Why did eukaryotes evolve only once? Genetic and energetic aspects of conflict and conflict mediation

According to multi-level theory, evolutionary transitions require mediating conflicts between lower-level units in favour of the higher-level unit. By this view, the origin of eukaryotes and the origin of multicellularity would seem largely equivalent. Yet, eukaryotes evolved only once in the history of life, whereas multicellular eukaryotes have evolved many times. Examining conflicts between evolutionary units and mechanisms that mediate these conflicts can illuminate these differences. Energy-converting endosymbionts that allow eukaryotes to transcend surface-to-volume constraints also can allocate energy into their own selfish replication. This principal conflict in the origin of eukaryotes can be mediated by genetic or energetic mechanisms. Genome transfer diminishes the heritable variation of the symbiont, but requires the de novo evolution of the protein-import apparatus and was opposed by selection for selfish symbionts. By contrast, metabolic signalling is a shared primitive feature of all cells. Redox state of the cytosol is an emergent feature that cannot be subverted by an individual symbiont. Hypothetical scenarios illustrate how metabolic regulation may have mediated the conflicts inherent at different stages in the origin of eukaryotes. Aspects of metabolic regulation may have subsequently been coopted from within-cell to between-cell pathways, allowing multicellularity to emerge repeatedly.     

Mhc‐linked survival and lifetime reproductive success in a wild population of great tits

Major histocompatibility complex (Mhc) genes are frequently used as a model for adaptive genetic diversity. Although associations between Mhc and disease resistance are frequently documented, little is known about the fitness consequences of Mhc variation in wild populations. Further, most work to date has involved testing associations between Mhc genotypes and fitness components. However, the functional diversity of the Mhc, and hence the mechanism by which selection on Mhc acts, depends on how genotypes map to the functional properties of Mhc molecules. Here, we test three hypotheses that relate Mhc diversity to fitness: (i) the maximal diversity hypothesis, (ii) the optimal diversity hypothesis and (iii) effect of specific Mhc types. We combine mark–recapture methods with analysis of long‐term breeding data to investigate the effects of Mhc class I functional diversity (Mhc supertypes) on individual fitness in a wild great tit (Parus major) population. We found that the presence of three different Mhc supertypes was associated with three different components of individual fitness: survival, annual recruitment and lifetime reproductive success (LRS). Great tits possessing Mhc supertype 3 experienced higher survival rates than those that did not, whereas individuals with Mhc supertype 6 experienced higher LRS and were more likely to recruit offspring each year. Conversely, great tits that possessed Mhc supertype 5 had reduced LRS. We found no evidence for a selective advantage of Mhc diversity, in terms of either maximal or optimal supertype diversity. Our results support the suggestion that specific Mhc types are an important determinant of individual fitness.     

Poland syndrome a rare congenital anomaly

Poland syndrome is a rare congenital anomaly classically consisting of unilateral hypoplasia of the sternocostal head of the pectoralis major muscle and ipsilateral brachysyndactyly. It was first described by Alfred Poland in 1840 and may occur with different gravity. Our patient is an eight-year-old Nigerian girl with left-sided anterior chest wall defect with no detectable structural heart abnormality but presented with repeated episodes of syncopal attacks following minor trauma to the anterior chest wall.     

Comparison of 454 pyrosequencing methods for characterizing the major histocompatibility complex of nonmodel species and the advantages of ultra deep coverage

Characterization and population genetic analysis of multilocus genes, such as those found in the major histocompatibility complex (MHC) is challenging in nonmodel vertebrates. The traditional method of extensive cloning and Sanger sequencing is costly and time‐intensive and indirect methods of assessment often underestimate total variation. Here, we explored the suitability of 454 pyrosequencing for characterizing multilocus genes for use in population genetic studies. We compared two sample tagging protocols and two bioinformatic procedures for 454 sequencing through characterization of a 185‐bp fragment of MHC DRB exon 2 in wolverines (Gulo gulo) and further compared the results with those from cloning and Sanger sequencing. We found 10 putative DRB alleles in the 88 individuals screened with between two and four alleles per individual, suggesting amplification of a duplicated DRB gene. In addition to the putative alleles, all individuals possessed an easily identifiable pseudogene. In our system, sequence variants with a frequency below 6% in an individual sample were usually artefacts. However, we found that sample preparation and data processing procedures can greatly affect variant frequencies in addition to the complexity of the multilocus system. Therefore, we recommend determining a per‐amplicon‐variant frequency threshold for each unique system. The extremely deep coverage obtained in our study (approximately 5000×) coupled with the semi‐quantitative nature of pyrosequencing enabled us to assign all putative alleles to the two DRB loci, which is generally not possible using traditional methods. Our method of obtaining locus‐specific MHC genotypes will enhance population genetic analyses and studies on disease susceptibility in nonmodel wildlife species.     

Family‐assisted inference of the genetic architecture of major histocompatibility complex variation

With their direct link to individual fitness, genes of the major histocompatibility complex (MHC) are a popular system to study the evolution of adaptive genetic diversity. However, owing to the highly dynamic evolution of the MHC region, the isolation, characterization and genotyping of MHC genes remain a major challenge. While high‐throughput sequencing technologies now provide unprecedented resolution of the high allelic diversity observed at the MHC, in many species, it remains unclear (i) how alleles are distributed among MHC loci, (ii) whether MHC loci are linked or segregate independently and (iii) how much copy number variation (CNV) can be observed for MHC genes in natural populations. Here, we show that the study of allele segregation patterns within families can provide significant insights in this context. We sequenced two MHC class I (MHC‐I) loci in 1267 European barn owls (Tyto alba), including 590 offspring from 130 families using Illumina MiSeq technology. Coupled with a high per‐individual sequencing coverage (~3000×), the study of allele segregation patterns within families provided information on three aspects of the architecture of MHC‐I variation in barn owls: (i) extensive sharing of alleles among loci, (ii) strong linkage of MHC‐I loci indicating tandem architecture and (iii) the presence of CNV in the barn owl MHC‐I. We conclude that the additional information that can be gained from high‐coverage amplicon sequencing by investigating allele segregation patterns in families not only helps improving the accuracy of MHC genotyping, but also contributes towards enhanced analyses in the context of MHC evolutionary ecology.     

Racial Disparities in Prostate Cancer Mortality in the 50 Largest US Cities

IntroductionThis paper presents race-specific prostate cancer mortality rates and the corresponding disparities for the largest cities in the US over two decades.MethodsThe 50 largest cities in the US were the units of analysis. Data from two 5-year periods were analyzed: 1990–1994 and 2005–2009. Numerator data were abstracted from national death files where the cause was malignant neoplasm of prostate (prostate cancer) (ICD9 = 185 and ICD10 = C61). Population-based denominators were obtained from US Census data. To measure the racial disparity, we calculated non-Hispanic Black: non-Hispanic White rate ratios (RRs), rate differences (RDs), and corresponding confidence intervals for each 5-year period. We also calculated correlation and unadjusted regression coefficients for 11 city-level variables, such as segregation and median income, and the RDs.ResultsAt the final time point (2005–2009), the US and all 41 cities included in the analyses had a RR greater than 1 (indicating that the Black rate was higher than the White rate) (range = 1.13 in Minneapolis to 3.24 in Los Angeles), 37 of them statistically significantly so. The US and 26 of the 41 cities saw an increase in the Black:White RR between the time points. The level of disparity within a city was associated with the degree of Black segregation.ConclusionThis analysis revealed large disparities in Black:White prostate cancer mortality in the US and many of its largest cities over the past two decades. The data show considerable variation in the degree of disparity across cities, even among cities within the same state. This type of specific city-level data can be used to motivate public health professionals, government officials, cancer control agencies, and community-based organizations in cities with large or increasing disparities to demand more resources, focus research efforts, and implement effective policy and programmatic changes in order to combat this highly prevalent condition.     

Secukinumab,a novel anti–IL-17A antibody,shows low immunogenicity potential in human in vitro assays comparable to other marketed biotherapeutics with low clinical immunogenicity

Secukinumab is a human monoclonal antibody that selectively targets interleukin-17A and has been demonstrated to be highly efficacious in the treatment of moderate to severe plaque psoriasis, starting at early time points, with a sustained effect and a favorable safety profile. Biotherapeutics—including monoclonal antibodies (mAbs)—can be immunogenic, leading to formation of anti-drug antibodies (ADAs) that can result in unwanted effects, including hypersensitivity reactions or compromised therapeutic efficacy. To gain insight into possible explanations for the clinically observed low immunogenicity of secukinumab, we evaluated its immunogenicity potential by applying 2 different in vitro assays: T-cell activation and major histocompatibility complex–associated peptide proteomics (MAPPs). For both assays, monocyte-derived dendritic cells (DCs) from healthy donors were exposed in vitro to biotherapeutic proteins. DCs naturally process proteins and present the derived peptides in the context of human leukocyte antigen (HLA)-class II. HLA-DR–associated biotherapeutic-derived peptides, representing potential T–cell epitopes, were identified in the MAPPs assay. In the T-cell assay, autologous CD4⁺ T cells were co-cultured with secukinumab-exposed DCs and T-cell activation was measured by proliferation and interleukin-2 secretion. In the MAPPs analysis and T-cell activation assays, secukinumab consistently showed relatively low numbers of potential T-cell epitopes and low T-cell response rates, respectively, comparable to other biotherapeutics with known low clinical immunogenicity. In contrast, biotherapeutics with elevated clinical immunogenicity rates showed increased numbers of potential T-cell epitopes and increased T-cell response rates in T-cell activation assays, indicating an approximate correlation between in vitro assay results and clinical immunogenicity incidence.     

Sexual size dimorphism and Rensch's rule in Canidae

The size variation between males and females of a species is a phenomenon known as sexual size dimorphism (SSD). The observed patterns of variation in SSD among species has led to the formulation of Rensch's rule, which establishes that, in species showing a male size bias, SSD increases with an increase in the body size of the species. However, for species in which there is a female size bias, the SSD would decrease when the body size of the species increases. In the present study, we examined the variation in body size and SSD of 33 species of canids from estimates of body mass and body length. We studied its relationship with life‐history characteristics and tested Rensch's rule using phylogenetic generalized least squares and phylogenetic reduced major axis regressions, respectively. We observed the existence of correlation between body mass and body length, although the SSDs from these estimators are uncorrelated. SSD did not show the pattern predicted by Rensch's rule. SSD also did not show any correlation with life‐history traits. It is likely that the low SSD observed in canids is related to the monogamy observed in the family, which is a rare situation in mammals.