic acid binding site and thus that these dimers are probably not involved as intermediates in cooperative protein binding to the DNA. On the other hand, dimerization apparently results in a conformational change which fully exposes the "reporter" tryptophan to iodide quenching. These results are used to formulate a model of some of the nucleic acid-protein and protein-protein interactions involved in the cooperative binding of gene 32-protein to single-stranded DNA.

Binding Sites↗

PubMed1976

Effect of bovine serum albumin on monoacyl- and diacylglycerol 3-phosphate formation in mitochondrial and microsomal fractions of rabbit hearts.

The formation of monoacyl- and diacylglycerol 3-phosphate (P) by rabbit heart mitochondrial and microsomal fractions was studied by varying the concentration of acyl-CoA and that of bovine serum albumin in the assay system. The two subcellular fractions were prepared by the conventional differential centrifugation technique. The optimal concentration of acyl-CoA for both mitochondrial and microsomal acylation of glycerol 3-P was shifted to a higher range of acyl-CoA concentrations by greater amounts of albumin. A similar shift in the acyl-CoA concentration-enzyme activity relationship was observed in the acylation reaction of 1-palmitoylglycerol 3-P by the heart microsomes. The addition of albumin increased slightly the rate of diacylglycerol 3-P accumulation but increased greatly the rate of monoacylglycerol 3-P accumulation at any concentration of acyl-CoA; the effect was observed with mitochondrial or microsomal fraction as the crude enzyme source. Moreover, palmitoyl-CoA and linoleoyl-CoA served equally well as the acyl donor for the acylation reaction. However, relatively more monoacyl- than diacylglycerol 3-P was accumulated in the assays with rabbit heart mitochondrial fraction in the presence of albumin, whereas more diacyl- than monoacylglycerol 3-P was formed by the microsomal fraction. As a result, the microsomal diacyl:monoacyl-glycerol 3-P ratio was invariably greater than the mitochondrial ratio at a given concentration of acyl-CoA and albumin.

Animals↗

PubMed1976

The action of Ca2+ , Mg2+ and H+ on the contraction threshold of frog skeletal muscle: Evidence for surface charges controlling electro-mechanical coupling.

The dependence of the threshold potential for contraction of pH and the concentration of Ca2+ and Mg2+ in the bathing solution was measured in frog skeletal muscle. Decreasing the pH from 10.3 to 4.65 resulted in a threshold shift to more positive potentials. Between pH 6.5 and 8.5 the concentration threshold was almost pH -independent. Increasing [Ca2+]o (in the concentration range 0.5-50 mM) shifted the curves relating contraction threshold to pH to less negative potentials and diminished the overall pH-dependence. The contraction threshold exhibited a similar dependence on [Ca2+]o and [Mg2+]o, the two curves running parallel in the concentration range of 5-50 mM, but Mg2+ was only c. 0.6 as effective as Ca2+. To explain these results a surface charge model is proposed which assumes that two acidic groups, sigma1 and sigma2, and one basic group, sigma3, reside at the outer surface of the membrane of the T-system. Alterations in the extracellular medium exert their influence on the electro-mechanical coupling process by changing the surface potential. The groups will be titrated by protons and their charges screened off by the divalent cations. In addition, Ca2+ was supposed to bind with a weak dissociation constant (23 M) to the two acidic groups. The chosen charge densities are: sigma1 = -0.0085/A2 [= -1e/(10.8 A)2], sigma2 = -0.0037/A2 [= -1e/(16.4 A)2], sigma3 = 0.0028/A2 [= + 1e/(18.9 A)2] with intrinsic dissociation constants KH1 = 10(-2.0)M, KH2 = 10(-4.1)M, and KH3 = 10(-8.5) M. The measured threshold values are satisfactorily described by this model except at extreme alkaline and acid pH values.

Animals↗

PubMed1979

Covalently bound non-coenzyme phosphorus residues in flavoproteins: 31P nuclear magnetic resonance studies of Azotobacter flavodoxin.

In addition to the 5'-phosphate ester on its flavin mononucleotide (FMN) moiety, flavodoxin from Azotobacter vinelandii contains 2 moles of tightly bound phosphate. One non-coenzyme phosphate group is covalently bound to the protein, as it remains with the protein on acid precipitation, whereas the other phosphate is released. The invariance of the (31)P nuclear magnetic resonance chemical shift of the covalently bound phosphate (-0.8 ppm relative to 85% phosphoric acid) with pH, even in the presence of protein denaturants, implies it is in a diester linkage to the protein. Because no evidence could be found for the presence of covalently bound sugars, nucleotides, or phospholipids, it is suggested that the phosphate residue forms a diester linkage with two hydroxyl amino acids in the protein. The only other suggestion of a phosphodiester linkage in proteins is from previous studies on pepsin and pepsinogen [Perlmann, G. E. (1955) Adv. Prot. Chem. 10, 1-30]. The observed changes in (31)P chemical shift with pH show that the covalent phosphorus in pepsinogen has ionization properties of a monoester rather than a diester. The (31)P resonance of the FMN phosphate occurs at -5.6 ppm in native Azotobacter flavodoxin. No ionization of the protein-bound FMN phosphate is observed since the chemical shift does not change appreciably in the pH range of 5.5-9.5. The chemical shift data suggest, but do not prove, that the coenzyme phosphate in its protein-bound form is dianionic. Chemical analysis of several other flavoenzymes from a variety of sources shows the presence of covalently bound phosphorus in quantities stoichiometric with the flavin content in most of the enzymes tested. Thus, the presence of covalent phosphorus in flavoenzymes may be a general phenomenon with currently unknown catalytic significance.

Apoproteins↗

PubMed1976

Response of unmyelinated (C) polymodal nociceptors to thermal stimuli applied to monkey's face.

1. The response of C polymodal nociceptors to thermal and mechanical stimuli applied to the monkey's face was recorded extracellulary in the trigeminal ganglion in rhesus monkeys anesthetized with sodium pentobarbital. Conduction velocities, determined from electrical stimulation of receptive fields (RFs), were in the range for unmyelinated C fibers (mean=0.82 m/s, n=20; SD=+/-0.17). With two exceptions cutaneous RFs were single spots (median=2 mm2; n=37) and usually were identical for thermal and mechanical stimuli. The median force threshold for the sample of units was 1.2 g (von Frey technique; n = 39; range = 0.07-8.5 g). 2. Discharges to thermal stimuli were investigated with a feedback-controlled contact thermode which permitted temperature changes less than or equal 12.0 degrees C/s. Thermal thresholds ranged from 38 degree to 49 degree C (median=46 degrees C; n=37), and maximum discharge frequencies were obtained in the noxious heat range (45-55 degrees C). For a graded series of 5 s duration stimuli from an adapting temperature of 35 degrees C, the number of impulses increased as a monotonic function of stimulus intensity over the range from threshold temperature to 50-53 degrees C. Many stimulus-response functions were positively accelerated, and linear regression analyses showed that most units examined were best fit by nonlinear functions. 3. The typical pattern of activity to 5 s duration temperature shifts into the noxious heat range was a short accelerating burst of impulses followed by deceleration to a lower rate of discharge prior to termination of the stimulus. The temporal profile of the discharge of impulses was virtually identical at different adapting temperatures. In units tested with 30 s duration stimuli at 2-6 degrees C above threshold, the mean frequency of discharge during the final 25 s was 1.46 impulses/s (n=6; SD=+/-0.89). 4. Application of noxious heat stimuli a few degrees above threshold temperature typically sensitized or enhanced the response of the unit to subsequent application of heat stimuli. The signs of sensitization consisted of a decrease in threshold temperature, increased frequency of discharge, decreased latency to the first impulse, and afterdischarges. Units failed to respond throughout the duration of 30 s stimuli if the final temperature exceeded 50 degrees C. Depressed responses were sometimes produced by application of intense (greater than or equal 55 degrees C) stimuli, presumably as a result of partial inactivation of the receptor. 5. In a correlative analysis, the latency and pattern of discharge in a sample of units were compared with escape responses in two monkeys to temperature shifts into the noxious heat range (49 and 51 degrees C). The analysis revealed that the discharge of C polymodal nociceptors alone cannot account for fast escape responses, but the discharge may contribute to escape responses which occur more than 3.5 s after the onset of stimulation.

Adaptation, Physiological↗

PubMed1977

Hypoxic ventilatory response of cats at high altitude: an interpretation of 'blunting'.

Cats acclimatized to a simulated altitude of 5500 m developed attenuated ventilatory response in the hypoxic test range of PAO2 = 60-45 torr, but their CO2 response remained normal, although the curve was shifted to a lower PACO2 range. The acclimatized cats a high respiratory frequency and maintained hyperventilation under normoxia. Cats from 3100 m altitude had hypoxic reponses which were, on the average, slightly below sea level standards, but the difference was not statistically significant. Two cats raised at 4640 m had a normal hypoxic ventilatory response even though the frequency response was 'blunted'. These data suggest the possibility of hypoxic 'threshold' near 5500 m to produce an attenuation effect. Another series of cats acclimatized to 5500 m were tested with more severe hypoxia, and they exhibited brisk ventilatory response in range PAO2, 40-25 torr, although they showed typical 'blunting' in the range PAO2, 60-45 torr. These results suggested that the phenomenon of attenuated hypoxic response at high altitude was a reflection of shift of hypoxic set point to a lower PAO2. Finally, it was shown that the hypoxic responses of 'blunted' animals were restored to normal after mid-collicular decerebration; and that decortication resulted in a typical hyperexcitability of the hypoxic response. These results are discussed in terms of hypothesized suprapontine modulating influences on the control of breathing, and possiblities for a contribution of these mechanisms in pathogenesis of hypoxic 'blunting' are raised.

Acclimatization↗

PubMed2025

Harnessing Landscape Genomics to Evaluate Genomic Vulnerability and Future Climate Resilience in an East Asia Perennial.

In this era of rapid climate change, understanding the adaptive potential of organisms is imperative for buffering biodiversity loss. Genomic forecasting provides invaluable insights into population vulnerability and adaptive potential under diverse climatic conditions, thereby facilitating management interventions and bolstering shaping species-specific germplasm conservation strategies. We primarily employed landscape genomics approaches, leveraging single-nucleotide polymorphisms obtained through whole-genome resequencing of 201 individuals across 43 Rheum palmatum complex populations, to pinpoint adaptive variation and its significance in the context of future climates, delineate seed zones, and establish guidelines for ex situ germplasm conservation. The species complex exhibited strong signatures of local adaptation and differential genomic vulnerabilities across its distribution range, with eastern lineage populations facing significant maladaptation risks under future climate scenarios. Using diverse datasets of putatively adaptive loci and climate change scenarios, we delineated three distinct seed zones within the species' range, estimated varying sample sizes per zone to capture most adaptive diversity, and predicted shifts in seed zone centroids ranging from 48.3 to 359.3 km from historical distributions to mitigate climate change impacts. Collectively, our findings underscore the importance of integrating genomic and environmental data to forecast the adaptive trajectory of an East Asian perennial under anticipated climate changes, guide seed zone delineation for germplasm conservation and enhance population resilience. These results provide a blueprint for designing targeted conservation strategies and restoration plans in other imperilled species.

Climate Change↗

PubMed1978

Aural representation in the Doppler-shifted-CF processing area of the auditory cortex of the mustache bat.

In the mustache bat (Pteronotus pamellii rubiginosus) the frequency and amplitude of an acoustic signal are represented in the coordinates parallel to the surface of the Doppler-shifted-CF (constant frequency) processing area ofthe primary auditory cortex. In this area all cortical neurons studied were excited by contralateral stimuli, and almost all of them were either excited or inhibited by ipsilateral stimuli. These are called E-E (ipsilateral and contralateral excitatory) and I-E (ipsilateral inhibitory and contralateral excitatory) neurons, respectively. The I-E neurons are directionally sensitive, while the E-E neurons are not. The E-E neurons are equally sensitive to echoes between 30 degrees contralateral and 30 degrees ipsilateral. Of the electrode penetrations orthogonal to the Doppler-shifted-CF processing area, 57 percent were characterized by either E-E or I-E neurons. Thus, there are at least two types of binaural columns: E-E columns, mainly located in a ventral part of the Doppler-shifted-CF processing area, where neurons are tuned to weak echoes; and IE columns, mainly distributed in a dorsal part, where neurons are tuned to moderate to intense echoes. Therefore, neurons tuned to weaker echoes integrate or even multiply faint signals from both ears for effective detection of a distant small target, while neurons tuned to moderate to intense echoes are suited for processing directional information and are stimulated when a bat approaches a target at short range. The Doppler-shifted-CF processing area may be considered to consist of two functional subdivisions.

Animals↗

PubMed1979

Very low density and low density lipoprotein subfractions in type III and type IV hyperlipoproteinemia. Chemical and physical properties.

Subfractions of CLDL (VLDL), Sf 100-400; CLDL2, Sf 60--100; VLDL3, Sf 20--60) and LDL (LDL), Sf 12--20; LDL2, Sf 6--12; LDL3, Sf 3--6) were isolated from the plasma of three normal, three type III and four type IV hyperlipoproteinemic subjects. In the type IV group, all VLDL subspecies were of normal composition but were increased in concentration in the order VLDL1 greater than VLDL2 greater than VLDL3. In the same subjects, although LDL2 was lowered and LDL3 increased, the total plasma LDL concentration was normal. All VLDL subfractions were elevated in the type III group, but in this case VLDL3 predominated. These subfractions were enriched in cholesteryl esters and depleted in triglyceride. In the LDL density range there was a shift of mass towards the least dense fraction, LDL1, which was of normal composition. EPR studies of the VLDL and LDL subfractions in a type IV subject demonstrated a decrease in fluidity with increasing density. The major change occurred between VLDL3 and LDL1 and was attributed to a substantial alteration in the cholesteryl ester : triglyceride ratio in the particle. A similar argument was used to explain thction in normal or type IV subjects. Particle diameters, determined by laser light-scattering spectroscopy were in good agreement with the values obtained by electron microscopy. This study provides a baseline for the examination of the relationship between the physical and metabolic properties of VLDL and LDL subfractions in type III and IV hyperlipoproteinemia.

Apolipoproteins↗

PubMed1976

Genetic factors in myopia.

A school population has been screened to locate same-sexed twins with myopia and also to compare intelligence test performance of myopic and nonmyopic individuals. Augmentation of the twin data by a survey of the world literature has led to the identification of a total of 106 MZ twin pairs, 100 of them concordant for myopia, as well as 41 DZ pairs, 12 concordant. Myopic students score eight points higher on IQ tests than nonmyopes, the entire bell shaped distribution curve being shifted to a higher range. The intellectual gain precedes in time the development of nearsightedness.

Adolescent↗

PubMed1976

Proton-nuclear-magnetic-resonance study of the conformation of neurotoxin II from Middle-Asian cobra (Naja naja oxiana) venom.

A proton nuclear magnetic resonance (NMR) study at 100 and 300 MHz of neurotoxin II from the venom of Middle-Asian cobra Naja naja oxiana has been performed in 2H2O and H2O solutions. By means of chemical modification and double resonance all the aromatic residue resonances have been assigned. From the NMR titration curves, pK values of histidine 4 and histidine 31 residues have been determined. For one of the two neighbouring tryptophan residues pH dependence (in the 2-8-pH range) of the chemical shifts of indole protons has been revealed. According to the different sensitivity of the linewidth of indole NH resonances to pH in H2O solution, the accessibility of each of the tryptophan residues has been estimated. Temperature dependence has been observed for the linewidth of the aromatic resonances of the tyrosine 24 residue. Deuterium exchange rates have been measured for amide protons as well as for C(2)H histidine resonances. The NMR data obtained have allowed the conclusions to be made that the two histidine residues and one of the tryptophan residues should be localized on the surface of the protein globule, that arginine residues should be present in the environment of histidine 4, that histidine 31 and the buried tryptophan are possibly localized in close spatial proximity and that the side chain of tyrosine 24 is buried within the protein globule.

Amino Acid Sequence↗

PubMed2026

Fault Lines in the Genome: Somatic DNA Mutations in Aging and Neurodegeneration.

The human genome is both fragile and resilient: prone to alteration yet protected by extensive repair mechanisms. With age, individuals accumulate genetic damage from environmental factors and cell-intrinsic processes, with effects ranging from benign nucleotide shifts to disease-driving mutations. Such alterations to the genetic code outside the germline are described as somatic mutations and display striking heterogeneity across cell types. Recently, somatic mutations have emerged as a hallmark feature of aging in the body's longest-lived tissue: the central nervous system (CNS). The distinctively long lifespan, high metabolism, electrochemical activity, and unique epigenome of CNS cells may render them especially vulnerable to mutational accumulation. The CNS therefore provides a model for understanding how somatic mutations drive cellular dysfunction beyond an established role in cancer. Here, we review the somatic mutations that arise in the brain across lifespan, the mechanisms that lead to their formation, and their potential contributions to aging and age-related disease.

Journal Article↗