Salomon MP et al. (2009) Genetics "Comparing mutational and standing genetic variability for fitness and size in Caenorhabditis briggsae and C. elegans."

Bour W, Phillips N, Baer CF, Salomon MP, Ostrow D, Sylvestre T, Upadhyay A, Keller TE, Blanton D, Levy L

[Genetics, 2009]

The genetic variation present in a species depends on the interplay between mutation, population size, and natural selection. At mutation-(purifying) selection balance (MSB) in a large population, the standing genetic variance for a trait (VG) is predicted to be proportional to the mutational variance for the trait (VM); VM is proportional to the mutation rate for the trait. The ratio VM/VG predicts the average strength of selection (S) against a new mutation. Here we compare VM and VG for lifetime reproductive success (approximately fitness) and body volume in two species of self-fertilizing rhabditid nematodes, Caenorhabditis briggsae and C. elegans, which the evidence suggests have different mutation rates. Averaged over traits, species, and populations within species, the relationship between VG and VM is quite stable, consistent with the hypothesis that differences among groups in standing variance can be explained by differences in mutational input. The average (homozygous) selection coefficient inferred from VM/VG is a few percent, smaller than typical direct estimates from mutation accumulation (MA) experiments. With one exception, the variance present in a worldwide sample of these species is similar to the variance present within a sample from a single locale. These results are consistent with specieswide MSB and uniform purifying selection, but genetic draft (hitchhiking) is a plausible alternative possibility.

Farhadifar R et al. (2016) Genetics "Mutation Is a Sufficient and Robust Predictor of Genetic Variation for Mitotic Spindle Traits in Caenorhabditis elegans."

Andersen EC, Ponciano JM, Baer CF, Needleman DJ, Farhadifar R

[Genetics, 2016]

Different types of phenotypic traits consistently exhibit different levels of genetic variation in natural populations. There are two potential explanations: either mutation produces genetic variation at different rates, or natural selection removes or promotes genetic variation at different rates. Whether mutation or selection is of greater general importance is a longstanding unresolved question in evolutionary genetics. We report mutational variances (VM) for 19 traits related to the first mitotic cell division in C. elegans, and compare them to the standing genetic variances (VG) for the same suite of traits in a worldwide collection C. elegans Two robust conclusions emerge. First, the mutational process is highly repeatable: the correlation between VM in two independent sets of mutation accumulation lines is ~0.9. Second, VM for a trait is a good predictor of VG for that trait: the correlation between VM and VG is ~0.9. This result is predicted for a population at mutation-selection balance; it is not predicted if balancing selection plays a primary role in maintaining genetic variation.

Etienne V et al. (2015) Evolution "The red death meets the abdominal bristle: polygenic mutation for susceptibility to a bacterial pathogen in Caenorhabditis elegans."

Blanton D, Ponciano JM, Cadavid A, Joyner-Matos J, Baer CF, Andersen EC, Matsuba C, Etienne V, Tabman B

[Evolution, 2015]

Understanding the genetic basis of susceptibility to pathogens is an important goal of medicine and of evolutionary biology. A key first step toward understanding the genetics and evolution of any phenotypic trait is characterizing the role of mutation. However, the rate at which mutation introduces genetic variance for pathogen susceptibility in any organism is essentially unknown. Here, we quantify the per-generation input of genetic variance by mutation (VM) for susceptibility of Caenorhabditis elegans to the pathogenic bacterium Pseudomonas aeruginosa (defined as the median time of death, LT50). VM for LT50 is slightly less than VM for a variety of life-history and morphological traits in this strain of C. elegans, but is well within the range of reported values in a variety of organisms. Mean LT50 did not change significantly over 250 generations of mutation accumulation. Comparison of VM to the standing genetic variance (VG) implies a strength of selection against new mutations of a few tenths of a percent. These results suggest that the substantial standing genetic variation for susceptibility of C. elegans to P. aeruginosa can be explained by polygenic mutation coupled with purifying selection.

Murthy PK et al. (2002) Clin Diagn Lab Immunol "Preadult stage parasites and multiple timed exposure to infective larvae are involved in development of limb edema in Brugia malayi-infected Indian leaf monkeys (Presbytis entellus)."

Khan MA, Srivastava VM, Murthy PK, Rajani HB

[Clin Diagn Lab Immunol, 2002]

The pathogenesis of filarial limb edema is not known. The role of parasitological variables and parasite-mediated phenomena in the development of limb edema was investigated in the Presbytis entellus-Brugia malayi model. Infection was initiated with subcutaneous inoculation of infective third-stage larvae (L(3)), and the animals were reexposed to different doses of L(3) at the prepatent, patent, and diminishing microfilaremia (0 to 5% of peak microfilaremia count) stages of infection. A large L(3) inoculum size and repeated inoculation in the ankle region during the prepatent, patent, and diminishing microfilaremia stages of infection were found to be necessary for reproducible induction of limb edema. The preadult stage of the parasite was found to be the most potent inducer of limb edema, followed by L(5) and L(4). The presence of the proinflammatory cytokines tumor necrosis factor alpha, interleukin-1beta, and interleukin-6 in edema fluid in the leg receiving the parasite challenge indicated that the limb edema development was due to parasite-mediated cytokine responses. The absence of bacterial infection or anti-streptolysin O titer in the edema fluid and blood indicated that bacterial infection is not necessary for the development of limb edema.

Gupta R et al. (2004) Parasitology "Macrophages in the development of protective immunity against experimental Brugia malayi infection."

Jain SK, Gupta R, Srivastava VM, Misra-Bhattacharya S, Tripathi LM, Bajpai P

[Parasitology, 2004]

The present report compares the macrophage function in rodent hosts susceptible and resistant to the human lymphatic filariid Brugia malayi. Macrophages from both mastomys (resistant) and gerbil (susceptible) infected intraperitoneally (i.p.) with the infective larvae (L3) of B. malayi were isolated from peritoneal lavage at different time-intervals and formation rate of NO, H2O2, O2-, TNF-alpha, glutathione peroxidase and reductase was assayed. NO release was found to be significantly increased in resistant mastomys as compared to gerbils and the release was markedly suppressed by i.p. administration of the NOS inhibitor aminoguanidine (AG). The AG-treated mastomys also demonstrated significantly greater establishment of larvae which correlated well with suppressed formation of NO. Nitric oxide synergizes with superoxide to form peroxynitrite radical (potent oxidant), which is known to be more toxic per se than NO. Results indicate the possible involvement of peroxynitrite in the rapid killing of larvae in the peritoneal cavity of mastomys. In contrast, the production of H2O2 was found to be enhanced in both species indicating that B. malayi L3 could withstand the toxic effects of H2O2. The higher level of glutathione peroxidase and reductase, as observed in mastomys compared with the gerbil after larval introduction, possibly protects the cell against the injurious effect of H2O2. The TNF-alpha level remained virtually unchanged in both the hosts, suggesting an insignificant role for this cytokine in parasite establishment.

Tripathi RP et al. (2003) Acta Trop "7-O-[4-methyl piperazine-1-(2-acetyl)]-2H-1-benzopyran-2-one: a novel antifilarial lead compound."

Tyagi K, Tripathi RP, Misra-Bhattacharya S, Tiwari VK, Murthy PK, Srivastava VM

[Acta Trop, 2003]

In preliminary studies we found that benzopyrones (coumarins), which are known to exert many biological activities including anti-inflammatory effect, possess promising macrofilaricidal action as well. In order to explore the possibility of combining such a macrofilaricidal activity with the microfilaricidal potential of the known piperazine pharmacophore, we synthesized a series of compounds and evaluated their antifilarial effect. In the present study, one of these compounds, 7-O-[4-methyl piperazine-1-(2-acetyl)]-2H-1-benzopyran-2-one (2), which has shown promising macrofilaricidal action against rodent filariid Litomosoides carinii in cotton rats, was evaluated against infection with Brugia malayi in Mastomys coucha and jird (Meriones unguiculatus). In the B. malayi-M. coucha system, the compound at a dose of 300 mg/kg, oral (p.o.) x5 days showed 53.6% adulticidal and 46.0% microfilaricidal activity along with 46.3% sterilization effect on the female worms. In addition, the compound interfered with the establishment of infective larvae (L(3))-induced infection to an extent of 50% at the same dose level. At 1 microM concentration it inhibited protease activity of B. malayi to 82%. The compound thus provides a novel lead for further synthesis and development of antifilarial agents with macrofilaricidal, microfilaricidal, female-sterilizing and possible larvicidal efficacy.

Yeh SD et al. (2018) Heredity (Edinb) "The mutational decay of male-male and hermaphrodite-hermaphrodite competitive fitness in the androdioecious nematode C. elegans."

Feistel D, Lam I, Saxena AS, Baer CF, Saber S, Crombie TA, Yeh SD, Lam J, Johnson LM

[Heredity (Edinb), 2018]

Androdioecious Caenorhabditis have a high frequency of self-compatible hermaphrodites and a low frequency of males. The effects of mutations on male fitness are of interest for two reasons. First, when males are rare, selection on male-specific mutations is less efficient than in hermaphrodites. Second, males may present a larger mutational target than hermaphrodites because of the different ways in which fitness accrues in the two sexes. We report the first estimates of male-specific mutational effects in an androdioecious organism. The rate of male-specific inviable or sterile mutations is 5x10-4/generation, below the rate at which males would be lost solely due to those kinds of mutations. The rate of mutational decay of male competitive fitness is ~0.17%/generation; that of hermaphrodite competitive fitness is ~0.11%/generation. The point estimate of ~1.5X faster rate of mutational decay of male fitness is nearly identical to the same ratio in Drosophila. Estimates of mutational variance (VM) for male mating success and competitive fitness are not significantly different from zero, whereas VM for hermaphrodite competitive fitness is similar to that of non-competitive fitness. Two independent estimates of the average selection coefficient against mutations affecting hermaphrodite competitive fitness agree to within two-fold, 0.33-0.5%.

Arya U et al. (2009) Exp Gerontol "Reserpine ameliorates Abeta toxicity in the Alzheimer's disease model in Caenorhabditis elegans."

Dwivedi H, Arya U, Subramaniam JR

[Exp Gerontol, 2009]

Earlier we have reported that reserpine, an antihypertensive drug, known to downregulate biogenic amines through inhibition of the vesicular monoamine transporter (VMAT), increases longevity of Caenorhabditis elegans with a high quality of life, namely, enhanced and prolonged mobility (Srivastava et al., 2008). As neurodegenerative diseases are of adult onset, we addressed the protective ability of reserpine against neurodegenerative diseases, especially Alzheimer's disease (AD). In the well established AD model in C. elegans, Amyloid beta (Abeta) is expressed in the muscles and Abeta toxicity is manifested as paralysis (Link, 1995). In this model, reserpine significantly delayed paralysis and increased the longevity. In addition, reserpine provided thermotolerance, but interestingly the Abeta transcript and expression levels remains grossly unchanged.

Pokharel DR et al. (2006) Vaccine "Vaccination with Setaria cervi 175 kDa collagenase induces high level of protection against Brugia malayi infection in jirds."

Nandakumar Kodumudi K, Rai R, Pokharel DR, Rathaur S, Reddy MV

[Vaccine, 2006]

A zinc containing metalloprotease, 175 kDa collagenase, purified from adult female Setaria cervi showed strong cross-reactivity with sera from putatively immune (PI) individuals (unpublished observation) and induced cytotoxicity to B. malayi L3 larvae and microfilariae by ADCC mechanism [Srivastava Y, Bhandari YP, Reddy MVR, Harinath BC, Rathaur S. An adult 175 kDa collagenase antigen of Setaria cervi in immunoprophylaxis against Brugia malayi. J Helminth 2004;78:347-52]. These preliminary observations suggested the immunoprotective nature of collagenase. To confirm the vaccine potential of this protease, a vaccine trial was conducted in jirds (Meriones unguiculatus) against human filarial parasite B. malayi. The vaccination resulted into a mean protection level of 75.86% and produced high level of protease neutralizing antibodies. Cytokine analysis in immune jirds sera suggested a mixed Th1/Th2 type cellular immune response whereas ELISA, immunoblotting and enzyme antibody inhibition assay revealed the presence of specific anti-collagenase antibodies. Taken together, all these results suggest that S. cervi 175 kDa collagenase could form the basis of an effective molecular vaccine against human lymphatic filariasis.

Davies SK et al. (2016) Evolution "The mutational structure of metabolism in Caenorhabditis elegans."

Leroi A, Bundy JG, Burt A, Baer CF, Davies SK

[Evolution, 2016]

A properly functioning organism must maintain metabolic homeostasis. Deleterious mutations degrade organismal function, presumably at least in part via effects on metabolic function. Here we present an initial investigation into the mutational structure of the Caenorhabditis elegans metabolome by means of a mutation accumulation experiment. We find that pool sizes of 29 metabolites vary greatly in their vulnerability to mutation, both in terms of the rate of accumulation of genetic variance (the mutational variance, VM) and the rate of change of the trait mean (the mutational bias, M). Strikingly, some metabolites are much more vulnerable to mutation than any other trait previously studied in the same way. Although we cannot statistically assess the strength of mutational correlations between individual metabolites, principal component analysis provides strong evidence that some metabolite pools are genetically correlated, but also that there is substantial scope for independent evolution of different groups of metabolites. Averaged over MA lines, PC3 is positively correlated with relative fitness, but a model in which metabolites are uncorrelated with fitness is nearly as good by Akaike's Information Criterion (AIC). This article is protected by copyright. All rights reserved.