Beneficial Fitness Effects Are Not Exponential for Two Viruses

The distribution of fitness effects for beneficial mutations is of paramount importance in determining the outcome of adaptation. It is generally assumed that fitness effects of beneficial mutations follow an exponential distribution, for example, in theoretical treatments of quantitative genetics, clonal interference, experimental evolution, and the adaptation of DNA sequences. This assumption has been justified by the statistical theory of extreme values, because the fitnesses conferred by beneficial mutations should represent samples from the extreme right tail of the fitness distribution. Yet in extreme value theory, there are three different limiting forms for right tails of distributions, and the exponential describes only those of distributions in the Gumbel domain of attraction. Using beneficial mutations from two viruses, we show for the first time that the Gumbel domain can be rejected in favor of a distribution with a right-truncated tail, thus providing evidence for an upper bound on fitness effects. Our data also violate the common assumption that small-effect beneficial mutations greatly outnumber those of large effect, as they are consistent with a uniform distribution of beneficial effects

Genetic Modifiers of Oral Nicotine Consumption in Chrna5 Null Mutant Mice

The gene CHRNA5 is strongly associated with the level of nicotine consumption in humans and manipulation of the expression or function of Chrna5 similarly alters nicotine consumption in rodents. In both humans and rodents, reduced or complete loss of function of Chrna5 leads to increased nicotine consumption. However, the mechanism through which decreased function of Chrna5 increases nicotine intake is not well-understood. Toward a better understanding of how loss of function of Chrna5 increases nicotine consumption, we have initiated efforts to identify genetic modifiers of Chrna5 deletion-dependent oral nicotine consumption in mice. For this, we introgressed the Chrna5 knockout (KO) mutation onto a panel of C57BL/6J-Chr#A/J/NAJ chromosome substitution strains (CSS) and measured oral nicotine consumption in 18 CSS and C57BL/6 (B6) mice homozygous for the Chrna5 KO allele as well as their Chrna5 wild type littermates. As expected, nicotine consumption was significantly increased in Chrna5 KO mice relative to Chrna5 wildtype mice on a B6 background. Among the CSS homozygous for the Chrna5 KO allele, several exhibited altered nicotine consumption relative to B6 Chrna5 KO mice. Sex-independent modifiers were detected in CSS possessing A/J chromosomes 5 and 11 and a male-specific modifier was found on chromosome 15. In all cases nicotine consumption was reduced in the CSS Chrna5 KO mice relative to B6 Chrna5 KO mice and consumption in the CSS KO mice was indistinguishable from their wild type littermates. Nicotine consumption was also reduced in both Chrna5 KO and wildtype CSS mice possessing A/J chromosome 1 and increased in both KO and wild type chromosome 17 CSS relative to KO and wild type B6 mice. These results demonstrate the presence of several genetic modifiers of nicotine consumption in Chrna5 KO mice as well as identify loci that may affect nicotine consumption independent of Chrna5 genotype. Identification of the genes that underlie the altered nicotine consumption may provide novel insight into the mechanism through which Chrna5 deletion increases nicotine consumption and, more generally, a better appreciation of the neurobiology of nicotine intake. &nbsp;</p

Cross-country migration linked to people who inject drugs challenges the long-term impact of national HCV elimination programmes

To the Editor: As of 2018, the majority of Western European countries – including Spain – have lifted restrictions to therapy based on disease severity in the context of HCV infections.1 Long overdue, most national elimination programmes now also include access to care for people who inject drugs (PWID), 2 who are at the core of ongoing HCV transmission.3 Macías et al.4 have recently shown in this Journal that high viral cure rates can be achieved in this group, hereby providing evidence that targeting PWID in treatment programmes is worthwhile. However, the extent to which such national efforts can reduce the HCV burden not only depends on the uptake into care and treatment success rates, it is also determined by the relative importance of within-country transmission and virus importation from elsewhere. As the chronic nature of most HCV infections hampers reliably reconstructing contact networks from patient interviews, virus genetic data can be a valuable alternative source of information for elucidating the geographic history of virus lineages (e.g. [5], [6]). Using such data, we have recently shown that for the most prevalent subtype among PWID in Spain (40%, 7), HCV1a, infections often link to infections abroad – in recent years >50% link to Western European countries, mostly European Union (EU) member states – as opposed to other infections ..

Quadriceps Strength Influences Patient Function More Than Single Leg Forward Hop During Late-Stage ACL Rehabilitation

# Background A comprehensive battery of tests are used to inform return to play decisions following anterior cruciate ligament (ACL) reconstruction. Performance measures contribute to patient function, but it is not clear if achieving symmetrical performance on strength and hop tests is sufficient or if a patient also needs to meet minimum unilateral thresholds. # Hypothesis/Purpose To determine the association of quadriceps strength and single-leg forward hop performance with patient-reported function, as measured by the IKDC Subjective Knee Form (IKDC), during late-stage ACL rehabilitation. A secondary purpose was to determine which clinical tests were the most difficult for participants to pass. # Study Design Descriptive Laboratory Study # Methods Forty-eight individuals with a history of ACL-R (32 female, 16 male; mean±SD age=18.0±2.7 y; height=172.4±7.6 cm; mass=69.6±11.4 kg; time since surgery=7.7±1.8 months; IKDC=86.8±10.6) completed the IKDC survey, quadriceps isometric strength, and single-leg forward hop performance. The relationship between IKDC scores and performance measures (LSI and involved limb) was determined using stepwise linear regression. Frequency counts were used to determine whether participants met clinical thresholds (IKDC $\geq$ 90%, quadriceps and single-leg forward hop LSI $\geq$ 90%, quadriceps peak torque $\geq$ 3.0 Nm/kg, and single-leg forward hop $\geq$ 80% height for females and $\geq$ 90% height for males). # Results Quadriceps LSI and involved limb peak torque explained 39% of the variance in IKDC scores while measures of single-leg forward hop performance did not add to the predictive model. Nearly 90% of participants could not meet established clinical thresholds on all five tests and quadriceps strength (LSI and peak torque) was the most common unmet criteria (71% of participants). # Conclusions During late-stage ACL rehabilitation deficits in quadriceps strength contribute more to patient function and are greater in magnitude compared to hop test performance. # Level of evidence Cross-Sectional Study, Level

The Genetics of Adaptation for Eight Microvirid Bacteriophages

Theories of adaptive molecular evolution have recently experienced significant expansion, and their predictions and assumptions have begun to be subjected to rigorous empirical testing. However, these theories focus largely on predicting the first event in adaptive evolution, the fixation of a single beneficial mutation. To address long-term adaptation it is necessary to include new assumptions, but empirical data are needed for guidance. To empirically characterize the general properties of adaptive walks, eight recently isolated relatives of the single-stranded DNA (ssDNA) bacteriophage φX174 (family Microviridae) were adapted to identical selective conditions. Three of the eight genotypes were adapted in replicate, for a total of 11 adaptive walks. We measured fitness improvement and identified the genetic changes underlying the observed adaptation. Nearly all phages were evolvable; nine of the 11 lineages showed a significant increase in fitness. However, fitness plateaued quickly, and adaptation was achieved through only three substitutions on average. Parallel evolution was rampant, both across replicates of the same genotype as well as across different genotypes, yet adaptation of replicates never proceeded through the exact same set of mutations. Despite this, final fitnesses did not vary significantly among replicates. Final fitnesses did vary significantly across genotypes but not across phylogenetic groupings of genotypes. A positive correlation was found between the number of substitutions in an adaptive walk and the magnitude of fitness improvement, but no correlation was found between starting and ending fitness. These results provide an empirical framework for future adaptation theory

Enabling Practice-driven Innovation in the Animal Production Sector

Using the laying hen sector as a case study, the EU-H2020-funded Hennovation project has been testing mechanisms to enable practice-driven innovation through the establishment of innovation networks of farmers and within the laying-hen-processing industry that are facilitated to proactively search for, share and use new ideas to improve hen welfare, efficiency and sustainability. Networks are variably supported by scientists, veterinarians, advisors and others. Nineteen multi-actor networks have been mobilised on local and regional levels across the UK, Sweden, Netherlands, Spain and Czech-Republic.Practice-driven innovation processes were network specific and evolved as the actors within the network came together to share common problems, experiment with possible solutions and learn. Their success was also affected by the institutional context, the structure of the poultry sector, current market forces and wider Agricultural Innovation Systems in each country. This paper explores the circumstances considered necessary by the facilitators to enable practice-driven innovation, providing examples of conditions affecting the innovation process. Further influences included conditions for innovation to happen (e.g. shared opportunity, motivation and knowledge), conditions to work effectively as a network (e.g. trust, collective purpose and contacts) and conditions for successful application in practice (e.g. capacity within the production system and market and legislative ability)

Investigating variation in replicability

Although replication is a central tenet of science, direct replications are rare in psychology. This research tested variation in the replicability of 13 classic and contemporary effects across 36 independent samples totaling 6,344 participants. In the aggregate, 10 effects replicated consistently. One effect – imagined contact reducing prejudice – showed weak support for replicability. And two effects – flag priming influencing conservatism and currency priming influencing system justification – did not replicate. We compared whether the conditions such as lab versus online or US versus international sample predicted effect magnitudes. By and large they did not. The results of this small sample of effects suggest that replicability is more dependent on the effect itself than on the sample and setting used to investigate the effect

Population-Based Resequencing of Experimentally Evolved Populations Reveals the Genetic Basis of Body Size Variation in Drosophila melanogaster

Body size is a classic quantitative trait with evolutionarily significant variation within many species. Locating the alleles responsible for this variation would help understand the maintenance of variation in body size in particular, as well as quantitative traits in general. However, successful genome-wide association of genotype and phenotype may require very large sample sizes if alleles have low population frequencies or modest effects. As a complementary approach, we propose that population-based resequencing of experimentally evolved populations allows for considerable power to map functional variation. Here, we use this technique to investigate the genetic basis of natural variation in body size in Drosophila melanogaster. Significant differentiation of hundreds of loci in replicate selection populations supports the hypothesis that the genetic basis of body size variation is very polygenic in D. melanogaster. Significantly differentiated variants are limited to single genes at some loci, allowing precise hypotheses to be formed regarding causal polymorphisms, while other significant regions are large and contain many genes. By using significantly associated polymorphisms as a priori candidates in follow-up studies, these data are expected to provide considerable power to determine the genetic basis of natural variation in body size

Hidden heterochromatin: Characterization in the Rodentia species Cricetus cricetus, Peromyscus eremicus (Cricetidae) and Praomys tullbergi (Muridae)

The use of in situ restriction endonuclease (RE) (which cleaves DNA at specific sequences) digestion has proven to be a useful technique in improving the dissection of constitutive heterochromatin (CH), and in the understanding of the CH evolution in different genomes. In the present work we describe in detail the CH of the three Rodentia species, Cricetus cricetus, Peromyscus eremicus (family Cricetidae) and Praomys tullbergi (family Muridae) using a panel of seven REs followed by C-banding. Comparison of the amount, distribution and molecular nature of C-positive heterochromatin revealed molecular heterogeneity in the heterochromatin of the three species. The large number of subclasses of CH identified in Praomys tullbergi chromosomes indicated that the karyotype of this species is the more derived when compared with the other two genomes analyzed, probably originated by a great number of complex chromosomal rearrangements. The high level of sequence heterogeneity identified in the CH of the three genomes suggests the coexistence of different satellite DNA families, or variants of these families in these genomes

The Properties of Adaptive Walks in Evolving Populations of Fungus

A novel method to infer the number and fitness effect of beneficial mutations reveals that the bulk of adaptive evolution is attributable to a few mutations with variable effects on fitness