bluuebunny/crossref_metadata_2025 huggingface dataset:
Simulating the outcome of amyloid treatments in Alzheimer's disease from imaging and clinical data
Authors: Abi Nader Clément , Ayache Nicholas , Frisoni Giovanni B , Robert Philippe , Lorenzi Marco ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: April 2021

In this study, we investigate SimulAD, a novel quantitative instrument for the development of intervention strategies for disease-modifying drugs in Alzheimer's disease. SimulAD is based on the modeling of the spatio-temporal dynamics governing the joint evolution of imaging and clinical biomarkers along the history of the disease, and allows the simulation of the effect of intervention time and drug dosage on the biomarkers' progression. When applied to multi-modal imaging and clinical data from the Alzheimer's Disease Neuroimaging Initiative the method enables to generate hypothetical scenarios of amyloid lowering interventions. The results quantify the crucial role of intervention time, and provide a theoretical justification for testing amyloid modifying drugs in the pre-clinical stage. Our experimental simulations are compatible with the outcomes observed in past clinical trials, and suggest that anti-amyloid treatments should be administered at least 7 years earlier than what is currently being done in order to obtain statistically powered improvement of clinical endpoints.
Circulating concentrations of thyroid hormones and cortisol in wild and semi-natural Yangtze finless porpoise (Neophocaena asiaeorientalis)
Authors: Nabi Ghulam , Robeck Todd R , Yujiang Hao , Tang Bin , Zheng Jinsong , Wang Kexiong , Wang Ding
Published: April 2021

Our understanding about how environmental and biological variables may influence circulating thyroid and adrenal hormones in free-ranging cetaceans is limited. As such, we used liquid chromatography–mass spectrometry to determine concentrations of circulating cortisol and thyroid hormones (THs; tT3, tT4) in 132 Yangtze finless porpoises (YFPs) located in Poyang Lake, (PL, n = 92) and Tian-E-Zhou Oxbow reserve (TZO, n = 40). For overall hormone comparisons, animals were partitioned by age [juvenile and adult (male and non-pregnant, non-lactating female)], sex, season (winter or spring) and geographical location. Geographically, during winter, circulating THs were significantly higher in the PL versus TZO population. Seasonally, within PL, THs were significantly higher in the winter versus spring season. Animals were further binned into groups as follows: juvenile male (JM) and juvenile female (JF), adult male (AM), non-pregnant adult female, pregnant female and non-pregnant lactating female. Intra-group comparisons between locations showed a significant increase in JM THs at PL. Significant increases in THs during winter compared to spring were detected between JM and JF groups. Mean comparisons of cortisol within and between locations for each group identified a significant increase for TZO AM versus TZO pregnant female and JM and JF. Seasonally, in PL, only JF has significantly higher cortisol in winter versus spring. Finally, we established reference values of THs and cortisol for YFPs in different geographical locations. These references are important baselines from which the effects of environmental and biological variables on THs and cortisol may be evaluated.
Cardiovascular risk factors, cardiovascular disease, and COVID-19: an umbrella review of systematic reviews
Authors: Harrison Stephanie L , Buckley Benjamin J R , Rivera-Caravaca José Miguel , Zhang Juqian , Lip Gregory Y H
Published: April 2021

Aims

To consolidate evidence to determine (i) the association between cardiovascular risk factors and health outcomes with coronavirus 2019 (COVID-19); and (ii) the impact of COVID-19 on cardiovascular health.

Methods and results

An umbrella review of systematic reviews was conducted. Fourteen medical databases and pre-print servers were searched from 1 January 2020 to 5 November 2020. The review focused on reviews rated as moderate or high-quality using the AMSTAR 2 tool. Eighty-four reviews were identified; 31 reviews were assessed as moderate quality and one was high-quality. The following risk factors were associated with higher mortality and severe COVID-19: renal disease [odds ratio (OR) (95% confidence interval) for mortality 3.07 (2.43–3.88)], diabetes mellitus [OR 2.09 (1.80–2.42)], hypertension [OR 2.50 (2.02–3.11)], smoking history [risk ratio (RR) 1.26 (1.20–1.32)], cerebrovascular disease [RR 2.75 (1.54–4.89)], and cardiovascular disease [OR 2.65 (1.86–3.78)]. Liver disease was associated with higher odds of mortality [OR 2.81 (1.31–6.01)], but not severe COVID-19. Current smoking was associated with a higher risk of severe COVID-19 [RR 1.80 (1.14–2.85)], but not mortality. Obesity associated with higher odds of mortality [OR 2.18 (1.10–4.34)], but there was an absence of evidence for severe COVID-19. In patients hospitalized with COVID-19, the following incident cardiovascular complications were identified: acute heart failure (2%), myocardial infarction (4%), deep vein thrombosis (7%), myocardial injury (10%), angina (10%), arrhythmias (18%), pulmonary embolism (19%), and venous thromboembolism (25%).

Conclusion

Many of the risk factors identified as associated with adverse outcomes with COVID-19 are potentially modifiable. Primary and secondary prevention strategies that target cardiovascular risk factors may improve outcomes for people following COVID-19.
Primary cardiovascular risk prediction by LDL-cholesterol in Caucasian middle-aged and older adults: a joint analysis of three cohorts
Authors: Hilvo Mika , Dhar Indu , Lääperi Mitja , Lysne Vegard , Sulo Gehard , Tell Grethe S , Jousilahti Pekka , Nygård Ottar K , Brenner Hermann , Schöttker Ben , Laaksonen Reijo
Published: April 2021

Aims

Low-density lipoprotein cholesterol (LDL-C) is an established causal driver of atherosclerotic cardiovascular disease (ASCVD), but its performance and age-dependency as a biomarker for incident events and mortality arising from ASCVD is less clear. The aim was to determine the value of LDL-C as a susceptibility/risk biomarker for incident coronary heart disease (CHD), ASCVD, and stroke events and deaths, for the age groups <50 and ≥50 years.

Methods and results

The performance of LDL-C was evaluated in three cohorts, FINRISK 2002 (n = 7709), HUSK (n = 5431), and ESTHER (n = 4559), by Cox proportional hazards models, C-statistics, and net reclassification index calculations. Additionally, the hazard ratios (HRs) for the three cohorts were pooled by meta-analysis. The most consistent association was observed for CHD [95% confidence interval (CI) for HRs per standard deviation ranging from 0.99 to 1.37], whereas the results were more modest for ASCVD (0.96–1.18) due to lack of association with stroke (0.77–1.24). The association and discriminatory value of LDL-C with all endpoints in FINRISK 2002 and HUSK were attenuated in subjects 50 years and older [HRs (95% CI) obtained from meta-analysis 1.11 (1.04–1.18) for CHD, 1.15 (1.02–1.29) for CHD death, 1.02 (0.98–1.06) for ASCVD, 1.12 (1.02–1.23) for ASCVD death, and 0.97 (0.89–1.05) for stroke].

Conclusion

In middle-aged and older adults, associations between LDL-C and all the studied cardiovascular endpoints were relatively weak, while LDL-C showed stronger association with rare events of pre-mature CHD or ASCVD death among middle-aged adults. The predictive performance of LDL-C also depends on the studied cardiovascular endpoint.
Household food spending, parental and childhood’s diet quality, in financial crisis: a cross-sectional study in Greece
Authors: Kosti Rena I , Kanellopoulou Aikaterini , Notara Venetia , Antonogeorgos George , Rojas-Gil Andrea Paola , Kornilaki Ekaterina N , Lagiou Areti , Panagiotakos Demosthenes B
Published: April 2021

Background

Over the past decade, the financial crisis has affected harshly the household income of Greek people. This study aimed to investigate whether the effect of the financial crisis on food spending has affected the dietary habits in the family environment.

Methods

Under a cross-sectional study conducted during 2014–2016, 1145 children and their parents completed questionnaires examining socio-economic and dietary characteristics. The MedDietScore and the KIDMED Score were used to assess parental and childhood adherence to the Mediterranean diet, respectively.

Results

The parents who reported that the financial crisis has affected food spending used to consume weekly fewer fruits (3.26 ± 0.94 vs. 3.41 ± 0.90, P = 0.016), carbohydrate foods (3.16 ± 0.57 vs. 2.99 ± 0.55, P < 0.001) and legumes (3.28 ± 0.76 vs. 3.14 ± 0.67, P = 0.001) and more nutrient-poor/energy-dense foods (2.55 ± 0.98 vs. 2.20 ± 0.82, P < 0.001) compared with non-affected parents. Their children showed a decreased weekly consumption of vegetables (2.82 ± 0.90 vs. 2.97 ± 0.98, P = 0.019) and increased weekly consumption of nutrient-poor/energy-dense foods (2.38 ± 0.97 vs. 2.19 ± 0.80, P < 0.001). The affected parents had a lower MedDietScore than non-affected parents (25.76 ± 8.10 vs. 27.03 ± 8.11, P = 0.034). No difference was revealed on the KIDMED Score (P = 0.294).

Conclusions

The constrained food spending due to financial crisis has an independent and inverse impact on parent’s diet quality while keeping unaffected preadolescent’s diet quality. This finding highlights the role of parents as a protective ‘wall’ against the deterioration of their children’s diet quality. The modification on the prices of healthy food and the provision of food aid particularly in economically disadvantaged households is underlined.
The US Congress and Rogue States
Authors: Kotb Shereen , Jeong Gyung-Ho
Published: April 2021

Foreign policy has become one of the most polarizing issues in American politics. This paper investigates the extent to which this division extends to arguably one of the most bipartisan foreign policy issues: policies toward rogue states. Our examination of congressional voting and sponsorship data related to rogue states since 1991 finds that, while there is a high degree of bipartisanship on the issue, there are nuanced but significant partisan differences. First, we find that Democrats are significantly more likely to support a rogue state bill dealing with human rights concerns, whereas Republicans are significantly less likely to support a conciliatory bill. We also find that members of Congress are less likely to propose and support a rogue state bill in the presence of a co-partisan president. We thus conclude that, despite the overall high degree of bipartisanship on rogue state issues, partisanship plays an important role in influencing legislative behavior.
Efficient Recovery of Centric Heterochromatin P-Element Insertions in Drosophila melanogaster
Authors: Yan Christopher M , Dobie Kenneth W , Le Hiep D , Konev Alexander Y , Karpen Gary H
Published: April 2021

Approximately one-third of the human and Drosophila melanogaster genomes are heterochromatic, yet we know very little about the structure and function of this enigmatic component of eukaryotic genomes. To facilitate molecular and cytological analysis of heterochromatin we introduced a yellow+ (y+)-marked P element into centric heterochromatin by screening for variegated phenotypes, that is, mosaic gene inactivation. We recovered >110 P insertions with variegated yellow expression from ∼3500 total mobilization events. FISH analysis of 71 of these insertions showed that 69 (97%) were in the centric heterochromatin, rather than telomeres or euchromatin. High-resolution banding analysis showed a wide but nonuniform distribution of insertions within centric heterochromatin; variegated insertions were predominantly recovered near regions of satellite DNA. We successfully used inverse PCR to clone and sequence the flanking DNA for ∼63% of the insertions. BLAST analysis of the flanks demonstrated that either most of the variegated insertions could not be placed on the genomic scaffold, and thus may be inserted within novel DNA sequence, or that the flanking DNA hit multiple sites on the scaffold, due to insertions within different transposons. Taken together these data suggest that screening for yellow variegation is a very efficient method for recovering centric insertions and that a large-scale screen for variegated yellow P insertions will provide important tools for detailed analysis of centric heterochromatin structure and function.
Subfunctionalization of DuplicatemitfGenes Associated With Differential Degeneration of Alternative Exons in Fish
Authors: Altschmied Joachim , Delfgaauw Jacqueline , Wilde Brigitta , Duschl Jutta , Bouneau Laurence , Volff Jean-Nicolas , Schartl Manfred
Published: April 2021

The microphthalmia-associated transcription factor (MITF) exists in at least four isoforms. These are generated in higher vertebrates using alternative 5′ exons and promoters from a single gene. Two separate genes (mitf-m and mitf-b), however, are present in different teleost fish species including the poeciliid Xiphophorus, the pufferfishes Fugu rubripes and Tetraodon nigroviridis, and the zebrafish Danio rerio. Fish proteins MITF-m and MITF-b correspond at both the structural and the expression levels to one particular bird/mammalian MITF isoform. In the teleost lineage subfunctionalization of mitf genes after duplication at least 100 million years ago is associated with the degeneration of alternative exons and, probably, regulatory elements and promoters. For example, a remnant of the first exon specific for MITF-m is detected within the pufferfish gene encoding MITF-b. Retracing the evolutionary history of mitf genes in vertebrates uncovered the differential recruitment of new introns specific for either the teleost or the bird/mammalian lineage.
Codon Bias Differentiates Between the Duplicated Amylase Loci Following Gene Duplication in Drosophila
Authors: Zhang Ze , Inomata Nobuyuki , Ohba Tomohiro , Cariou Marie-Louise , Yamazaki Tsuneyuki
Published: April 2021

We examined the pattern of synonymous substitutions in the duplicated Amylase (Amy) genes (called the Amy1- and Amy3-type genes, respectively) in the Drosophila montium species subgroup. The GC content at the third synonymous codon sites of the Amy1-type genes was higher than that of the Amy3-type genes, while the GC content in the 5′-flanking region was the same in both genes. This suggests that the difference in the GC content at third synonymous sites between the duplicated genes is not due to the temporal or regional changes in mutation bias. We inferred the direction of synonymous substitutions along branches of a phylogeny. In most lineages, there were more synonymous substitutions from G/C (G or C) to A/T (A or T) than from A/T to G/C. However, in one lineage leading to the Amy1-type genes, which is immediately after gene duplication but before speciation of the montium species, synonymous substitutions from A/T to G/C were predominant. According to a simple model of synonymous DNA evolution in which major codons are selectively advantageous within each codon family, we estimated the selection intensity for specific lineages in a phylogeny on the basis of inferred patterns of synonymous substitutions. Our result suggested that the difference in GC content at synonymous sites between the two Amy-type genes was due to the change of selection intensity immediately after gene duplication but before speciation of the montium species.
Genetic Analysis of Sunflower Domestication
Authors: Burke John M , Tang Shunxue , Knapp Steven J , Rieseberg Loren H
Published: April 2021

Quantitative trait loci (QTL) controlling phenotypic differences between cultivated sunflower and its wild progenitor were investigated in an F3 mapping population. Composite interval mapping revealed the presence of 78 QTL affecting the 18 quantitative traits of interest, with 2–10 QTL per trait. Each QTL explained 3.0–68.0% of the phenotypic variance, although only 4 (corresponding to 3 of 18 traits) had effects >25%. Overall, 51 of the 78 QTL produced phenotypic effects in the expected direction, and for 13 of 18 traits the majority of QTL had the expected effect. Despite being distributed across 15 of the 17 linkage groups, there was a substantial amount of clustering among QTL controlling different traits. In several cases, regions influencing multiple traits harbored QTL with antagonistic effects, producing a cultivar-like phenotype for some traits and a wild-like phenotype for others. On the basis of the directionality of QTL, strong directional selection for increased achene size appears to have played a central role in sunflower domestication. None of the other traits show similar evidence of selection. The occurrence of numerous wild alleles with cultivar-like effects, combined with the lack of major QTL, suggests that sunflower was readily domesticated.
Estimating Mutation Parameters, Population History and Genealogy Simultaneously From Temporally Spaced Sequence Data
Authors: Drummond Alexei J , Nicholls Geoff K , Rodrigo Allen G , Solomon Wiremu
Published: April 2021

Molecular sequences obtained at different sampling times from populations of rapidly evolving pathogens and from ancient subfossil and fossil sources are increasingly available with modern sequencing technology. Here, we present a Bayesian statistical inference approach to the joint estimation of mutation rate and population size that incorporates the uncertainty in the genealogy of such temporally spaced sequences by using Markov chain Monte Carlo (MCMC) integration. The Kingman coalescent model is used to describe the time structure of the ancestral tree. We recover information about the unknown true ancestral coalescent tree, population size, and the overall mutation rate from temporally spaced data, that is, from nucleotide sequences gathered at different times, from different individuals, in an evolving haploid population. We briefly discuss the methodological implications and show what can be inferred, in various practically relevant states of prior knowledge. We develop extensions for exponentially growing population size and joint estimation of substitution model parameters. We illustrate some of the important features of this approach on a genealogy of HIV-1 envelope (env) partial sequences.
Multileveled Selection on Plasmid Replication
Authors: Paulsson Johan
Published: April 2021

The replication control genes of bacterial plasmids face selection at two conflicting levels. Plasmid copies that systematically overreplicate relative to their cell mates have a higher chance of fixing in descendant cells, but these cells typically have a lower chance of fixing in the population. Apart from identifying the conflict, this mathematical discussion characterizes the efficiency of the selection levels and suggests how they drive the evolution of kinetic mechanisms. In particular it is hypothesized that: (1) tighter replication control is more vulnerable to selfishness; (2) cis-acting replication activators are relics of a conflict where a plasmid outreplicated its intracellular competitors by monopolizing activators; (3) high-copy plasmids with sloppy replication control arise because intracellular selection favors overreplication, thereby relieving intercellular selection for lower loss rates; (4) the excessive synthesis of cis-acting replication activators and trans-acting inhibitors is the result of an arms race between cis selfishness and trans retaliations; (5) site-specific recombination of plasmid dimers is equivalent to self-policing; and (6) plasmids modify their horizontal transfer to spread without promoting selfishness. It is also discussed how replication control may be subject to a third level of selection acting on the entire population of plasmid-containing cells.
Genetics of Mother-Dependent Sex Ratio in Blue Mussels (Mytilus spp.) and Implications for Doubly Uniparental Inheritance of Mitochondrial DNA
Authors: Kenchington Ellen , MacDonald Barry , Cao Liqin , Tsagkarakis Defkalion , Zouros Eleftherios
Published: April 2021

Previous studies have shown that in most pair matings of Mytilus edulis, M. trossulus, and M. galloprovincialis there is a large sex-ratio bias in favor of either males or females. The degree of bias is a characteristic property of the female parent, as matings of the same female with different males produce the same sex ratio, but matings of the same male with different females produce different sex ratios. All three species possess the unusual feature of doubly uniparental inheritance of mitochondrial DNA (mtDNA); i.e., they contain two distinct types of mtDNA, one that is transmitted matrilinearly and one that is transmitted patrilinearly. This coupling of sex and mtDNA transmission raises the possibility that the mechanism of sex-ratio determination in mussels might be under the control of the mtDNA of the female parent. Here we present data from pedigreed crosses that confirm the previous observations that in mussel matings there is a strong sex-ratio bias and that the bias is under the control of the female parent. In addition, these data strongly suggest that this control is exercised by the mother's nuclear rather than mitochondrial genotype. Making use of these findings we develop a model of mother-dependent sex determination and use data from crosses involving wild females to test the model's predictions at the population level.
Ethylnitrosourea-Induced Base Pair Substitution Affects Splicing of the Mouse γE-Crystallin Encoding Gene Leading to the Expression of a Hybrid Protein and to a Cataract
Authors: Graw Jochen , Neuhäuser-Klaus Angelika , Löster Jana , Klopp Norman , Favor Jack
Published: April 2021

A novel ENU-induced mutation in the mouse leading to a nuclear and cortical opacity of the eye lens (ENU418) was mapped to proximal chromosome 1 by a genome-wide mapping approach. It suggests that the cluster of γ-crystallin encoding genes (Cryg) and the βA2-crystallin encoding gene Cryba2 are excellent candidate genes. An A → G exchange in the middle of intron 1 of the Cryge gene was found as the only alteration cosegregating with the cataractous phenotype. The mutation was confirmed by the presence of a novel restriction site for ApaI in the corresponding genomic DNA fragment. The mutation represses splicing of intron 1; the additional 92 bp in the corresponding cDNA leads to a frameshift and the expression of a novel hybrid protein containing 3 amino acids of the γE-crystallin at the N terminus, but 153 novel amino acids. The CrygeENU418 protein has a calculated molecular mass of ∼15.6 kD and an alkaline isoelectric point (pH 10.1) and is predicted to have two hydrophobic domains. Western blot analysis using a polyclonal antibody against the hydrophilic C-terminal part of the CrygeENU418-specific protein demonstrated its stable expression in the cataractous lenses; it was not found in the wild types. Histological analysis of the cataractous lenses indicated that the expression of the new protein disrupts the cellular structure of the eye lens.
Evolution and Organization of a Highly Dynamic, Subtelomeric Helicase Gene Family in the Rice Blast Fungus Magnaporthe grisea
Authors: Gao Weimin , Khang Chang Hyun , Park Sook-Young , Lee Yong-Hwan , Kang Seogchan
Published: April 2021

Sequence analysis of a 13-kb telomeric region in O-137, a rice pathogenic isolate of Magnaporthe grisea, uncovered a novel gene, designated TLH1 (telomere-linked helicase 1). The TLH1 gene is a member of a gene family, and the sequences flanking this gene family have also been amplified. Genetic mapping showed that most members of the TLH gene family are tightly linked to the telomeres. A physical mapping technique, termed RecA-mediated Achilles’ heel cleavage, and cloning and sequencing of two additional telomeres of O-137 associated with the TLH gene family confirmed that most members of the TLH gene family are located within 10 kb from the telomeric repeat. A survey of M. grisea strains from diverse hosts revealed that the gene family is ubiquitously present among rice pathogens, but is absent from almost all isolates of hosts other than rice. The gene family appears to be highly dynamic, undergoing frequent deletion/amplification events. Given the presence of similar helicase gene families in chromosome ends of Saccharomyces cerevisiae and Ustilago maydis, the initial association of helicase genes with fungal telomeres might date back to very early stages of the fungal evolution.
Genetic Requirements for Spontaneous and Transcription-Stimulated Mitotic Recombination in Saccharomyces cerevisiae
Authors: Freedman Jennifer A , Jinks-Robertson Sue
Published: April 2021

The genetic requirements for spontaneous and transcription-stimulated mitotic recombination were determined using a recombination system that employs heterochromosomal lys2 substrates that can recombine only by crossover or only by gene conversion. The substrates were fused either to a constitutive low-level promoter (pLYS) or to a highly inducible promoter (pGAL). In the case of the “conversion-only” substrates the use of heterologous promoters allowed either the donor or the recipient allele to be highly transcribed. Transcription of the donor allele stimulated gene conversions in rad50, rad51, rad54, and rad59 mutants, but not in rad52, rad55, and rad57 mutants. In contrast, transcription of the recipient allele stimulated gene conversions in rad50, rad51, rad54, rad55, rad57, and rad59 mutants, but not in rad52 mutants. Finally, transcription stimulated crossovers in rad50, rad54, and rad59 mutants, but not in rad51, rad52, rad55, and rad57 mutants. These data are considered in relation to previously proposed molecular mechanisms of transcription-stimulated recombination and in relation to the roles of the recombination proteins.
hairy: A Quantitative Trait Locus for Drosophila Sensory Bristle Number
Authors: Robin Charles , Lyman Richard F , Long Anthony D , Langley Charles H , Mackay Trudy F C
Published: April 2021

Advances in medicine, agriculture, and an understanding of evolution depend on resolving the genetic architecture of quantitative traits, which is challenging since variation for complex traits is caused by multiple interacting quantitative trait loci (QTL) with small and conditional effects. Here, we show that the key developmental gene, hairy (h), is a QTL for Drosophila sternopleural bristle number, a model quantitative trait. Near-isoallelic lines (NIL) for the h gene region exhibited significant variation in bristle number and failed to complement a hairy mutation. Sequencing 10 h alleles from a single population revealed 330 polymorphic sites in ∼10 kb. Genotypes for 25 of these and 14 additional sites in the flanking regions were determined for the 57 NIL and associated with variation in bristle number in four genetic backgrounds. A highly significant association was found for a complicated insertion/deletion polymorphism upstream of the transcription start site. This polymorphism, present in 17.5% of the h alleles, was associated with an increase of 0.5 bristle and accounted for 31% of the genetic variance in bristle number in the NIL.
Polymorphism Patterns in Two Tightly Linked Developmental Genes,Idgf1andIdgf3, ofDrosophila melanogaster
Authors: Z˘urovcová Martina , Ayala Francisco J
Published: April 2021

A new developmental gene family, recently identified in D. melanogaster, has been called imaginal disc growth factors (IDGF) because the proteins promote growth of cell lineages derived from imaginal discs. These are the first genes reported that encode polypeptide factors with mitotic activity in invertebrates. Characteristics such as similar arrangement of introns and exons, small size, and different cytological localization make this family an excellent candidate for evolutionary studies. We focus on the loci Idgf1 and Idgf3, two genes that possess the most distinctive features. We examine the pattern of intra- and interspecific nucleotide variation in the sequences from 20 isogenic lines of D. melanogaster and sequences from D. simulans and D. yakuba. While MK, HKA, and Tajima’s tests of neutrality fail to reject a neutral model of molecular evolution, Fu and Li’s test with outgroup and McDonald’s test suggest that balancing selection is modulating the evolution of the Idgf1 locus. The rate of recombination between the two loci is high enough to uncouple any linkage disequilibrium arising between Idgf1 and Idgf3, despite their close physical proximity.
Genetic Control of Mammalian Meiotic Recombination. I. Variation in Exchange Frequencies Among Males From Inbred Mouse Strains
Authors: Koehler Kara E , Cherry Jonathan P , Lynn Audrey , Hunt Patricia A , Hassold Terry J
Published: April 2021

Genetic background effects on the frequency of meiotic recombination have long been suspected in mice but never demonstrated in a systematic manner, especially in inbred strains. We used a recently described immunostaining technique to assess meiotic exchange patterns in male mice. We found that among four different inbred strains—CAST/Ei, A/J, C57BL/6, and SPRET/Ei—the mean number of meiotic exchanges per cell and, thus, the recombination rates in these genetic backgrounds were significantly different. These frequencies ranged from a low of 21.5 exchanges in CAST/Ei to a high of 24.9 in SPRET/Ei. We also found that, as expected, these crossover events were nonrandomly distributed and displayed positive interference. However, we found no evidence for significant differences in the patterns of crossover positioning between strains with different exchange frequencies. From our observations of >10,000 autosomal synaptonemal complexes, we conclude that achiasmate bivalents arise in the male mouse at a frequency of 0.1%. Thus, special mechanisms that segregate achiasmate chromosomes are unlikely to be an important component of mammalian male meiosis.
Genetic and Molecular Characterization of the Maize rp3 Rust Resistance Locus
Authors: Webb Craig A , Richter Todd E , Collins Nicholas C , Nicolas Marie , Trick Harold N , Pryor Tony , Hulbert Scot H
Published: April 2021

In maize, the Rp3 gene confers resistance to common rust caused by Puccinia sorghi. Flanking marker analysis of rust-susceptible rp3 variants suggested that most of them arose via unequal crossing over, indicating that rp3 is a complex locus like rp1. The PIC13 probe identifies a nucleotide binding site-leucine-rich repeat (NBS-LRR) gene family that maps to the complex. Rp3 variants show losses of PIC13 family members relative to the resistant parents when probed with PIC13, indicating that the Rp3 gene is a member of this family. Gel blots and sequence analysis suggest that at least 9 family members are at the locus in most Rp3-carrying lines and that at least 5 of these are transcribed in the Rp3-A haplotype. The coding regions of 14 family members, isolated from three different Rp3-carrying haplotypes, had DNA sequence identities from 93 to 99%. Partial sequencing of clones of a BAC contig spanning the rp3 locus in the maize inbred line B73 identified five different PIC13 paralogues in a region of ∼140 kb.
In Candida albicans, White-Opaque Switchers Are Homozygous for Mating Type
Authors: Lockhart Shawn R , Pujol Claude , Daniels Karla J , Miller Matthew G , Johnson Alexander D , Pfaller Michael A , Soll David R
Published: April 2021

The relationship between the configuration of the mating type locus (MTL) and white-opaque switching in Candida albicans has been examined. Seven genetically unrelated clinical isolates selected for their capacity to undergo the white-opaque transition all proved to be homozygous at the MTL locus, either MTLa or MTLα. In an analysis of the allelism of 220 clinical isolates representing the five major clades of C. albicans, 3.2% were homozygous and 96.8% were heterozygous at the MTL locus. Of the seven identified MTL homozygotes, five underwent the white-opaque transition. Of 20 randomly selected MTL heterozygotes, 18 did not undergo the white-opaque transition. The two that did were found to become MTL homozygous at very high frequency before undergoing white-opaque switching. Our results demonstrate that only MTL homozygotes undergo the white-opaque transition, that MTL heterozygotes that become homozygous at high frequency exist, and that the generation of MTL homozygotes and the white-opaque transition occur in isolates in different genetic clades of C. albicans. Our results demonstrate that mating-competent strains of C. albicans exist naturally in patient populations and suggest that mating may play a role in the genesis of diversity in this pernicious fungal pathogen.
Dissecting the Fidelity of Bacteriophage RB69 DNA Polymerase: Site-Specific Modulation of Fidelity by Polymerase Accessory Proteins
Authors: Bebenek Anna , Carver Geraldine T , Dressman Holly Kloos , Kadyrov Farid A , Haseman Joseph K , Petrov Vasiliy , Konigsberg William H , Karam Jim D , Drake John W
Published: April 2021

Bacteriophage RB69 encodes a replicative B-family DNA polymerase (RB69 gp43) with an associated proofreading 3′ exonuclease. Crystal structures have been determined for this enzyme with and without DNA substrates. We previously described the mutation rates and kinds of mutations produced in vivo by the wild-type (Pol+ Exo+) enzyme, an exonuclease-deficient mutator variant (Pol+ Exo-), mutator variants with substitutions at Tyr567 in the polymerase active site (PolM Exo+), and the double mutator PolM Exo-. Comparing the mutational spectra of the Pol+ Exo- and Pol+ Exo+ enzymes revealed the patterns and efficiencies of proofreading, while Tyr567 was identified as an important determinant of base-selection fidelity. Here, we sought to determine how well the fidelities of the same enzymes are reflected in vitro. Compared to their behavior in vivo, the three mutator polymerases exhibited modestly higher mutation rates in vitro and their mutational predilections were also somewhat different. Although the RB69 gp43 accessory proteins exerted little or no effect on total mutation rates in vitro, they strongly affected mutation rates at many specific sites, increasing some rates and decreasing others.
Estimating the Spontaneous Mutation Rate of Loss of Sex in the Human Pathogenic Fungus Cryptococcus neoformans
Authors: Xu Jianping
Published: April 2021

Few events have evolutionary consequences as pervasive as changes in reproductive behavior. Among those changes, the loss of the ability to undergo sexual reproduction is probably the most profound. However, little is known about the rate of loss of sex. Here I describe an experimental system using the fungus Cryptococcus neoformans and provide the first empirical estimate of the spontaneous mutation rate of loss of sex in fungi. Two critical steps in sexual reproduction in C. neoformans were examined: mating and filamentation. Mating, the fusion of cells of opposite sexes, is a universal first step in eukaryotic sexual reproduction. In contrast, filamentation, a prerequisite process preceding meiosis and sexual spore development, is restricted to C. neoformans and a few other fungal species. After ∼600 mitotic divisions under favorable asexual growth conditions, mean abilities for mating and filamentation decreased significantly by >67 and 24%, respectively. Similarly, though statistically not significant, the mean vegetative growth rates also decreased and among the mutation accumulation lines, the vegetative growth rates were negatively correlated to the mating ability. The estimated mutation rates to decreases in mating ability and filamentation were in excess of 0.0172 and 0.0036, respectively. The results show that C. neoformans can be a highly attractive model for analyses of reproductive system evolution in fungi.
A Genetic Screen for Suppressors and Enhancers of the Drosophila Cdk1-Cyclin B Identifies Maternal Factors That Regulate Microtubule and Microfilament Stability
Authors: Ji Jun-Yuan , Haghnia Marjan , Trusty Cory , Goldstein Lawrence S B , Schubiger Gerold
Published: April 2021

Coordination between cell-cycle progression and cytoskeletal dynamics is important for faithful transmission of genetic information. In early Drosophila embryos, increasing maternal cyclin B leads to higher Cdk1-CycB activity, shorter microtubules, and slower nuclear movement during cycles 5-7 and delays in nuclear migration to the cortex at cycle 10. Later during cycle 14 interphase of six cycB embryos, we observed patches of mitotic nuclei, chromosome bridges, abnormal nuclear distribution, and small and large nuclei. These phenotypes indicate disrupted coordination between the cell-cycle machinery and cytoskeletal function. Using these sensitized phenotypes, we performed a dosage-sensitive genetic screen to identify maternal proteins involved in this process. We identified 10 suppressors classified into three groups: (1) gene products regulating Cdk1 activities, cdk1 and cyclin A; (2) gene products interacting with both microtubules and microfilaments, Actin-related protein 87C; and (3) gene products interacting with microfilaments, chickadee, diaphanous, Cdc42, quail, spaghetti-squash, zipper, and scrambled. Interestingly, most of the suppressors that rescue the astral microtubule phenotype also reduce Cdk1-CycB activities and are microfilament-related genes. This suggests that the major mechanism of suppression relies on the interactions among Cdk1-CycB, microtubule, and microfilament networks. Our results indicate that the balance among these different components is vital for normal early cell cycles and for embryonic development. Our observations also indicate that microtubules and cortical microfilaments antagonize each other during the preblastoderm stage.
Regulation of Larval Hematopoiesis in Drosophila melanogaster: A Role for the multi sex combs Gene
Authors: Remillieux-Leschelle Nathalie , Santamaria Pedro , Randsholt Neel B
Published: April 2021

Drosophila larval hematopoietic organs produce circulating hemocytes that ensure the cellular host defense by recognizing and neutralizing non-self or noxious objects through phagocytosis or encapsulation and melanization. Hematopoietic lineage specification as well as blood cell proliferation and differentiation are tightly controlled. Mutations in genes that regulate lymph gland cell proliferation and hemocyte numbers in the body cavity cause hematopoietic organ overgrowth and hemocyte overproliferation. Occasionally, mutant hemocytes invade self-tissues, behaving like neoplastic malignant cells. Two alleles of the Polycomb group (PcG) gene multi sex combs (mxc) were previously isolated as such lethal malignant blood neoplasm mutations. PcG genes regulate Hox gene expression in vertebrates and invertebrates and participate in mammalian hematopoiesis control. Hence we investigated the need for mxc in Drosophila hematopoietic organs and circulating hemocytes. We show that mxc-induced hematopoietic hyperplasia is cell autonomous and that mxc mainly controls plasmatocyte lineage proliferation and differentiation in lymph glands and circulating hemocytes. Loss of the Toll pathway, which plays a similar role in hematopoiesis, counteracted mxc hemocyte proliferation but not mxc hemocyte differentiation. Several PcG genes tested in trans had no effects on mxc hematopoietic phenotypes, whereas the trithorax group gene brahma is important for normal and mutant hematopoiesis control. We propose that mxc provides one of the regulatory inputs in larval hematopoiesis that control normal rates of plasmatocyte and crystal lineage proliferation as well as normal rates and timing of hemocyte differentiation.
Variation in Chiasma Frequency Among Eight Accessions of Arabidopsis thaliana
Authors: Sanchez-Moran E , Armstrong S J , Santos J L , Franklin F C H , Jones G H
Published: April 2021

Natural variation in meiotic recombination frequency in Arabidopsis thaliana has been assessed by analyzing chiasma frequency variation among a range of geographically and ecologically diverse accessions. Fifty pollen mother cells at metaphase I of meiosis were analyzed from each of eight accessions and fluorescence in situ hybridization was applied to enable identification of all 10 chromosome arms. There was no significant variation in mean chiasma frequency between plants within accessions, but there was significant variation between accessions. Further analysis confirmed this finding and identified two particular accessions, Cvi and Ler, as having chiasma frequencies significantly lower than those of the other accessions. The analysis also revealed that the pattern of chiasma distribution between arms and among chromosomes is not consistent over accessions. Further detailed analyses were conducted on each individual chromosome (1-5) in turn, revealing that chromosome 4, one of the acrocentric chromosomes, is the least variable while the other acrocentric chromosome (2) is the most variable. These findings indicate the existence of recombination regulatory elements in Arabidopsis and we conclude that it may be possible in the future to identify these elements and determine their mode of action. The practical implications of such developments are considerable.
Highly Condensed Potato Pericentromeric Heterochromatin Contains rDNA-Related Tandem Repeats
Authors: Stupar Robert M , Song Junqi , Tek Ahmet L , Cheng Zhukuan , Dong Fenggao , Jiang Jiming
Published: April 2021

The heterochromatin in eukaryotic genomes represents gene-poor regions and contains highly repetitive DNA sequences. The origin and evolution of DNA sequences in the heterochromatic regions are poorly understood. Here we report a unique class of pericentromeric heterochromatin consisting of DNA sequences highly homologous to the intergenic spacer (IGS) of the 18S•25S ribosomal RNA genes in potato. A 5.9-kb tandem repeat, named 2D8, was isolated from a diploid potato species Solanum bulbocastanum. Sequence analysis indicates that the 2D8 repeat is related to the IGS of potato rDNA. This repeat is associated with highly condensed pericentromeric heterochromatin at several hemizygous loci. The 2D8 repeat is highly variable in structure and copy number throughout the Solanum genus, suggesting that it is evolutionarily dynamic. Additional IGS-related repetitive DNA elements were also identified in the potato genome. The possible mechanism of the origin and evolution of the IGS-related repeats is discussed. We demonstrate that potato serves as an interesting model for studying repetitive DNA families because it is propagated vegetatively, thus minimizing the meiotic mechanisms that can remove novel DNA repeats.
amontillado, the Drosophila Homolog of the Prohormone Processing Protease PC2, Is Required During Embryogenesis and Early Larval Development
Authors: Rayburn Lowell Y M , Gooding Holly C , Choksi Semil P , Maloney Dhea , Kidd Ambrose R , Siekhaus Daria E , Bender Michael
Published: April 2021

Biosynthesis of most peptide hormones and neuropeptides requires proteolytic excision of the active peptide from inactive proprotein precursors, an activity carried out by subtilisin-like proprotein convertases (SPCs) in constitutive or regulated secretory pathways. The Drosophila amontillado (amon) gene encodes a homolog of the mammalian PC2 protein, an SPC that functions in the regulated secretory pathway in neuroendocrine tissues. We have identified amon mutants by isolating ethylmethanesulfonate (EMS)-induced lethal and visible mutations that define two complementation groups in the amon interval at 97D1 of the third chromosome. DNA sequencing identified the amon complementation group and the DNA sequence change for each of the nine amon alleles isolated. amon mutants display partial embryonic lethality, are defective in larval growth, and arrest during the first to second instar larval molt. Mutant larvae can be rescued by heat-shock-induced expression of the amon protein. Rescued larvae arrest at the subsequent larval molt, suggesting that amon is also required for the second to third instar larval molt. Our data indicate that the amon proprotein convertase is required during embryogenesis and larval development in Drosophila and support the hypothesis that AMON acts to proteolytically process peptide hormones that regulate hatching, larval growth, and larval ecdysis.
Genetic Analysis of the Interface Between Cdc42p and the CRIB Domain of Ste20p in Saccharomyces cerevisiae
Authors: Ash Josée , Wu Cunle , Larocque Robert , Jamal Maleek , Stevens Willem , Osborne Mike , Thomas David Y , Whiteway Malcolm
Published: April 2021

Mutagenesis was used to probe the interface between the small GTPase Cdc42p and the CRIB domain motif of Ste20p. Members of a cluster of hydrophobic residues of Cdc42p were changed to alanine and/or arginine. The interaction of the wild-type and mutant proteins was measured using the two-hybrid assay; many, but not all, changes reduced interaction between Cdc42p and the target CRIB domain. Mutations in conserved residues in the CRIB domain were also tested for their importance in the association with Cdc42p. Two conserved CRIB domain histidines were changed to aspartic acid. These mutants reduced mating, as well as responsiveness to pheromone-induced gene expression and cell cycle arrest, but did not reduce in vitro the kinase activity of Ste20p. GFP-tagged mutant proteins were unable to localize to sites of polarized growth. In addition, these point mutants were synthetically lethal with disruption of CLA4 and blocked the Ste20p-Cdc42p two-hybrid interaction. Compensatory mutations in Cdc42p that reestablished the two-hybrid association with the mutant Ste20p CRIB domain baits were identified. These mutations improved the pheromone responsiveness of cells containing the CRIB mutations, but did not rescue the lethality associated with the CRIB mutant CLA4 deletion interaction. These results suggest that the Ste20p-Cdc42p interaction plays a direct role in Ste20p kinase function and that this interaction is required for efficient activity of the pheromone response pathway.
Std1p (Msn3p) Positively Regulates the Snf1 Kinase in Saccharomyces cerevisiae
Authors: Kuchin Sergei , Vyas Valmik K , Kanter Ellen , Hong Seung-Pyo , Carlson Marian
Published: April 2021

The Snf1 protein kinase of the glucose signaling pathway in Saccharomyces cerevisiae is regulated by an autoinhibitory interaction between the regulatory and catalytic domains of Snf1p. Transitions between the autoinhibited and active states are controlled by an upstream kinase and the Reg1p-Glc7p protein phosphatase 1. Previous studies suggested that Snf1 kinase activity is also modulated by Std1p (Msn3p), which interacts physically with Snf1p and also interacts with glucose sensors. Here we address the relationship between Std1p and the Snf1 kinase. Two-hybrid assays showed that Std1p interacts with the catalytic domain of Snf1p, and analysis of mutant kinases suggested that this interaction is incompatible with the autoinhibitory interaction of the regulatory and catalytic domains. Overexpression of Std1p increased the two-hybrid interaction of Snf1p with its activating subunit Snf4p, which is diagnostic of an open, uninhibited conformation of the kinase complex. Overexpression of Std1p elevated Snf1 kinase activity in both in vitro and in vivo assays. These findings suggest that Std1p stimulates the Snf1 kinase by an interaction with the catalytic domain that antagonizes autoinhibition and promotes an active conformation of the kinase.