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This review article highlights the potential role of KMT2D mutations in developing neurodevelopmental disorders, specifically Kabuki syndrome and schizophrenia. Neurodevelopmental disorders are complex conditions with a multifactorial etiology, but genetic mutations have been shown to play a crucial role in their pathogenesis. Recent studies suggest that KMT2D mutations may contribute to the development of these disorders by interfering with enhancer function and histone monomethylation, which are essential epigenetic mechanisms involved in brain development and function. The review article explores the hypothesis that KMT2D mutations may be a cause or a risk factor for Kabuki syndrome and schizophrenia. The article discusses potential areas of interest, such as the characterization of KMT2D mutations in patient populations and the investigation of their functional impact on gene expression and brain development. Additionally, the article proposes research methods to investigate further the relationship between KMT2D mutations and these disorders, including animal models and the use of cutting-edge technologies such as CRISPR/Cas9. Identifying KMT2D mutations in both Kabuki syndrome and schizophrenia may provide a new avenue for understanding the underlying mechanisms of these disorders and developing new treatments. The potential impact of this research is significant, as it may lead to the development of targeted therapies for individuals with Kabuki syndrome and schizophrenia who harbor KMT2D mutations. Additionally, identifying KMT2D mutations as a risk factor for these disorders may facilitate early detection and intervention, improving outcomes and quality of life for affected individuals and their families. In summary, this review article provides valuable insights into the potential role of KMT2D mutations in the pathogenesis of Kabuki syndrome and schizophrenia. It highlights the importance of further research in this area. [ABSTRACT FROM AUTHOR]

Solid tumours are composed of cancer cells characterised by genetic mutations that underpin the disease, but also contain a suite of genetically normal cells and the extracellular matrix (ECM). These two latter components are constituents of the tumour microenvironment (TME), and are key determinants of tumour biology and thereby the outcomes for patients. The tumour ECM has been the subject of intense research over the past two decades, revealing key biochemical and mechanobiological principles that underpin its role in tumour cell proliferation and survival. However, the ECM also strongly influences the genetically normal immune cells within the microenvironment, regulating not only their proliferation and survival, but also their differentiation and access to tumour cells. Here we review recent advances in our knowledge of how the ECM regulates the tumour immune microenvironment and vice versa, comparing normal skin wound healing to the pathological condition of tumour progression. [ABSTRACT FROM AUTHOR]

Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that are resolved asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of long interspersed nuclear elements. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric. [ABSTRACT FROM AUTHOR]

Pituitary adenomas (PAs) can be classified as non-secreting adenomas, somatotroph adenomas, corticotroph adenomas, lactotroph adenomas, and thyrotroph adenomas. Substantial advances have been made in our knowledge of the pathobiology of PAs. To obtain a comprehensive understanding of the molecular biological characteristics of different types of PAs, we reviewed the important advances that have been made involving genetic and epigenetic variation, comprising genetic mutations, chromosome number variations, DNA methylation, microRNA regulation, and transcription factor regulation. Classical tumor predisposition syndromes include multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4) syndromes, Carney complex, and X-LAG syndromes. PAs have also been described in association with succinate dehydrogenase-related familial PA, neurofibromatosis type 1, and von Hippel–Lindau, DICER1, and Lynch syndromes. Patients with aryl hydrocarbon receptor-interacting protein (AIP) mutations often present with pituitary gigantism, either in familial or sporadic adenomas. In contrast, guanine nucleotide-binding protein G(s) subunit alpha (GNAS) and G protein-coupled receptor 101 (GPR101) mutations can lead to excess growth hormone. Moreover, the deubiquitinase gene USP8 , USP48 , and BRAF mutations are associated with adrenocorticotropic hormone production. In this review, we describe the genetic and epigenetic landscape of PAs and summarize novel insights into the regulation of pituitary tumorigenesis. [ABSTRACT FROM AUTHOR]

The study utilized molecular-genetic, cytogenetic, and statistical analyzes methods. A cytogenetic and molecular genetic analysis of the inhabitants of the villages of Amangeldy, Belbulak, in whose territory warehouses of unused pesticides are located, was carried out. Residents of the Basshi village, on the territory of which there are no products of disposal of pesticides, were taken as control. Cytogenetic analysis showed a high level of chromosomal aberrations for the inhabitants of the Belbulak village, an increased level for the inhabitants of the Amangeldy village and a low level in the Basshi cohort. Molecular genetic analysis did not reveal a significant correlation between the polymorphisms of the XRCC1 Arg194Trp, XRCC3 Thr241Met and XPD Lys751Gln genes and the frequency of chromosomal aberrations. However, study determined the associative relationship of the polymorphism of the DNA repair gene XRCC1 Arg399Gln with the development of cardiovascular diseases in a population living near foci of pesticidal contamination. [ABSTRACT FROM AUTHOR]

Motivation Accurate prediction of protein stability changes upon single-site variations (ΔΔ G) is important for protein design, as well as for our understanding of the mechanisms of genetic diseases. The performance of high-throughput computational methods to this end is evaluated mostly based on the Pearson correlation coefficient between predicted and observed data, assuming that the upper bound would be 1 (perfect correlation). However, the performance of these predictors can be limited by the distribution and noise of the experimental data. Here we estimate, for the first time, a theoretical upper-bound to the ΔΔ G prediction performances imposed by the intrinsic structure of currently available ΔΔ G data. Results Given a set of measured ΔΔ G protein variations, the theoretically "best predictor" is estimated based on its similarity to another set of experimentally determined ΔΔ G values. We investigate the correlation between pairs of measured ΔΔ G variations, where one is used as a predictor for the other. We analytically derive an upper bound to the Pearson correlation as a function of the noise and distribution of the ΔΔ G data. We also evaluate the available datasets to highlight the effect of the noise in conjunction with ΔΔ G distribution. We conclude that the upper bound is a function of both uncertainty and spread of the ΔΔ G values, and that with current data the best performance should be between 0.7 and 0.8, depending on the dataset used; higher Pearson correlations might be indicative of overtraining. It also follows that comparisons of predictors using different datasets are inherently misleading. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Objective: The relationship between genomic variables (genome size, gene number, intron size, and intron number) and evolutionary forces has two implications. First, they help to unravel the mechanism underlying genome evolution. Second, they provide a solution to the debate over discrepancy between genome size variation and organismal complexity. Previously, a clear correlation between genomic variables and effective population size and mutation rate (Neu) led to an important hypothesis to consider random genetic drift as a major evolutionary force during evolution of genome size and complexity. But recent reports also support natural selection as the leading evolutionary force. As such, the debate remains unresolved. Results: Here, we used a multivariate method to explore the relationship between genomic variables and Neu in order to understand the evolution of genome. Previously reported patterns between genomic variables and Neu were not observed in our multivariate study. We found only one association between intron number and Neu, but no relationships were observed between genome size, intron size, gene number, and Neu, suggesting that Neu of the organisms solely does not influence genome evolution. We, therefore, concluded that Neu influences intron evolution, while it may not be the only force that provides mechanistic insights into genome evolution and complexity. [ABSTRACT FROM AUTHOR]

Background: Esophageal carcinoma (EC), consists of two histological types, esophageal squamous carcinoma (ESCC) and esophageal adenocarcinoma (EAC). EAC accounted for 10% of EC for centuries; however, the prevalence of EAC has alarmingly risen 6 times and increased to about 50% of EC in recent 30 years in the western countries, while treatment options for EAC patients are still limited. Stratification of molecular subtypes by gene expression profiling methods had offered opportunities for targeted therapies. However, the molecular subtype in EAC has not been defined. Hence, Identification of EAC molecular subtypes is needed and will provide important insights for future new therapies. Results: We performed meta-analysis of gene expression profiling data on three independent EAC cohorts and showed that there are two common molecular subtypes in EAC. Each of the two EAC molecular subtypes has subtype specific expression patterns and mutation signatures. Genes which were over-expressed in subtype I EACs rather than subtype II EAC cases, were enriched in biological processes including epithelial cell differentiation, keratinocyte differentiation, and KEGG pathways including basal cell carcinoma. TP53 and CDKN2A are significantly mutated in both EAC subtypes. 24 genes including SMAD4 were found to be only significantly mutated in subtype I EAC cases, while 30 genes including ARID1A are only significantly mutated in subtype II EACs. Conclusion: Two EAC molecular subtypes were defined and validated. This finding may offer new opportunities for targeted therapies. [ABSTRACT FROM AUTHOR]

Since the last decade, a lot of advancement has been made to understand biological processes involving complex intracellular pathways. The major challenge faced was monitoring and trafficking of metabolites in real time. Although a range of quantitative and imaging techniques have been developed so far, the discovery of green fluorescent proteins (GFPs) has revolutionized the advancement in the field of metabolomics. GFPs and their variants have enabled researchers to ‘paint’ a wide range of biological molecules. Fluorescence resonance energy transfer (FRET)-based genetically encoded sensors is a promising technology to decipher the real-time monitoring of the cellular events inside living cells. GFPs and their variants, due to their intrinsic fluorescence properties, are extensively being used nowadays in cell-based assays. This review focuses on structure and function of GFP and its derivatives, mechanism emission and their use in the development of FRET-based sensors for metabolites. [ABSTRACT FROM AUTHOR]

Bovine leukemia virus (BLV) is the etiological agent of enzootic bovine leukosis (EBL), which causes enormous economic losses in the livestock industry worldwide. To reduce the economic loss caused by BLV infection, it is important to clarify the characters associated with BLV transmissibility and pathogenesis in cattle. In this study, we focused on viral characters and examined spontaneous mutations in the virus and viral properties by analyses of whole genome sequences and BLV molecular clones derived from cows with and without EBL. Genomic analysis indicated that all 28 strains harbored limited genetic variations but no deletion mutations that allowed classification into three groups (A, B, and C), except for one strain. Some nucleotide/amino acid substitutions were specific to a particular group. On the other hand, these genetic variations were not associated with the host bovine leukocyte antigen-DRB3 allele, which is known to be related to BLV pathogenesis. The viral replication activity in vitro was high, moderate, and low in groups A, B, and C, respectively. In addition, the proviral load, which is related to BLV transmissibility and pathogenesis, was high in cows infected with group A strains and low in those infected with group B/C strains. Therefore, these results suggest that limited genetic variations could affect viral properties relating to BLV transmissibility and pathogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To identify the molecular genetic cause in four families of various ethnic backgrounds with cornea plana. Methods: Detailed ophthalmological examination and direct sequencing of the KERA coding region in five patients of Czech and Turkish origin and their available family members. Results: Compound heterozygosity for a novel missense mutation c.209C>T; p.(Pro70Leu) and a novel splice site mutation c.887‐1G>A in KERA were detected in two affected siblings of Czech origin. In silico analysis supported the pathogenicity of both variants. The second proband of Czech origin harboured c.835C>T; p.(Arg279*) in a homozygous state. Homozygous mutations c.740A>G; p.(Asn247Ser) and c.674C>T; p.(Ile225Thr) were identified in the Turkish probands, both born out of consanguineous marriages. Observed ocular phenotypes were typical of cornea plana with the exception of one Czech patient who also had marked thinning and protrusion in the superior part of the left cornea (mean keratometry 47.2 D). No corneal endothelial cell pathology was found by specular microscopy in seven eyes, in three eyes visualization of the posterior corneal surface was unsuccessful. Conclusion: KERA mutation c.740A>G has been identified to date in three different populations, which makes it the most frequently occurring mutation in patients with cornea plana. Marked corneal thinning and ectasia are a very rare finding in this disorder and longitudinal follow‐up needs to be performed to determine its potential progressive nature. [ABSTRACT FROM AUTHOR]

Complex behavioral traits, such as those making up a migratory phenotype, are regulated by multiple environmental factors and multiple genes. We investigated possible relationships between microsatellite variation at two candidate genes implicated in the control of migratory behavior, Clock and Adcyap1, and several aspects of migratory life-history and evolutionary divergence in the Painted Bunting (Passerina ciris), a species that shows wide variation in migratory and molting strategies across a disjunct distribution. We focused on Clock and Adcyap1 microsatellite variation across three Painted Bunting populations in Oklahoma, Louisiana, and North Carolina, and for the Oklahoma breeding population we used published migration tracking data on adult males to explore phenotypic variation in individual migratory behavior. We found no correlation between microsatellite allele size within either Clock and Adcyap1 relative to the initiation or duration of fall migration in adult males breeding in Oklahoma. We also show the lack of significant correlations with aspects of the migratory phenotype for the Louisiana population. Our research highlights the limitations of studying microsatellite allelic mutations that are of undetermined functional influence relative to complex behavioral phenotypes. [ABSTRACT FROM AUTHOR]

Technological innovation and increased affordability have contributed to the widespread adoption of genome sequencing technologies in biomedical research. In particular large cancer research consortia have embraced next generation sequencing, and have used the technology to define the somatic mutation landscape of multiple cancer types. These studies have primarily utilised the Illumina HiSeq platforms. In this study we performed whole genome sequencing of three malignant pleural mesothelioma and matched normal samples using a new platform, the BGISEQ-500, and compared the results obtained with Illumina HiSeq X Ten. Germline and somatic, single nucleotide variants and small insertions or deletions were independently identified from data aligned human genome reference. The BGISEQ-500 and HiSeq X Ten platforms showed high concordance for germline calls with genotypes from SNP arrays (>99%). The germline and somatic single nucleotide variants identified in both sequencing platforms were highly concordant (86% and 72% respectively). These results indicate the potential applicability of the BGISEQ-500 platform for the identification of somatic and germline single nucleotide variants by whole genome sequencing. The BGISEQ-500 datasets described here represent the first publicly-available cancer genome sequencing performed using this platform. [ABSTRACT FROM AUTHOR]

Background Marfan syndrome (MFS), a congenital connective tissue disorder leading to aortic aneurysm development, is caused by fibrillin-1 ( FBN1 ) gene mutations. Transforming growth factor beta (TGF-β) might play a role in the pathogenesis. It is still a matter of discussion if and how TGF-β up-regulates the intracellular downstream pathway, although TGF-β receptor 3 ( TGFBR3 or Betaglycan) is thought to be involved. We aimed to elucidate the role of TGFBR3 protein in TGF-β signaling in Marfan patients. Methods Dermal fibroblasts of MFS patients with haploinsufficient (HI; n=9) or dominant negative (DN; n=4) FBN1 gene mutations, leading to insufficient or malfunctioning fibrillin-1, respectively, were used. Control cells ( n =10) were from healthy volunteers. We quantified TGFBR3 protein expression by immunofluorescence microscopy and gene expression of FBN1 , TGFB1 , its receptors, and downstream transcriptional target genes by quantitative polymerase chain reaction. Results Betaglycan protein expression in FBN1 mutants pooled was higher than in controls ( P =.004) and in DN higher than in HI ( P =.015). In DN, significantly higher mRNA expression of FBN1 ( P =.014), SMAD7 ( P =.019), HSP47 ( P =.023), and SERPINE1 ( P =.008), but a lower HSPA5 expression ( P =.029), was observed than in HI. A pattern of higher expression was noted for TGFB1 ( P =.059), FN1 ( P =.089), and COL1A1 ( P =.089) in DN as compared to HI. TGFBR3 protein expression in cells, both presence in the endoplasmic reticulum and amount of vesicles per cell, correlated positively with TGFB1 mRNA expression (Rs=0.60, P =.017; Rs=0.55, P =.029; respectively). TGFBR3 gene expression did not differ between groups. Conclusion We demonstrated that activation of TGF-β signaling is higher in patients with a DN than an HI FBN1 gene mutation. Also, TGFBR3 protein expression is increased in the DN group and correlates positively with TGFB1 expression in groups pooled. We suggest that TGFBR3 protein expression is involved in up-regulated TGF-β signaling in MFS patients with a DN FBN1 gene mutation. [ABSTRACT FROM AUTHOR]

Changes in pig fertility have occurred as a result of domestication, but are not understood at the level of genetic variation. To identify variations potentially responsible for prolificacy, we sequenced the genomes of the highly prolific Taihu pig breed and four control breeds. Genes involved in embryogenesis and morphogenesis were targeted in the Taihu pig, consistent with the morphological differences observed between the Taihu pig and others during pregnancy. Additionally, excessive functional non-coding mutations have been specifically fixed or nearly fixed in the Taihu pig.We focused attention on an oestrogen response element (ERE) within the first intron of the bone morphogenetic protein receptor type-1B gene (BMPR1B) that overlaps with a known quantitative trait locus (QTL) for pig fecundity. Using 242 pigs from 30 different breeds, we confirmed that the genotype of the ERE was nearly fixed in the Taihu pig. ERE function was assessed by luciferase assays, examination of histological sections, chromatin immunoprecipitation, quantitative polymerase chain reactions, and western blots. The results suggest that the ERE may control pig prolificacy via the cis-regulation of BMPR1B expression. This study provides new insight into changes in reproductive performance and highlights the role of non-coding mutations in generating phenotypic diversity between breeds. [ABSTRACT FROM AUTHOR]

Oncolytic virotherapy is an experimental treatment of cancer patients. This method is based on the administration of replication-competent viruses that selectively destroy tumor cells but remain healthy tissue unaffected. In order to obtain optimal dosage for complete tumor eradication, we derive and analyze a new oncolytic virotherapy model with a fixed time period τ and non-local infection which is caused by the diffusion of the target cells in a continuous bounded domain, where τ is assumed to be the duration that oncolytic viruses spend to destroy the target cells and to release new viruses since they enter into the target cells. This model is a delayed reaction diffusion system with nonlocal reaction term. By analyzing the global stability of tumor cell eradication equilibrium, we give different treatment strategies for cancer therapy according to the different genes mutations (oncogene and antioncogene). [ABSTRACT FROM AUTHOR]

Studying hybridization has the potential to elucidate challenging questions in evolutionary biology such as the nature of adaptive genetic variation and reproductive isolation. A growing body of work highlights that the merging of divergent genomes goes beyond the reshuffling of standing variation from related species and promotes mutations (Abbott et al., ). However, to what extent such genome instability generates evolutionary significant variation remains largely elusive. In this issue of Molecular Ecology, Dennenmoser et al. () report considerable dynamics of transposable elements ( TEs) in a recent invasive fish species of hybrid origin ( Cottus; Figure [ABSTRACT FROM AUTHOR]

Familial Mediterranean fever is a common hereditary disease in Turkey. To date, different mutational spectrum of MEFV gene was observed in studies carried out in different regions of Turkey but in most of these studies association of clinical symptoms of FMF to mutant genotypes have not been investigated in details. Here we report the MEFV gene variations in exons 2, 3, 5 and 10 and their relations to major clinical symptoms of FMF in 514 unrelated (245 males and 269 females) Turkish patients. MEFV mutations were found in 45% ( n = 230) of patients and 55% ( n = 284) of patients did not have any mutations. One hundred and thirty-seven (60%) patients were heterozygous, 57 (24.7%) patients were compound heterozygous, 33 (14%) patients were homozygous and 3 (1.3%) patients were having a complex genotype. Allele frequencies of MEFV mutations were M694V (48%), E148Q (18%), M680I (15%), V726A (12.5%), P369S (3.3%), R761H (0.9), K695R (0.9), E148V (0.9) and A744S (0.5%). Abdominal pain (76%) and fever (58%) were two most seen complications among patients followed by arthritis (28%) and chest pain (19%). Almost all major clinical symptoms of FMF were higher in patients with one or more M694V or M680I mutant allele. In contrast, patients having E148Q or V726A mutant allele showed fewer clinical FMF symptoms. Patients with P369S have higher abdominal pain, chest pain and fever than expected. Arthritis was high in K695R heterozygous genotype. One hundred and eighteen patients were carrying more than one polymorphic allele. The most common polymorphism was R202Q (13%). In addition, a novel heterozygous polymorphism at 564th nucleotide (C > T) of exon2 were found in 2 patients. [ABSTRACT FROM AUTHOR]

Objective Locus and allellic heterogeneity in polycystic kidney disease (PKD) is a great challenge in precision diagnosis. We aim to establish comprehensive methods to distinguish the pathogenic mutations from the variations in PKD1 , PKD2 and PKHD1 genes in a limited time and lay the foundation for precisely prenatal diagnosis, preimplantation genetic diagnosis and presymptom diagnosis of PKD. Methods Nested PCR combined with direct DNA sequencing were used to screen variations in PKD1 , PKD2 and PKHD1 genes. The pathogenicity of de novel variations was assessed by the comprehensive methods including clinic data and literature review, databases query, analysis of co-segregation of the variants with the disease, variant frequency screening in the population, evolution conservation comparison, protein structure analysis and splice sites predictions. Results 17 novel mutations from 15 Chinese Han families were clarified including 10 mutations in PKD1 gene and 7 mutations in PKHD1 gene. The novel mutations were classified as 4 definite pathogenic, 2 highly likely pathogenic, 4 likely pathogenic, 7 indeterminate by the comprehensive analysis. The results were verified the truth by the follow-up visits. Conclusions The comprehensive methods may be useful in distinguishing the pathogenic mutations from the variations in PKD1 , PKD2 and PKHD1 genes for prenatal diagnosis and presymptom diagnosis of PKD. Our results also enriched PKD genes mutation spectrum and evolved possible genotype-phenotype correlations of Chinese Han population. [ABSTRACT FROM AUTHOR]

Landscape genetic studies based on neutral genetic markers have contributed to our understanding of the influence of landscape composition and configuration on gene flow and genetic variation. However, the potential for species to adapt to changing landscapes will depend on how natural selection influences adaptive genetic variation. We demonstrate how landscape resistance models can be combined with genetic simulations incorporating natural selection to explore how the spread of adaptive variation is affected by landscape characteristics, using desert bighorn sheep (Ovis canadensis nelsoni) in three differing regions of the southwestern United States as an example. We conducted genetic sampling and least-cost path modeling to optimize landscape resistance models independently for each region, and then simulated the spread of an adaptive allele favored by selection across each region. Optimized landscape resistance models differed between regions with respect to landscape variables included and their relationships to resistance, but the slope of terrain and the presence of water barriers and major roads had the greatest impacts on gene flow. Genetic simulations showed that differences among landscapes strongly influenced spread of adaptive genetic variation, with faster spread (1) in landscapes with more continuously distributed habitat and (2) when a pre-existing allele (i.e., standing genetic variation) rather than a novel allele (i.e., mutation) served as the source of adaptive genetic variation. The combination of landscape resistance models and genetic simulations has broad conservation applications and can facilitate comparisons of adaptive potential within and between landscapes. [ABSTRACT FROM AUTHOR]

Protein modeling and molecular dynamics hold a unique toolset to aide in the characterization of clinical variants that may result in disease. Not only do these techniques offer the ability to study under characterized proteins, but they do this with the speed that is needed for time-sensitive clinical cases. In this paper we retrospectively study a clinical variant in the XIAP protein, C203Y, while addressing additional variants seen in patients with similar gastrointestinal phenotypes as the C203Y mutation. In agreement with the clinical tests performed on the C203Y patient, protein modeling and molecular dynamics suggest that direct interactions with RIPK2 and Caspase3 are altered by the C203Y mutation and subsequent loss of Zn coordination in the second BIR domain of XIAP. Interestingly, the variant does not appear to alter interactions with SMAC, resulting in further damage to the caspase and NOD2 pathways. To expand the computational strategy designed when studying XIAP, we have applied the molecular modeling tools to a list of 140 variants seen in CFTR associated with cystic fibrosis, and a list of undiagnosed variants in 17 different genes. This paper shows the exciting applications of molecular modeling in the classification and characterization of genetic variants identified in next generation sequencing. [ABSTRACT FROM AUTHOR]

The article informs about research on B cell translocation gene 1 mutation yields supercompetitive B cells primed for malignant transformation of abnormal cells. Topics include Diffuse large B cell lymphomas originate from specialized B cells participating in the germinal center (GC) reaction; and GCs are transient structures within which antigenactivated B cells undergo proliferative somatic hypermutation of their immunoglobulin genes to improve affinity against the encountered antigen.

The article presents a study related to coexistence of gain-of-function JAK2 germ line mutations with JAK2V617F in polycythemia vera. Topics discussed include Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs); clonal premalignant disorders that precede development of acute leukemia; and signal transduction of JAK2 mutant.

Theoretical and empirical work has described a range of scenarios in which plasticity may shape adaptation to a novel environment. For example, recent studies have implicated a role for both adaptive and non-adaptive plasticity in facilitating adaptive evolution, yet we lack a broad mechanistic framework to predict under what conditions each scenario is likely to dominate evolutionary processes. We propose that such a framework requires understanding how transcriptional, protein, and developmental networks change in response to different rearing environments across evolutionary time scales. Our central argument is that these hierarchical networks generate and maintain phenotypic variation in populations, both by buffering organisms from developmental noise and mutational inputs and by exhibiting flexible responses to environmental cues. These network properties in turn lead to predictions about how plasticity should influence adaptive evolution. Because buffering mechanisms allow the build-up of cryptic genetic variation (i.e., genetic variation without phenotypic consequences), the initial response of individuals colonizing novel environments should be a release of genetic and phenotypic variation that selection acts upon; some of which is adaptive and some of which is not. Thus, in the early stages of adaptation, strong selection against maladaptive phenotypes should result in rapid evolution acting on standing cryptic variation. However, over longer time scales, evolutionary change should largely be compensatory, to rebuild robust developmental processes and promote integrated phenotypes. We argue that considering how hierarchical networks respond over developmental and evolutionary time encompasses a more mechanistic understanding of the genotype-phenotype map, and will result in a more predictive framework for understanding the role of plasticity in adaptive evolution. [ABSTRACT FROM AUTHOR]

Background: The study of genomic variation has provided key insights into the functional role of mutations. Predominantly, studies have focused on single nucleotide variants (SNV), which are relatively easy to detect and can be described with rich mathematical models. However, it has been observed that genomes are highly plastic, and that whole regions can be moved, removed or duplicated in bulk. These structural variants (SV) have been shown to have significant impact on phenotype, but their study has been held back by the combinatorial complexity of the underlying models. Results: We describe here a general model of structural variation that encompasses both balanced rearrangements and arbitrary copy-number variants (CNV). Conclusions: In this model, we show that the space of possible evolutionary histories that explain the structural differences between any two genomes can be sampled ergodically. [ABSTRACT FROM AUTHOR]

Craniofacial disease phenotypes exhibit significant variation in penetrance and severity. Although many genetic contributions to phenotypic variation have been identified, genotype–phenotype correlations remain imprecise. Recent work in evolutionary developmental biology has exposed intriguing developmental mechanisms that potentially explain incongruities in genotype–phenotype relationships. This review focuses on two observations from work in comparative and experimental animal model systems that highlight how development structures variation. First, multiple genetic inputs converge on relatively few developmental processes. Investigation of when and how variation in developmental processes occurs may therefore help predict potential genetic interactions and phenotypic outcomes. Second, genetic mutation is typically associated with an increase in phenotypic variance. Several models outlining developmental mechanisms underlying mutational increases in phenotypic variance are discussed using Satb2 -mediated variation in jaw size as an example. These data highlight development as a critical mediator of genotype–phenotype correlations. Future research in evolutionary developmental biology focusing on tissue-level processes may help elucidate the “black box” between genotype and phenotype, potentially leading to novel treatment, earlier diagnoses, and better clinical consultations for individuals affected by craniofacial anomalies. [ABSTRACT FROM AUTHOR]

Mendelian mutations are the most medically actionable variants in the human genome and have always played a central role in its functional annotation. Despite the relative ease with which Mendelian mutations are identified compared to other classes of variants, the pace of their discovery has until recently been slow. However, recent technological advances in genomic sequencing have made the prospect of identifying all genes that can harbor Mendelian mutations an achievable near-term goal. The many lessons learned from previous discoveries of Mendelian mutations should inform future studies as I will discuss in this review. Also discussed are some of the challenges that will gain more prominence as we approach the last phase of the effort to map all Mendelian genes. [ABSTRACT FROM AUTHOR]

Objective Familial adenomatous polyposis (FAP) is mainly caused by germline mutations in the adenomatous polyposis coli ( APC ) gene. This study aimed to detect pathogenic variants in five Chinese FAP families and review all previously reported pathogenic variants of APC gene in Chinese population. Methods Five non-consanguineous FAP families and 100 unrelated ethnicity-matched controls were included in the study. Sanger sequencing was performed to screen for APC coding and splicing variants. Chinese and English literature on APC germline mutations were reviewed to compile the mutation spectrum of APC gene in Chinese FAP patients. Results One pathogenic variant was detected in each family for the five pedigrees we tested. Three variants (c.3183_3187delACAAA, c.2626C > T and c.1312 + 1G > A) were previously reported as pathogenic. The other two variants were novel: c.794_795insG/p.Val266SerfsTer11 and c.2142_2143insG/p.His715AlafsTer19. They are absent from public databases (1000 Genomes, dbSNP, ESP and ExAC) and 100 normal controls, and are classified as pathogenic based on the new ACMG/AMP variant classification guidelines. Literature review and current study revealed a total of 82 different pathogenic variants from 127 Chinese FAP families. Among these families, 83 families had frameshift variants (65.35%), 26 with nonsense variants (20.47%), six with splice site variants (4.72%), three with missense variants (2.36%) and nine with large deletion or duplication variants (7.09%). Apart from the two previously reported mutation hotspots c.3927_3931delAAAGA (20.47%) and c.3183_3187delACAAA (7.09%), c.847C > T/p.Arg283Ter variant occurred with a frequency of 3.15% (4 out of 127) in Chinese FAP patients. Conclusions We reported two novel pathogenic variants. The comprehensive compilation of variants and comparison revealed largely similar mutation spectrum between Chinese and Western patient populations. Some unique features noticed in Chinese patient population may help to better understand the pathogenesis of FAP. [ABSTRACT FROM AUTHOR]

On December 18,2014, a yellow female fly quietly emerged from her pupal case. What made her unique was that she had only one parent carrying a mutant allele of this classic recessive locus. Then, one generation later, after mating with a wild-type male, all her offspring displayed the same recessive yellow phenotype. Further analysis of other such yellow females revealed that the construct causing the mutation was converting the opposing chromosome with 95% efficiency. These simple results, seen also in mosquitoes and yeast, open the door to a new era of genetics wherein the laws of traditional Mendelian inheritance can be bypassed for a broad variety of purposes. Here, we consider the implications of this fundamentally new form of active genetics, its applications for gene drives, reversal and amplification strategies, its potential for contributing to cell and gene therapy strategies, and ethical/biosafety considerations associated with such active genetic elements. [ABSTRACT FROM AUTHOR]

Posterior cortical atrophy (PCA) is an understudied visual impairment syndrome most often due to "posterior Alzheimer's disease (AD)" pathology. Case studies detected mutations in PSEN1, PSEN2, GRN, MAPT, and PRNP in subjects with clinical PCA. To detect the frequency and spectrum of mutations in known dementia genes in PCA, we screened 124 European-American subjects with clinical PCA (n = 67) or posterior AD neuropathology (n = 57) for variants in genes implicated in AD, frontotemporal dementia, and prion disease using NeuroX, a customized exome array. Frequencies in PCA of the variants annotated as pathogenic or potentially pathogenic were compared against ~4300 European-American population controls from the NHLBI Exome Sequencing Project. We identified 2 rare variants not previously reported in PCA, TREM2 Arg47His, and PSEN2 Ser130Leu. No other pathogenic or potentially pathogenic variants were detected in the screened dementia genes. In this first systematic variant screen of a PCA cohort, we report 2 rare mutations in TREM2 and PSEN2, validate our previously reported APOE ε4 association, and demonstrate the utility of NeuroX. [ABSTRACT FROM AUTHOR]

Summary In sexual species, gametes have to find and recognize one another. Signaling is thus central to sexual reproduction and involves a rapidly evolving interplay of shared and divergent interests [ 1–4 ]. Among Caenorhabditis nematodes, three species have evolved self-fertilization, changing the balance of intersexual relations [ 5 ]. Males in these androdioecious species are rare, and the evolutionary interests of hermaphrodites dominate. Signaling has shifted accordingly, with females losing behavioral responses to males [ 6, 7 ] and males losing competitive abilities [ 8, 9 ]. Males in these species also show variable same-sex and autocopulatory mating behaviors [ 6, 10 ]. These behaviors could have evolved by relaxed selection on male function, accumulation of sexually antagonistic alleles that benefit hermaphrodites and harm males [ 5, 11 ], or neither of these, because androdioecy also reduces the ability of populations to respond to selection [ 12–14 ]. We have identified the genetic cause of a male-male mating behavior exhibited by geographically dispersed C. elegans isolates, wherein males mate with and deposit copulatory plugs on one another’s excretory pores. We find a single locus of major effect that is explained by segregation of a loss-of-function mutation in an uncharacterized gene, plep-1 , expressed in the excretory cell in both sexes. Males homozygous for the plep-1 mutation have excretory pores that are attractive or receptive to copulatory behavior of other males. Excretory pore plugs are injurious and hermaphrodite activity is compromised in plep-1 mutants, so the allele might be unconditionally deleterious, persisting in the population because the species’ androdioecious mating system limits the reach of selection. [ABSTRACT FROM AUTHOR]

Post-reproductive lifespan is a common trait among mammals and is usually considered to be neutral; i.e. with no influence on population dynamics. Here, we explore the role of post-reproductive lifespan in the fixation probability of beneficial genetic variation. We compare two separate, stationary populations living in a constant environment that are equivalent except for the average time their respective members spend in the post-reproductive stage of life. Using a recently derived approximation, we show that fixation of a beneficial mutation is more likely in the population with greater post-reproductive longevity. This finding is surprising, as the population with more prolonged post-reproductive lifespan has smaller effective size and the classic population-genetic model would suggest that decreasing effective size reduces fixation chances of beneficial mutations. Yet, as we explain, in the age-structured case, when effective size gets smaller because of longer post-reproductive lifespan but census size is kept equal, a beneficial mutation has a higher likelihood to get fixed because it finds itself at higher initial frequency. [ABSTRACT FROM AUTHOR]

Summary Gene regulatory networks (GRNs) comprising interactions between transcription factors (TFs) and regulatory loci control development and physiology. Numerous disease-associated mutations have been identified, the vast majority residing in non-coding regions of the genome. As current GRN mapping methods test one TF at a time and require the use of cells harboring the mutation(s) of interest, they are not suitable to identify TFs that bind to wild-type and mutant loci. Here, we use gene-centered yeast one-hybrid (eY1H) assays to interrogate binding of 1,086 human TFs to 246 enhancers, as well as to 109 non-coding disease mutations. We detect both loss and gain of TF interactions with mutant loci that are concordant with target gene expression changes. This work establishes eY1H assays as a powerful addition to the toolkit of mapping human GRNs and for the high-throughput characterization of genomic variants that are rapidly being identified by genome-wide association studies. [ABSTRACT FROM AUTHOR]

MtDNA has been a widely used tool in human evolutionary and population genetic studies over the past three decades. Its maternal inheritance and lack of recombination have offered the opportunity to explore genealogical relationships among individuals and to study the frequency differences of matrilineal clades among human populations at continental and regional scales. The whole mtDNA genome sequencing delivers molecular resolution that is sufficient to distinguish patterns that have arisen over thousands of years. However, mutation rate is highly variable among the functional and non-coding domains of mtDNA which makes it challenging to obtain accurate split dates of the mitochondrial clades. Due to the shallow coalescent time of mitochondrial TMRCA at approximately 100 to 200 thousand years (ky), mtDNA data have only limited power to inform us about the more distant past and the early stages of human evolutionary history. The variation shared by mitochondrial genomes of individuals drawn from different continents outside Africa has been used to illuminate the details of the colonization process of the Old World, whereas regional patterns of variation have been at the focus of studies addressing questions of a more recent time scale. In the era of whole nuclear genome sequencing, mitochondrial genomes are continuing to be informative as a unique tool for the assessment of female-specific aspects of the demographic history of human populations. [ABSTRACT FROM AUTHOR]

Schmid-type metaphyseal chondrodysplasia (MCDS) is characterized by short stature with short legs, bowing of the long bones, coxa vara, and waddling gait. MCDS is a relatively common form of MCD. Most mutations that cause MCDS occur within the carboxyl-terminal non-collagenous domain (NC1) of the COL10A1 gene. We performed mutational analysis of the COL10A1 genes in 4 unrelated Korean patients with diagnosed MCDS. Mutational analysis of COL10A1 identified c.1904_1915delinsT (p.Gln635LeufsX10) and c.1969dupG (p.Ala657GlyfsX10), 2 novel frameshift mutations, and c.2030T>A (p.Val677Glu) and c.862G>C (p.Gly288Arg) at unusual mutational sites, which could be pathogenic. We present the first report of the molecular characteristics of MCDS in 4 Korean patients. Our findings suggest that a novel sequence variation involving an unusual mutational site of the COL10A1 gene can cause mild MCDS. [ABSTRACT FROM AUTHOR]

Dominant glaucoma, a heterogeneous, infrequent and irreversible optic neuropathy, is often associated with elevated intraocular pressure and early-onset. The role of FOXC1 in this type of glaucoma was investigated in twelve Spanish probands via nucleotide variation screening of its proximal promoter and unique exon. Functional evaluations of the identified variants included analyses of the transcriptional activity, protein stability, DNA binding ability and subcellular localization. Four different mutations that were identified in four probands (33.3%) were associated with remarkable phenotypic variability and were functionally classified as either hypermorphic (p.Y47X, p.Q106X and p.G447_G448insDG) or hypomorphic (p.I126S) alleles. To the best of our knowledge, three of the variants are novel (p.Y47X, p.I126S and p.G447_G448insDG) and, in addition, hypermorphic FOXC1 mutations are reported herein for the first time. The presence of an intact N-terminal activation domain in the truncated proteins p.Y47X and p.Q106X may underlie their associated transactivation hyperactivity by a gain-of-function mechanism involving dysregulated protein-protein interactions. Similarly, altered molecular interactions may also lead to increased p.G447_G448insDG activity. In contrast, the partial loss-of-function associated with p.I126S was due to impaired protein stability, DNA binding, protein phosphorylation and subcellular distribution. These results support that moderate and variable FOXC1 transactivation changes are associated with moderate goniodysgenesis, dominant glaucoma and remarkable phenotypic variability. [ABSTRACT FROM AUTHOR]

Variations of the ABCB4 and ABCB11 genes affect the composition of bile and are associated with cholestasis and cholelithiasis. However, their roles in the formation of primary intrahepatic stones (PIS) remains to be elucidated. The aim of the present study was to determine whether there is an association between PIS and variations in these genes. Exon sequencing was performed in order to analyze the ABCB4 and ABCB11 genes of 176 patients with PIS and 178 healthy subjects. One mutation in ABCB4 (no. 69233, G>A) and two other mutations in ABCB11, reference single nucleotide polymorphism (rs)118109635 and rs497692, were identified in association with PIS (P<0.001, P=0.04 and P=0.02, respectively). A synonymous mutation at no. 69233 G>A was detected in exon 26 of ABCB4 in 23 heterozygous patients with PIS. This mutation was not detected in healthy individuals or in the Single Nucleotide Polymorphism Database. No. 69233 G>A in ABCB4 was not associated with altered protein expression but with a reduced rate of PIS recurrence (P=0.01). The missense mutation rs118109635 was located on exon 21 of ABCB11 and was associated with the increased expression of ABCB11 protein (P=0.032) as well as altered bile salt export pump function. Another synonymous mutation, rs497692 in exon 24 was reported to decrease ABCB11 protein expression (P=0.001). In addition, the mutations of ABCB11 were associated with preoperative jaundice (P<0.001 and P=0.03, respectively). Consistently decreased levels of ABCB11 protein were associated with recurrent episodes of cholangitis (P=0.006) and preoperative jaundice (P=0.015). By contrast, ABCB4 expression was not found to be associated with clinical manifestations of PIS. In conclusion, the present study demonstrated that ABCB4 and ABCB11 may be promising candidate genes for evaluating the risk of developing PIS. Mutations in these genes have been shown to alter the expression and function of their corresponding proteins and therefore may be associated with the formation of PIS. [ABSTRACT FROM AUTHOR]

The production and maintenance of genetic and phenotypic diversity under temporally fluctuating selection and the signatures of environmental changes in the patterns of this variation have been important areas of focus in population genetics. On one hand, periods of constant selection pull the genetic makeup of populations toward local fitness optima. On the other, to cope with changes in the selection regime, populations may evolve mechanisms that create a diversity of genotypes. By tuning the rates at which variability is produced-such as the rates of recombination, mutation, or migration-populations may increase their long-term adaptability. Here we use theoretical models to gain insight into how the rates of these three evolutionary forces are shaped by fluctuating selection. We compare and contrast the evolution of recombination, mutation, and migration under similar patterns of environmental change and show that these three sources of phenotypic variation are surprisingly similar in their response to changing selection. We show that the shape, size, variance, and asymmetry of environmental fluctuation have different but predictable effects on evolutionary dynamics. [ABSTRACT FROM AUTHOR]

A common phenotype within bacterial biofilms is the small, “wrinkly” colony, which may associate with worse prognoses from biofilm-associated infections. The mechanisms that produce these variants in Burkholderia are undefined. Here we report the mutational and ecological causes of wrinkly (W) colonies that evolved during experimental biofilm evolution of Burkholderia cenocepacia . Mutations clustered in a homologous pathway to the Pseudomonas wsp operon but with a distinct terminal signaling mechanism, and their parallel evolution suggested that they inhabited an equivalent biofilm niche. We tested this hypothesis of niche complementarity by measuring effects of substituting different W variants in the same evolved biofilm community. Despite phenotypic differences among W mutants growing alone, fitness of reconstituted mixed biofilms did not differ significantly. In conclusion, the evolution of small-colony variants in Burkholderia biofilms appears to be driven by an ecological opportunity that generates strong selection for constitutive wsp mutants to inhabit a common niche. [ABSTRACT FROM AUTHOR]

The existence of complex (multiple-step) genetic adaptations that are 'irreducible' (i.e., all partial combinations are less fit than the original genotype) is one of the longest standing problems in evolutionary biology. In standard genetics parlance, these adaptations require the crossing of a wide adaptive valley of deleterious intermediate stages. Here, we demonstrate, using a simple model, that evolution can cross wide valleys to produce 'irreducibly complex' adaptations by making use of previously cryptic mutations. When revealed by an evolutionary capacitor, previously cryptic mutants have higher initial frequencies than do new mutations, bringing them closer to a valley-crossing saddle in allele frequency space. Moreover, simple combinatorics implies an enormous number of candidate combinations exist within available cryptic genetic variation. We model the dynamics of crossing of a wide adaptive valley after a capacitance event using both numerical simulations and analytical approximations. Although individual valley crossing events become less likely as valleys widen, by taking the combinatorics of genotype space into account, we see that revealing cryptic variation can cause the frequent evolution of complex adaptations. [ABSTRACT FROM AUTHOR]

Biologists have long observed that physiological and developmental processes are insensitive, or robust, to many genetic and environmental perturbations. A complete understanding of the evolutionary causes and consequences of this robustness is lacking. Recent progress has been made in uncovering the regulatory mechanisms that underlie environmental robustness in particular. Less is known about robustness to the effects of mutations, and indeed the evolution of mutational robustness remains a controversial topic. The controversy has spread to related topics, in particular the evolutionary relevance of cryptic genetic variation. This review aims to synthesize current understanding of robustness mechanisms and to cut through the controversy by shedding light on what is and is not known about mutational robustness. Some studies have confused mutational robustness with nonadditive interactions between mutations (epistasis). We conclude that a profitable way forward is to focus investigations (and rhetoric) less on mutational robustness and more on epistasis. [ABSTRACT FROM AUTHOR]

Rifamycins are mainstay agents in treatment of many widespread diseases, but how an improved rifamycin producer can be created is still incompletely understood. Here, we describe a comparative genomic approach to investigate the mutational patterns introduced by the classical mutate-and-screen method in the genome of an improved rifamycin producer. Comparing the genome of the rifamycin B overproducer Amycolatopsis mediterranei HP-130 with those of the reference strains A. mediterranei S699 and U32, we identified 250 variations, affecting 227 coding sequences (CDS), 109 of which were HP-130-specific since they were absent in both S699 and U32. Mutational and transcriptional patterns indicated a series of genomic manipulations that not only proved the causative effect of mutB2 (coding for methylmalonyl-CoA mutase large subunit) and argS2 (coding for arginyl tRNA synthetase) mutations on the overproduction of rifamycin, but also constituted a rational strategy to genetically engineer a reference strain into an overproducer. [ABSTRACT FROM AUTHOR]

Robustness and evolvability are highly intertwined properties of biological systems. The relationship between these properties determines how biological systems are able to withstand mutations and show variation in response to them. Computational studies have explored the relationship between these two properties using neutral networks of RNA sequences (genotype) and their secondary structures (phenotype) as a model system. However, these studies have assumed every mutation to a sequence to be equally likely; the differences in the likelihood of the occurrence of various mutations, and the consequence of probabilistic nature of the mutations in such a system have previously been ignored. Associating probabilities to mutations essentially results in the weighting of genotype space. We here perform a comparative analysis of weighted and unweighted neutral networks of RNA sequences, and subsequently explore the relationship between robustness and evolvability. We show that assuming an equal likelihood for all mutations (as in an unweighted network), underestimates robustness and overestimates evolvability of a system. In spite of discarding this assumption, we observe that a negative correlation between sequence (genotype) robustness and sequence evolvability persists, and also that structure (phenotype) robustness promotes structure evolvability, as observed in earlier studies using unweighted networks. We also study the effects of base composition bias on robustness and evolvability. Particularly, we explore the association between robustness and evolvability in a sequence space that is AU-rich – sequences with an AU content of 80% or higher, compared to a normal (unbiased) sequence space. We find that evolvability of both sequences and structures in an AU-rich space is lesser compared to the normal space, and robustness higher. We also observe that AU-rich populations evolving on neutral networks of phenotypes, can access less phenotypic variation compared to normal populations evolving on neutral networks. [ABSTRACT FROM AUTHOR]

Supercentenarians (110 years or older) are the world’s oldest people. Seventy four are alive worldwide, with twenty two in the United States. We performed whole-genome sequencing on 17 supercentenarians to explore the genetic basis underlying extreme human longevity. We found no significant evidence of enrichment for a single rare protein-altering variant or for a gene harboring different rare protein altering variants in supercentenarian compared to control genomes. We followed up on the gene most enriched for rare protein-altering variants in our cohort of supercentenarians, TSHZ3, by sequencing it in a second cohort of 99 long-lived individuals but did not find a significant enrichment. The genome of one supercentenarian had a pathogenic mutation in DSC2, known to predispose to arrhythmogenic right ventricular cardiomyopathy, which is recommended to be reported to this individual as an incidental finding according to a recent position statement by the American College of Medical Genetics and Genomics. Even with this pathogenic mutation, the proband lived to over 110 years. The entire list of rare protein-altering variants and DNA sequence of all 17 supercentenarian genomes is available as a resource to assist the discovery of the genetic basis of extreme longevity in future studies. [ABSTRACT FROM AUTHOR]

BRCA1/BRCA2 genes were screened in 117 patients with breast cancer by sequencing. Fourteen percent of patients tested positive for BRCA1/BRCA2 mutations. Four frame shift mutations, four pathogenic missense mutations, and 25 different sequence variations were detected. BRCA mutation positivity was significantly associated with Ki67 ( p = .001). BRCA protein expressions were decreased in the patients harboring important mutations and polymorphisms ( BRCA1;P508stop, V1740G, Q1182R, Q1756P and BRCA2;V2466A) related with disease. Our findings contribute significantly to the types of germline BRCA1/BRCA2 mutations and their biological effects in Turkish women. These data could help guide the management of BRCA1/BRCA2 mutation-carrying patients when considering breast-conserving therapy. [ABSTRACT FROM AUTHOR]

The fitness effects of mutations are context specific and depend on both external (e.g., environment) and internal (e.g., cellular stress, genetic background) factors. The influence of population size and density on fitness effects are unknown, despite the central role population size plays in the supply and fixation of mutations. We addressed this issue by comparing the fitness of 92 Keio strains (Escherichia coli K12 single gene knockouts) at comparatively high (1.2×107 CFUs/mL) and low (2.5×102 CFUs/mL) densities, which also differed in population size (high: 1.2×108; low: 1.25×103). Twenty-eight gene deletions (30%) exhibited a fitness difference, ranging from 5 to 174% (median: 35%), between the high and low densities. Our analyses suggest this variation among gene deletions in fitness responses reflected in part both gene orientation and function, of the gene properties we examined (genomic position, length, orientation, and function). Although we could not determine the relative effects of population density and size, our results suggest fitness effects of mutations vary with these two factors, and this variation is gene-specific. Besides being a mechanism for density-dependent selection (r-K selection), the dependence of fitness effects on population density and size has implications for any population that varies in size over time, including populations undergoing evolutionary rescue, species invasions into novel habitats, and cancer progression and metastasis. Further, combined with recent advances in understanding the roles of other context-specific factors in the fitness effects of mutations, our results will help address theoretical and applied biological questions more realistically. [ABSTRACT FROM AUTHOR]

The fitness effects of mutations are context specific and depend on both external (e.g., environment) and internal (e.g., cellular stress, genetic background) factors. The influence of population size and density on fitness effects are unknown, despite the central role population size plays in the supply and fixation of mutations. We addressed this issue by comparing the fitness of 92 Keio strains (Escherichia coli K12 single gene knockouts) at comparatively high (1.2×107 CFUs/mL) and low (2.5×102 CFUs/mL) densities, which also differed in population size (high: 1.2×108; low: 1.25×103). Twenty-eight gene deletions (30%) exhibited a fitness difference, ranging from 5 to 174% (median: 35%), between the high and low densities. Our analyses suggest this variation among gene deletions in fitness responses reflected in part both gene orientation and function, of the gene properties we examined (genomic position, length, orientation, and function). Although we could not determine the relative effects of population density and size, our results suggest fitness effects of mutations vary with these two factors, and this variation is gene-specific. Besides being a mechanism for density-dependent selection (r-K selection), the dependence of fitness effects on population density and size has implications for any population that varies in size over time, including populations undergoing evolutionary rescue, species invasions into novel habitats, and cancer progression and metastasis. Further, combined with recent advances in understanding the roles of other context-specific factors in the fitness effects of mutations, our results will help address theoretical and applied biological questions more realistically. [ABSTRACT FROM AUTHOR]

Abstract: MYOC gene variants are associated with autosomal dominant primary open angle glaucoma (POAG). In this study, we describe a previously unreported MYOC variant segregating with a POAG phenotype in an Australian family. Two individuals affected with POAG and three unaffected individuals from the same family were recruited through the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG). Direct sequencing of all MYOC coding exons identified the novel heterozygous single nucleotide transition MYOC:c.1119G>A, p.(Trp373*), predicted to encode an aberrant truncated MYOC protein in two affected siblings. Two unaffected siblings and an unaffected niece were negative for the MYOC sequence variant. [Copyright &y& Elsevier]

Determining the rate of protein evolution and identifying the causes of its variation across the genome are powerful ways to understand forces that are important for genome evolution. By using a multitissue transcriptome data set from great tit (Parus major), we analyzed patterns of molecular evolution between two passerine birds, great tit and zebra finch (Taeniopygia guttata), using the chicken genome (Gallus gallus) as an outgroup. We investigated whether a special feature of avian genomes, the highly variable recombinational landscape, modulates the efficacy of natural selection through the effects of Hill–Robertson interference, which predicts that selection should be more effective in removing deleterious mutations and incorporating beneficial mutations in high-recombination regions than in low-recombination regions. In agreement with these predictions, genes located in low-recombination regions tend to have a high proportion of neutrally evolving sites and relaxed selective constraint on sites subject to purifying selection, whereas genes that show strong support for past episodes of positive selection appear disproportionally in high-recombination regions. There is also evidence that genes located in high-recombination regions tend to have higher gene expression specificity than those located in low-recombination regions. Furthermore, more compact genes (i.e., those with fewer/shorter introns or shorter proteins) evolve faster than less compact ones. In sum, our results demonstrate that transcriptome sequencing is a powerful method to answer fundamental questions about genome evolution in nonmodel organisms. [ABSTRACT FROM AUTHOR]