Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome

Genetic studies of autism spectrum conditions (ASC) have mostly focused on the "low functioning" severe clinical subgroup, treating it as a rare disorder. However, ASC is now thought to be relatively common ( approximately 1%), and representing one end of a quasi-normal distribution of autistic traits in the general population. Here we report a study of common genetic variation in candidate genes associated with autistic traits and Asperger syndrome (AS). We tested single nucleotide polymorphisms in 68 candidate genes in three functional groups (sex steroid synthesis/transport, neural connectivity, and social-emotional responsivity) in two experiments. These were (a) an association study of relevant behavioral traits (the Empathy Quotient (EQ), the Autism Spectrum Quotient (AQ)) in a population sample (n=349); and (b) a case-control association study on a sample of people with AS, a "high-functioning" subgroup of ASC (n=174). 27 genes showed a nominally significant association with autistic traits and/or ASC diagnosis. Of these, 19 genes showed nominally significant association with AQ/EQ. In the sex steroid group, this included ESR2 and CYP11B1. In the neural connectivity group, this included HOXA1, NTRK1, and NLGN4X. In the socio-responsivity behavior group, this included MAOB, AVPR1B, and WFS1. Fourteen genes showed nominally significant association with AS. In the sex steroid group, this included CYP17A1 and CYP19A1. In the socio-emotional behavior group, this included OXT. Six genes were nominally associated in both experiments, providing a partial replication. Eleven genes survived family wise error rate (FWER) correction using permutations across both experiments, which is greater than would be expected by chance. CYP11B1 and NTRK1 emerged as significantly associated genes in both experiments, after FWER correction (P<0.05). This is the first candidate-gene association study of AS and of autistic traits. The most promising candidate genes require independent replication and fine mapping.

Omega-3 fatty acids, cardiovascular disease and stability of atherosclerotic plaques

Long-chain n-3 polyunsaturated fatty acids are found in oily fish and in fish oils and similar preparations. Substantial evidence from epidemiological and case-control studies indicates that consumption of fish, oily fish and long-chain n-3 fatty acids reduces risk of cardiovascular mortality. Secondary prevention studies using long-chain n-3 fatty acids in patients post-myocardial infarction have shown a reduction in total and cardiovascular mortality with an especially potent effect on sudden death. Long-chain n-3 fatty acids have been shown to beneficially modify a range of cardiovascular risk factors, which may result in primary cardiovascular prevention. However, reduced non-fatal and fatal events and a reduction in sudden death probably involve other mechanisms. Reduced thrombosis following long-chain n-3 fatty acids may play a role. A decrease in arrhythmias is a favoured mechanism of action of long-chain n-3 fatty acids and is supported by cell culture and animal studies. However human trials using implantable cardiac defibrillators have produced inconsistent findings and a recent meta-analysis does not support this mechanism of action. An alternative mechanism of action may be stabilisation of atherosclerotic plaques by long-chain n-3 fatty acids. This is suggested by one published human study which showed that incorporation of long-chain n-3 fatty acids into plaques collected at carotid endarterectomy resulted in fewer macrophages in the plaque and a morphology indicative of increased stability. These findings are supported from observations in an animal model and suggest that the primary effect of long-chain n-3 fatty acids might be on macrophages within the plaque.

Evolutionary bi-stability in pathogen transmission mode

Many pathogens transmit to new hosts by both infection (horizontal transmission) and transfer to the infected host's offspring (vertical transmission). These two transmission modes require speci®c adap- tations of the pathogen that can be mutually exclusive, resulting in a trade-off between horizontal and vertical transmission. We show that in mathematical models such trade-offs can lead to the simultaneous existence of two evolutionary stable states (evolutionary bi-stability) of allocation of resources to the two modes of transmission. We also show that jumping between evolutionary stable states can be induced by gradual environmental changes. Using quantitative PCR-based estimates of abundance in seed and vege- tative parts, we show that the pathogen of wheat, Phaeosphaeria nodorum, has jumped between two distinct states of transmission mode twice in the past 160 years, which, based on published evidence, we interpret as adaptation to environmental change. The ®nding of evolutionary bi-stability has impli- cations for human, animal and other plant diseases. An ill-judged change in a disease control programme could cause the pathogen to evolve a new, and possibly more damaging, combination of transmission modes. Similarly, environmental changes can shift the balance between transmission modes, with adverse effects on human, animal and plant health.

The effect of calcium removal from milk on casein micelle stability and structure

The total calcium level of raw skimmed milk was reduced by 10, 19, 29, 40 and 51% using Duolite® ion-exchange resin. The products were examined for concentrations of ionic calcium, sodium and potassium and the pH, ethanol stability, micelle diameter and ζ-potential were also measured. Ionic calcium decreased with removal of calcium and pH increased. Calcium removal resulted in an increase in the ethanol stability from 88% to above 100%. Casein micelle diameter increased as calcium was removed. The ζ-potential of the skimmed bulk milk was -24.4 mV, gradually becoming more negative with calcium removal to -30.6 mV after 51% calcium removal. The milk became more translucent as calcium was removed. To investigate the reversibility of this process, calcium chloride was added back to the depleted samples to restore their original total calcium content. At 51% removal, restoration of the total calcium level resulted in formation of clots. At levels of 10 and 19% calcium removal, the ethanol stability remained above 100%, but at higher levels of calcium removal the alcohol stability was adversely affected when the calcium was added back. Adding back calcium resulted in partial restoration of the original casein micelle diameter.

Effects of different calcium salts on properties of milk related to heat stability

Insoluble calcium salts were added to milk to increase total calcium by 30 mM, without changing properties influencing heat stability, such as pH and ionic calcium. There were no major signs of instability associated with coagulation, sediment formation or fouling when subjected to ultra high temperature (UHT) and in-container sterilisation. The buffering capacity was also unaltered. On the other hand, addition of soluble calcium salts reduced pH, increased ionic calcium and caused coagulation to occur. Calcium chloride showed the largest destabilising effect, followed by calcium lactate and calcium gluconate. Milk became unstable to UHT processing at lower calcium additions compared to in-container sterilisation.

Effects of stabiliser addition and in-container sterilisation on selected properties of milk related to casein micelle stability

Different stabilising salts and calcium chloride were added to raw milk to evaluate changes in pH, ionic calcium, ethanol stability, casein micelle size and zeta potential. These milk samples were then sterilised at 121 °C for 15 min and stored for 6 months to determine how these properties changed. Addition of tri-sodium citrate (TSC) and di-sodium hydrogen phosphate (DSHP) to milk reduced ionic calcium, increased pH and increased ethanol stability in a concentration-dependent fashion. There was relatively little change in casein micelle size and a slight decrease in zeta potential. Sodium hexametaphosphate (SHMP) also reduced ionic calcium considerably, but its effect on pH was less noticeable. In contrast, sodium dihydrogen phosphate (SDHP) reduced pH but had little effect on ionic calcium. In-container sterilisation of these samples reduced pH, increased ethanol stability and increased casein micelle size, but had variable effects on ionic calcium; for DSHP and SDHP, ionic calcium decreased after sterilisation but, for SHMP, it remained little changed or increased. Milk containing 3.2 mM SHMP and more than 4.5 mM CaCl2 coagulated upon sterilisation. All other samples were stable but there were differences in browning, which increased in intensity as milk pH increased. Heat-induced sediment was not directly related to ionic calcium concentration, so reducing ionic calcium was not the only consideration in terms of improving heat stability. After 6 months of storage, the most acceptable product, in appearance, was that containing SDHP, as this minimised browning during sterilisation and further development of browning during storage.

Ionic calcium and pH as predictors of stability of milk to UHT processing

This paper describes the use of pH and calcium ion electrodes for investigating factors affecting the heat stability of UHT milk with added calcium chloride. Calcium chloride was added to raw milk to manipulate ionic calcium and pH to within the range that may be typically encountered in raw milk of different compositions and microbial quality. Addition of only 5 mM calcium chloride was sufficient to induce considerable changes in pH, ionic calcium and ethanol stability and alter its stability to UHT treatment. There was a strong relationship between pH decrease and increase in ionic calcium when pH was reduced, whether by addition of calcium chloride or by acidification. Calcium chloride addition was found to increase sediment formation in UHT treated milk. However, sediment could be reduced by addition of stabilizers. Those most effective were ones which decreased ionic calcium and increased pH, such as trisodium citrate and disodium hydrogen phosphate. Sediment formation following UHT treatment was only slight for milk samples whose ethanol stability was greater than 80%.

Shrubs, granivores and annual plant community stability in an arid ecosystem

Compensatory population dynamics among species stabilise aggregate community variables. Inter-specific competition is thought to be stabilising as it promotes asynchrony among populations. However, we know little about other inter-specific interactions, such as facilitation and granivory. Such interactions are also likely to influence population synchrony and community stability, especially in harsh environments where they are thought to have relatively strong effects in plant communities. We use a manipulative experiment to test the effects of granivores (harvester ants) and nurse plants (dwarf shrubs) on annual plant community dynamics in the Negev desert, Israel. We present evidence for weak and inconsistent effects of harvester ants on plant abundance and on population and community stability. By contrast, we show that annual communities under shrubs were more species rich, had higher plant density and were temporally less variable than communities in the inter-shrub matrix. Species richness and plant abundance were also more resistant to drought in the shrub under-storey compared with the inter-shrub matrix, although population dynamics in both patch types were synchronised. Hence, we show that inter-specific interactions other than competition affect community stability, and that hypothesised mechanisms linking compensatory dynamics and community stability may not operate to the same extent in arid plant communities.

Tolerance traits and the stability of mutualism

Identifying factors which allow the evolution and persistence of cooperative interactions between species is a fundamental issue in evolutionary ecology. Various hypotheses have been suggested which generally focus on mechanisms that allow cooperative genotypes in different species to maintain interactions over space and time. Here, we emphasise the fact that even within mutualisms (interactions with net positive fitness effects for both partners), there may still be inherent costs, such as the occasional predation by ants upon aphids. Individuals engaged in mutualisms benefit from minimising these costs as long as it is not at the expense of breaking the interspecific interaction, which offers a net positive benefit. The most common and obvious defence traits to minimise interspecific interaction costs are resistance traits, which act to reduce encounter rate between two organisms. Tolerance traits, in contrast, minimise fitness costs to the actor, but without reducing encounter rate. Given that, by definition, it is beneficial to remain in mutualistic interactions, the only viable traits to minimise costs are tolerance-based 'defence' strategies. Thus, we propose that tolerance traits are an important factor promoting stability in mutualisms. Furthermore, because resistance traits tend to propagate coevolutionary arms races between antagonists, whilst tolerance traits do not, we also suggest that tolerance-based defence strategies may be important in facilitating the transition from antagonistic interactions into mutualisms. For example, the mutualism between ants and aphids has been suggested to have evolved from parasitism. We describe how phenotypic plasticity in honeydew production may be a tolerance trait that has prevented escalation into an antagonistic arms race and instead led to mutualistic coevolution.

Interference competition and high temperature reduce the ‘virulence’ of fig wasps and contribute to stability of a fig-wasp mutualism

Fig trees are pollinated by fig wasps, which also oviposit in female flowers. The wasp larvae gall and eat developing seeds. Although fig trees benefit from allowing wasps to oviposit, because the wasp offspring disperse pollen, figs must prevent wasps from ovipositing in all flowers, or seed production would cease, and the mutualism would go extinct. In Ficus racemosa, we find that syconia (‘figs’) that have few foundresses (ovipositing wasps) are underexploited in the summer (few seeds, few galls, many empty ovules) and are overexploited in the winter (few seeds, many galls, few empty ovules). Conversely, syconia with many foundresses produce intermediate numbers of galls and seeds, regardless of season. We use experiments to explain these patterns, and thus, to explain how this mutualism is maintained. In the hot summer, wasps suffer short lifespans and therefore fail to oviposit in many flowers. In contrast, cooler temperatures in the winter permit longer wasp lifespans, which in turn allows most flowers to be exploited by the wasps. However, even in winter, only in syconia that happen to have few foundresses are most flowers turned into galls. In syconia with higher numbers of foundresses, interference competition reduces foundress lifespans, which reduces the proportion of flowers that are galled. We further show that syconia encourage the entry of multiple foundresses by delaying ostiole closure. Taken together, these factors allow fig trees to reduce galling in the wasp-benign winter and boost galling (and pollination) in the wasp-stressing summer. Interference competition has been shown to reduce virulence in pathogenic bacteria. Our results show that interference also maintains cooperation in a classic, cooperative symbiosis, thus linking theories of virulence and mutualism. More generally, our results reveal how frequency-dependent population regulation can occur in the fig-wasp mutualism, and how a host species can ‘set the rules of the game’ to ensure mutualistic behavior in its symbionts.

Longevity, early emergence and body size in a pollinating fig wasp - implications for stability in a fig-pollinator mutualism

1. Fig trees (Ficus) are pollinated only by agaonid wasps, whose larvae also gall fig ovules. Each ovule develops into either a seed (when pollinated) or a wasp (when an egg is also laid inside) but not both. 2. Ovipositing wasps (foundresses) favour ovules near the centre of the enclosed inflorescence (syconium or 'fig'), leaving ovules near the outer wall to develop into seeds. This spatial stratification of wasps and seeds ensures reproduction in both partners, and thereby enables mutualism persistence. However, the mechanism(s) responsible remain(s) unknown. 3. Theory shows that foundresses will search for increasingly rare inner ovules and ignore outer ovules, as long as ovipositing in outer ovules is sufficiently slow and/or if inner ovules confer greater fitness to wasps. The fig-pollinator mutualism can therefore be stabilized by strong time constraints on foundresses and by offspring fitness gradients over variation in ovule position. 4. Female fig wasps cannot leave their galls without male assistance. We found that females in outer ovules were unlikely to be released. Inner ovules thus have added value to foundresses, because their female offspring are more likely to mate and disperse. 5. For those offspring that did emerge, gall position (inner/outer) and body size did not influence the order in which female pollinators exited syconia, nor did early emerging wasps enjoy increased life spans. 6. We also found that the life spans of female wasps nearly doubled when given access to moisture. We suggest that conflict resolution in the fig-pollinator mutualism may thus be influenced by tropical seasonality, because wasps may be less able to over-exploit ovules in dry periods due to time constraints.

On the stability of populations of mammals, birds, fish and insects

A key concern for conservation biologists is whether populations of plants and animals are likely to fluctuate widely in number or remain relatively stable around some steady-state value. In our study of 634 populations of mammals, birds, fish and insects, we find that most can be expected to remain stable despite year to year fluctuations caused by environmental factors. Mean return rates were generally around one but were higher in insects (1.09 +/- 0.02 SE) and declined with body size in mammals. In general, this is good news for conservation, as stable populations are less likely to go extinct. However, the lower return rates of the large mammals may make them more vulnerable to extinction. Our estimates of return rates were generally well below the threshold for chaos, which makes it unlikely that chaotic dynamics occur in natural populations - one of ecology's key unanswered questions.