bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimation of Effects of Quantitative Trait Loci in Large Complex Pedigrees
Authors: Meuwissen T H E , Goddard M E
Published: January 2021

A method was derived to estimate effects of quantitative trait loci (QTL) using incomplete genotype information in large outbreeding populations with complex pedigrees. The method accounts for background genes by estimating polygenic effects. The basic equations used are very similar to the usual linear mixed model equations for polygenic models, and segregation analysis was used to estimate the probabilities of the QTL genotypes for each animal. Method R was used to estimate the polygenic heritability simultaneously with the QTL effects. Also, initial allele frequencies were estimated. The method was tested in a simulated data set of 10,000 animals evenly distributed over 10 generations, where 0, 400 or 10,000 animals were genotyped for a candidate gene. In the absence of selection, the bias of the QTL estimates was <2%. Selection biased the estimate of the Aa genotype slightly, when zero animals were genotyped. Estimates of the polygenic heritability were 0.251 and 0.257, in absence and presence of selection, respectively, while the simulated value was 0.25. Although not tested in this study, marker information could be accommodated by adjusting the transmission probabilities of the genotypes from parent to offspring according to the marker information. This renders a QTL mapping study in large multi-generation pedigrees possible.
Recombination and the Progression of Meiosis in Saccharomyces cerevisiae
Authors: Galbraith Anne M , Bullard Steven A , Jiao Kai , Nau Johnathan J , Malone Robert E
Published: January 2021

Recombination is an essential part of meiosis; in almost all organisms, including Saccharomyces cerevisiae, proper chromosome segregation and the viability of meiotic products is dependent upon normal levels of recombination. In this article we examine the kinetics of the meiotic divisions in four mutants defective in the initiation of recombination. We find that mutations in any of three Early Exchange genes (REC104, REC114 or REC102) confer a phenotype in which the reductional division occurs earlier than in an isogenic wild-type diploid. We also present data confirming previous reports that strains with a mutation in the Early Exchange gene MEI4 undergo the first division at about the same time as wild-type cells. The rec104 mutation is epistatic to the mei4 mutation for the timing of the first division. These observations suggest a possible relationship between the initiation of recombination and the timing of the reductional division. These data also allow these four Early Exchange genes examined to be distinguished in terms of their role in coordinating recombination with the reductional division.
Cytosine Methylation Associated With Repeat-Induced Point Mutation Causes Epigenetic Gene Silencing in Neurospora crassa
Authors: Irelan Jeffrey T , Selker Eric U
Published: January 2021

Repeated DNA sequences are frequently mutated during the sexual cycle in Neurospora crassa by a process named repeat-induced point mutation (RIP). RIP is often associated with methylation of cytosine residues in and around the mutated sequences. Here we demonstrate that this methylation can silence a gene located in nearby, unique sequences. A large proportion of strains that had undergone RIP of a linked duplication flanking a single-copy transgene, hph (hygromycin B phosphotransferase), showed partial silencing of hph. These strains were all heavily methylated throughout the single-copy hph sequences and the flanking sequences. Silencing was alleviated by preventing methylation, either by 5-azacytidine (5AC) treatment or by introduction of a mutation (eth-I) known to reduce intracellular levels of S-adenosylmethionine. Silenced strains exhibited spontaneous reactivation of hph at frequencies of 10–4 to 0.5. Reactivated strains, as well as cells that were treated with 5AC, gave rise to cultures that were hypomethylated and partially hygromycin resistant, indicating that some of the original methylation was propagated by a maintenance mechanism. Gene expression levels were found to be variable within a population of clonally related cells, and this variation was correlated with epigenetically propagated differences in methylation patterns.
Mechanism of Activation of the Caenorhabditis elegans ras Homologue let-60 by a Novel, Temperature-Sensitive, Gain-of-Function Mutation
Authors: Eisenmann David M , Kim Stuart K
Published: January 2021

The Caenorhabditis elegans let-60 gene encodes a Ras protein that mediates induction of the hermaphrodite vulva. To better understand how mutations constitutively activate Ras and cause unregulated cell division, we have characterized ga89, a temperature-sensitive, gain-of-function mutation in let-60 ras. At 25°, ga89 increases let-60 activity resulting in a multivulva phenotype. At 15°, ga89 decreases let-60 activity resulting in a vulvaless phenotype in let-60(ga89)/Df animals. The ga89 mutation causes a leucine (L) to phenylalanine (F) substitution at amino acid 19, a residue conserved in all Ras proteins. We introduced the L19F change into human H-Ras protein and found that the in vitro GTPase activity of H-Ras became temperature-dependent. Genetic experiments suggest that LET-60(L19F) interacts with GAP and GNEF, since mutations that decrease GAP and GNEF activity affect the multivulva phenotype of let-60(ga89) animals. These results suggest that the L19F mutation primarily affects the intrinsic rate of GTP hydrolysis by Ras, and that this effect may be sufficient to account for the activated-Ras phenotype caused by let-60(ga89). Our results suggest that a mutation in a human ras gene analogous to ga89 might contribute to oncogenic transformation.
The CRE-Binding Protein dCREB-A Is Required for Drosophila Embryonic Development
Authors: Rose Ronald E , Gallaher Nicole M , Andrew Deborah J , Goodman Richard H , Smolik Sarah M
Published: January 2021

We have previously described the cloning of a cyclic AMP response-element (CRE)-binding protein, dCREB-A, in Drosophila melanogaster that is similar to the mammalian CRE-binding protein CREB. dCREB-A is a member of the bZIP family of transcription factors, shows specific binding to the (CRE), and can activate transcription in cell culture. In this report, we describe the gene structure for dCREB-A, protein expression patterns throughout development and the necessary role for this gene in embryogenesis. The 4.5-kb transcript is encoded in six exons that are distributed over 21 kb of DNA. There are seven start sites and no TATA consensus sequences upstream. The dCREB-A protein is expressed in the nuclei of the embryonic salivary gland, proventriculus and stomadeum. Late in embryogenesis, tracheal cell nuclei and specific nuclei within the segments show staining with anti-dCREB-A antibodies. In adult female ovaries, dCREB-A is expressed in the stage 9 through stage 11 follicle cell nuclei. Null mutations of the dCREB-A gene give rise to animals that no longer express dCREB-A protein and die late in embryogenesis before or at hatching. The absolute requirement of dCREB-A for embryogenesis demonstrates a nonredundant function for a CRE-binding protein that will be useful in studying the role of specific signal transduction cascades in development.
Recombination and Gene Flux Caused by Gene Conversion and Crossing Over in Inversion Heterokaryotypes
Authors: Navarro Arcadio , Betrán Esther , Barbadilla Antonio , Ruiz Alfredo
Published: January 2021

A theoretical analysis of the effects of inversions on recombination and gene flux between arrangements caused by gene conversion and crossing over was carried out. Two different mathematical models of recombination were used: the Poisson model (without interference) and the Counting model (with interference). The main results are as follows. (1) Recombination and gene flux are highly site-dependent both inside and outside the inverted regions. (2) Crossing over overwhelms gene conversion as a cause of gene flux in large inversions, while conversion becomes relatively significant in short inversions and in regions around the breakpoints. (3) Under the Counting model the recombination rate between two markers depends strongly on the position of the markers along the inverted segment. Two equally spaced markers in the central part of the inverted segment have less recombination than if they are in a more extreme position. (4) Inversions affect recombination rates in the uninverted regions of the chromosome. Recombination increases in the distal segment and decreases in the proximal segment. These results provide an explanation for a number of observations reported in the literature. Because inversions are ubiquitous in the evolutionary history of many Drosophila species, the effects of inversions on recombination are expected to influence DNA variation patterns.
Microsatellite DNA Variation and the Evolution, Domestication and Phylogeography of Taurine and Zebu Cattle (Bos taurus and Bos indicus)
Authors: MacHugh David E , Shriver Mark D , Loftus Ronan T , Cunningham Patrick , Bradley Daniel G
Published: January 2021

Genetic variation at 20 microsatellite loci was surveyed to determine the evolutionary relationships and molecular biogeography of 20 different cattle populations from Africa, Europe and Asia. Phylogenetic reconstruction and multivariate analysis highlighted a marked distinction between humpless (taurine) and humped (zebu) cattle, providing strong support for a separate origin for domesticated zebu cattle. A molecular clock calculation using bison (Bison sp.) as an outgroup gave an estimated divergence time between the two subspecies of 610,000-850,000 years. Substantial differences in the distribution of alleles at 10 of these loci were observed between zebu and taurine cattle. These markers subsequently proved very useful for investigations of gene flow and admixture in African populations. When these data were considered in conjunction with previous mitochondrial and Y chromosomal studies, a distinctive male-mediated pattern of zebu genetic introgression was revealed. The introgression of zebu-specific alleles in African cattle afforded a high resolution perspective on the hybrid nature of African cattle populations and also suggested that certain West African populations of valuable disease-tolerant taurine cattle are under threat of genetic absorption by migrating zebu herds.
Pathways for Homologous Recombination Between Chromosomal Direct Repeats in Salmonella typhimurium
Authors: Galitski Timothy , Roth John R
Published: January 2021

Homologous recombination pathways probably evolved primarily to accomplish chromosomal repair and the formation and resolution of duplications by sister-chromosome exchanges. Various DNA lesions initiate these events. Classical recombination assays, involving bacterial sex, focus attention on double-strand ends of DNA. Sexual exchanges, initiated at these ends, depend on the RecBCD pathway. In the absence of RecBCD function, mutation of the sbcB and sbcC genes activates the apparently cryptic RecF pathway. To provide a more general view of recombination, we describe an assay in which endogenous DNA damage initiates recombination between chromosomal direct repeats. The repeats flank markers conferring lactose utilization (Lac+) and ampicillin resistance (ApR); recombination generates Lac-ApS segregants. In this assay, the RecF pathway is not cryptic; it plays a major role without sbcBC mutations. Others have proposed that single-strand gaps are the natural substrate for RecF-dependent recombination. Supporting this view, recombination stimulated by a double-strand break (DSB) in a chromosomal repeat depended on RecB function, not RecF function. Without RecBCD function, sbcBC mutations modified the RecF pathway and allowed it to catalyze DSB-stimulated recombination. Sexual recombination assays overestimate the importance of RecBCD and DSBs, and underestimate the importance of the RecF pathway.
Point Mutations Within and Outside the Homeodomain Identify Sequences Required for proboscipedia Homeotic Function in Drosophila
Authors: Benassayag Corinne , Boube Muriel , Seroude Laurent , Cribbs David L
Published: January 2021

The Drosophila homeotic gene proboscipedia (pb) encodes a homeodomain protein homologous to vertebrate HoxA2/B2 required for adult mouthparts formation. A transgenic Hsp70-pb (HSPB) element that rescues pb mutations also induces the dominant transformation of antennae to maxillary palps. To identify sequences essential to PB protein function, we screened for EMS-induced HSPB mutations leading to phenotypic reversion of the HSPB transformation. Ten revertants harbor identified point mutations in HSPB coding sequences. The point mutations that remove all detectable phenotypes in vivo reside either within the homeodomain or, more unexpectedly,in evolutionarily nonconserved regions outside the homeodomain. Two independent homeodomain mutations that change the highly conserved Arginine-5 in the N-terminal hinge show effects on adult eye development, suggesting a previously unsuspected role for Arg5 in functional specificity. Three additional revertant mutations outside the homeodomain reduce but do not abolish PB+ activity, identifylng protein elements that contribute quantitatively to pb function. This in vivo analysis shows that apart from the conserved motifs of PB, other elements throughout the protein make important contributions to homeotic function.
Mapping a Quantitative Trait Locus Involved in Melanotic Encapsulation of Foreign Bodies in the Malaria Vector, Anopheles gambiae
Authors: Goman Maureen J , Severson David W , Cornel Anton J , Collins Frank H , Paskewitz Susan M
Published: January 2021

A Plasmodium-refractory strain of Anopheles gambiae melanotically encapsulates many species of Plasmodium, whereas wild-type mosquitoes are usually susceptible. This encapsulation trait can also be observed by studying the response of refractory and susceptible straintos intrathoracically injected CM-Sephadex beads. We report the results of broad-scale quantitative trait locus (QTL) mapping of the encapsulation trait using the bead model system. Interval mapping using the method of maximum likelihood identified one major QTL, Pen1. The 13.7-cM interval containing Pen1 was defined by marker AGH157 at 8E and AGH46 at 7A on 2R. Pen1 was associated with a maximum LOD score of 9.0 and accounted for 44% of the phenotypic variance in the distribution of phenotypes in the backcross. To test if this QTL is important for encapsulation of Plasmodium berghei, F2 progeny were infected with P. berghei and evaluated for degree of parasite encapsulation. For each of the two markers that define the interval containing Pen1, a significant difference of encapsulation was seen in progeny with at least one refractory allele in contrast with homozygous susceptible progeny. These results suggest that Pen1 is important for melanotic encapsulation of Plasmodium as well as beads.
Population Dynamics Inferred From Temporal Variation at Microsatellite Loci in the Selfing Snail Bulinus truncatus
Authors: Viard Frédérique , Justy Fabienne , Jarne Philippe
Published: January 2021

We analyzed short-term forces acting on the genetics of subdivided populations based on a temporal survey of the microsatellite variability in the hermaphrodite freshwater snail Bulinus truncatus. This species inhabits temporary habitats, has a short generation time and exhibits variable rates of selfing. We studied the variability over three sampling dates in 12 Sahelian populations (1161 individuals). Classical genetic parameters (estimators of Ho, He, f selfing rate and Fst) showed limited change over time whereas important temporal changes of allelic frequencies were detected for 10 of the ponds studied. These variations are not easily explained by selection, sampling drift and genetic drift alone and may be due to periodic migration. Indeed the habitats occupied by the populations studied are subject to large temporal fluctuations owing to annual cycles of drought and flood. In such ponds our results support a demographic model of population expansions and contractions under which available habitats, after the rainy season, are colonized by individuals originating from a smaller number of refuges (areas that never dry out in the deepest parts of the ponds). In contrast, selfing appeared to be an important force affecting the genetic structure in permanent ponds.
Effective Size and F-Statistics of Subdivided Populations. I. Monoecious Species with Partial Selfing
Authors: Wang Jinliang
Published: January 2021

Assuming discrete generations and autosomal inheritance involving genes that do not affect viability or reproductive ability, we have derived recurrence equations for the inbreeding coefficient and coancestry between individuals within and among subpopulations for a subdivided monoecious population with arbitrary distributions of male and female gametes per family, variable pollen and seed migration rates, and partial selfing. From the equations, formulas for effective size and expressions for F-statistics are obtained. For the special case of a single unsubdivided population, our equations reduce to the simple expressions derived by previous authors. It is shown that population structure (subdivision and migration) is important in determining the inbreeding coefficient and effective size. Failure to recognize internal structures of populations may lead to considerable bias in predicting effective size. Inbreeding coefficient, coancestry between individuals within and among subpopulations accrue at different and variable rates over initial generations before they converge to the same asymptotic rate of increase. For a given population, the smaller the pollen and seed migration rates, the more generations are required to attain the asymptotic rate and the larger the asymptotic effective size. The equations presented herein can be used for the study of evolutionary biology and conservation genetics.
A Functional Analysis of Notch Mutations in Drosophila
Authors: Brennan Keith , Tateson Richard , Lewis Karen , Arias Alfonso Martinez
Published: January 2021

The Notch gene encodes a receptor protein that is involved in many processes during development. Its best understood role is during neurogenesis in a process called “lateral inhibition.” However, it has been proposed that Notch also has a role in defining the proneural clusters in the first place. This raises the possibility that the Notch protein is acting as a multifunctional receptor. To test this hypothesis, we have carried out a genetic analysis of molecularly characterized Notch alleles to identify alleles that affect only one of the two proposed functions. Here we present evidence that Notch alleles can be identified that appear to affect the function of Notch during either lateral inhibition or the definition of proneural clusters. In addition our results indicate that there may be discrete regions of the Notch protein required for each function.
Polymorphism and Divergence at a Drosophila Pseudogene Locus
Authors: Pritchard Jonathan K , Schaeffer Stephen W
Published: January 2021

The larval cuticle protein (Lcp) cluster in Drosophila melanogaster contains four functional genes and a closely related pseudogene. A 630-bp fragment including the larval cuticle pseudogene locus (Lcpψ) was nucleotide sequenced in 10 strains of D. melanogaster and a 458-bp Lcpψ fragment from D. simulans was also sequenced. We used these data to test the hypotheses that the rates of synonymous and nonsynonymous substitution are equal, that the absolute levels of variation are higher than in functional genes, and that intraspecific polymorphism is correlated with interspecific divergence. As predicted, synonymous and nonsynonymous substitution rates were equivalent, and overall nucleotide divergence between D. melanogaster and D. simulans (Jukes-Cantor distance = 0.149 ± 0.150) was extremely high. However, within-species DNA sequence comparisons at Lcpψ revealed lower levels of polymorphism (ϴ^=0.001±0.001) than at many functional loci in D. melanogaster. Using the Hudson, Kreitman, and Aguade (HKA) test, we show that the level of polymorphism in Lcpψ within D. melanogaster is lower than expected given the amount of divergence between D. melanogaster and D. simulans when the pseudogene data are compared to the Adh 5′ flanking region. Because the Lcpψ lies in a region of relatively infrequent recombination, we suggest that the low level of within-species polymorphism is the result of background selection.
Dissection of a Synthesized Quantitative Trait to Characterize Transgene Interactions
Authors: Nap Jan-Peter , Conner Anthony J , Mlynárová Ludmila , Stiekema Willem J , Jansen Ritsert C
Published: January 2021

Six transgenic tobacco lines, each homozygous for the β-glucuronidase (GUS) gene at a different locus, and wild type were selfed and intercrossed to evaluate GUS activity in all possible hemizygous, homozygous and dihybrid combinations of GUS alleles. The transgenic lines are characterized by their GUS activity (two low, three intermediate, one high), T-DNA complexity (four single-copy, two more complex single-locus) and the presence of the chicken lysozyme matrix-associated region (MAR) around the full T-DNA (two lines). Gene action and interaction was analyzed by weighted linear regression with parameters for additivity, dominance and epistasis. The analysis showed that each of the four single-copy lines acted fully additively. In contrast, the two complex single-locus lines showed classical single-locus overdominance and were epistatic dominant over all other GUS alleles. The latter is manifested in severe suppression of GUS activity in dihybrid lines, irrespective of the presence of MAR elements around the GUS gene. Such elements apparently do not protect against epistatic dominance. The quantitative data suggested that the epistatic dominance and overdominance are based on the same molecular mechanism. Our approach of a genetic analysis of quantitative variation in well-characterized transgenic lines provides a powerful tool to gain insight into complex plant traits.
The Isolation and Characterization of Saccharomyces cerevisiae Mutants That Constitutively Express Purine Biosynthetic Genes
Authors: Guetsova Maria L , Lecoq Karine , Daignan-Fornier Bertrand
Published: January 2021

In response to an external source of adenine, yeast cells repress the expression of purine biosynthesis pathway genes. To identify necessary components of this signalling mechanism, we have isolated mutants that are constitutively active for expression. These mutants were named bra (for bypass of repression by adenine). BRA7 is allelic to FCY2, the gene encoding the purine cytosine permease and BRA9 is ADE12, the gene encoding adenylosuccinate synthetase. BRA6 and BRA1 are new genes encoding, respectively, hypoxanthine guanine phosphoribosyl transferase and adenylosuccinate lyase. These results indicate that uptake and salvage of adenine are important steps in regulating expression of purine biosynthetic genes. We have also shown that two other salvage enzymes, adenine phosphoribosyl transferase and adenine deaminase, are involved in activating the pathway. Finally, using mutant strains affected in AMP kinase or ribonucleotide reductase activities, we have shown that AMP needs to be phosphorylated to ADP to exert its regulatory role while reduction of ADP into dADP by ribonucleotide reductase is not required for adenine repression. Together these data suggest that ADP or a derivative of ADP is the effector molecule in the signal transduction pathway.
A Genetic and Mosaic Analysis of a Locus Involved in the Anesthesia Response of Drosophila melanogaster
Authors: Mir Bashir , Iyer Sharada , Ramaswami Mani , Krishnan K S
Published: January 2021

We describe a genetic and behavioral analysis of several alleles of har38, a mutant with altered sensitivity to the general anesthetic halothane. We obtained a P-element-induced allele of har38 and generated several excision alleles by remobilizing the P element. The mutants narrow abdomen (nu) and har85 are confirmed to be allelic to har38. Besides a decreased sensitivity to halothane, all mutant alleles of this locus cause a characteristic walking behavior in the absence of anesthetics. We have quantified this behavior using a geotaxis apparatus. Responses of the mutant alleles to different inhalational anesthetics were tested. The results strongly favor a multipathway model for the onset of anesthesia. Mosaic flies were tested for their response to halothane and checked for their abnormal walking behavior. The analysis suggests that both the behaviors are exhibited only by such mosaics as have the entire head of mutant origin. It is likely that this focus represents an element of a common pathway in the anesthetic response to several inhalational anesthetics but not all. This result is the first demonstration of regional specificity in the CNS of any animal for general anesthetic action.
Developmental Quantitative Genetics, Conditional Epigenetic Variability and Growth in Mice
Authors: Atchley William R , Zhu Jun
Published: January 2021

Ontogenetic variation in the causal components of phenotypic variability and covariability is described for body weight and tail length in mice derived from a full 7 × 7 diallel cross. Age-related changes in additive, dominance, sex-linked and maternal variance and covariance between 14 and 70 days of age are described. Age-specific variance components at time t are conditioned on the causal genetic effects at time (t – 1). This procedure demonstrates the generation of significant episodes of new genetic variation arising at specific intervals during ontogeny. These episodes of new genetic variation are placed in the context of epigenetic models in developmental quantitative genetics. These results are also concordant on recent findings on age-specific gene expression in mouse growth as shown by QTL analyses.
The Nuclear Gene Rf3 Affects the Expression of the Mitochondrial Chimeric Sequence R Implicated in S-Type Male Sterility in Maize
Authors: Zabala Gracia , Gabay-Laughnan Susan , Laughnan John R
Published: January 2021

The mitochondrial genomes of maize plants exhibiting S-type cytoplasmic male sterility (cms-S) contain a repeated DNA region designated R. This region was found to be rearranged in the mitochondria of all cms-S cytoplasmically revertant fertile plants in all nuclear backgrounds analyzed. A 1.6-kb mRNA transcribed from the R region in mitochondria of sterile plants was absent from all cytoplasmic revertants examined. The nuclear gene Rf3, which suppresses the cms-S phenotype, was found to have a specific effect on the expression of the R sequence; the abundance of the major R transcripts, including the cms-S-specific 1.6-kb mRNA, is decreased in mitochondria of restored plants. Nucleotide sequence analysis of R has revealed similarities to the R1 plasmid found in some South American maize races with RU cytoplasm, to the M1 plasmid found in one source of Zea luxurians teosinte, to the atp9 mitochondrial gene and its 3′ flanking sequence, and also to a region 3′ to the orf221 gene. The derived amino acid sequence of the R region predicts two open reading frames (ORFs). These ORFs contain the similarities to R1, M1, atp9 and orf221. The present report reveals the chimeric nature of the R region, describes the complex effect of Rf3 on the expression of the R sequence and implicates R in the sterile phenotype of cms-S maize.
The Evolution of Recombination: Removing the Limits to Natural Selection
Authors: Otto Sarah Perin , Barton Nick H
Published: January 2021

One of the oldest hypotheses for the advantage of recombination is that recombination allows beneficial mutations that arise in different individuals to be placed together on the same chromosome. Unless recombination occurs, one of the beneficial alleles is doomed to extinction, slowing the rate at which adaptive mutations are incorporated within a population. We model the effects of a modifier of recombination on the fixation probability of beneficial mutations when beneficial alleles are segregating at other loci. We find that modifier alleles that increase recombination do increase the fixation probability of beneficial mutants and subsequently hitchhike along as the mutants rise in frequency. The strength of selection favoring a modifier that increases recombination is proportional to λ2  Sδr/r when linkage is tight and λ2  S  3δr/N when linkage is loose, where λ is the beneficial mutation rate per genome per generation throughout a population of size N, S is the average mutant effect, r is the average recombination rate, and δr is the amount that recombination is modified. We conclude that selection for recombination will be substantial only if there is tight linkage within the genome or if many loci are subject to directional selection as during periods of rapid evolutionary change.
Bottleneck Effect on Evolutionary Rate in the Nearly Neutral Mutation Model
Authors: Araki Hitoshi , Tachida Hidenori
Published: January 2021

Variances of evolutionary rates among lineages in some proteins are larger than those expected from simple Poisson processes. This phenomenon is called overdispersion of the molecular clock. If population size N is constant, the overdispersion is observed only in a limited range of 2Nσ under the nearly neutral mutation model, where σ represents the standard deviation of selection coefficients of new mutants. In this paper, we investigated effects of changing population size on the evolutionary rate by computer simulations assuming the nearly neutral mutation model. The size was changed cyclically between two numbers, N  1 and N  2 (N  1 > N  2), in the simulations. The overdispersion is observed if 2N  2σ is less than two and the state of reduced size (bottleneck state) continues for more than ∼0.1/u generations, where u is the mutation rate. The overdispersion results mainly because the average fitnesses of only a portion of populations go down when the population size is reduced and only in these populations subsequent advantageous substitutions occur after the population size becomes large. Since the fitness reduction after the bottleneck is stochastic, acceleration of the evolutionary rate does not necessarily occur uniformly among loci. From these results, we argue that the nearly neutral mutation model is a candidate mechanism to explain the overdispersed molecular clock.
gon-2, a Gene Required for Gonadogenesis in Caenorhabditis elegans
Authors: Sun Andrew Y , Lambie Eric J
Published: January 2021

The gonad of the Caenorhabditis elegans hermaphrodite is generated by the postembryonic divisions of two somatic precursors, Z1 and Z4, and two germline precursors, Z2 and Z3. These cells begin division midway through the first larval stage. By the end of the fourth larval stage, Z1 and Z4 produce 143 descendants, while Z2 and Z3 give rise to ∼1000 descendants. The divisions of Z2 and Z3 are dependent on signals produced by Z1 and Z4, but not vice versa. We have characterized the properties of five loss-of-function alleles of a newly described gene, which we call gon-2. In gon-2 mutants, gonadogenesis is severely impaired; in some animals, none of the gonad progenitors undergo any postembryonic divisions. Mutations in gon-2 have a partial maternal effect: either maternal or zygotic expression is sufficient to prevent the severe gonadogenesis defects. By cell lineage analysis, we found that the primary defect in gon-2 mutants is a delay (sometimes a complete block) in the onset and continuation of gonadal divisions. The results of upshift experiments using a temperature-sensitive allele suggest that zygotic expression of gon-2 begins early in embryogenesis, before the birth of Z1 and Z4. The results of downshift experiments suggest that Z1 and Z4 can generate the full complement of gonadal tissues even when gon-2 function is inhibited until the end of the second larval stage. Thus, gon-2 activity is probably not required for the specification of gonadal cell fates, but appears to be generally required for gonadal cell divisions.
Advances in Statistical Methods to Map Quantitative Trait Loci in Outbred Populations
Authors: Hoeschele I , Uimari P , Grignola F E , Zhang Q , Gage K M
Published: January 2021

Statistical methods to map quantitative trait loci (QTL) in outbred populations are reviewed, extensions and applications to human and plant genetic data are indicated, and areas for further research are identified. Simple and computationally inexpensive methods include (multiple) linear regression of phenotype on marker genotypes and regression of squared phenotypic differences among relative pairs on estimated proportions of identity-by-descent at a locus. These methods are less suited for genetic parameter estimation in outbred populations but allow the determination of test statistic distributions via simulation or data permutation; however, further inferences including confidence intervals of QTL location require the use of Monte Carlo or bootstrap sampling techniques. A method which is intermediate in computational requirements is residual maximum likelihood (REML) with a covariance matrix of random QTL effects conditional on information from multiple linked markers. Testing for the number of QTLs on a chromosome is difficult in a classical framework. The computationally most demanding methods are maximum likelihood and Bayesian analysis, which take account of the distribution of multilocus marker-QTL genotypes on a pedigree and permit investigators to fit different models of variation at the QTL. The Bayesian analysis includes the number of QTLS on a chromosome as an unknown.
The Advantage of Sex in the RNA Virus φ6
Authors: Chao Lin , Tran Thu T , Tran Thutrang T
Published: January 2021

When laboratory populations of the RNA bacteriophage φ6 are subjected to intensified genetic drift, they experience a decline in fitness. These experiments demonstrate that the average effect of mutations is deleterious, and they are used to suggest that Muller's ratchet can operate in these viruses. However, the operation of Muller's ratchet does not alone guarantee an advantage of sex. When φ6 populations were subjected to a series of bottlenecks of one individual and then crossed, the measured advantage of sex was not significant. To determine whether a small sample size, as opposed to allelism or another explanation, can account for the negative result, we repeated the φ6 experiments by crossing a larger set of populations. We found that bottlenecked populations of φ6 could recover fitness through mutations. However, hybrids produced by crossing the populations recovered an additional amount over the contribution of mutations. This additional amount, which represents an advantage of sex to φ6, was determined to be significantly greater than zero. These results provide indirect support for an advantage of sex through Muller's ratchet. However, we also use our experimental design and results to propose an alternative to Muller's ratchet as a model for the evolution of sex.
Hardy-Weinberg Testing for Continuous Data
Authors: McIntyre Lauren M , Weir B S
Published: January 2021

Estimation of allelic and genotypic distributions for continuous data using kernel density estimation is discussed and illustrated for some variable number of tandem repeat data. These kernel density estimates provide a useful representation of data when only some of the many variants at a locus are present in a sample. Two Hardy-Weinberg test procedures are introduced for continuous data: a continuous chi-square test with test statistic TCCS and a test based on Hellinger's distance with test statistic TCCS. Simulations are used to compare the powers of these tests to each other and to the powers of a test of intraclass correlation TIC, as well as to the power of Fisher's exact test TFET applied to discretized data. Results indicate that the power of TCCS is better than that of THD but neither is as powerful as TFET. The intraclass correlation test does not perform as well as the other tests examined in this article.
Alu Evolution in Human Populations: Using the Coalescent to Estimate Effective Population Size
Authors: Sherry Stephen T , Harpending Henry C , Batzer Mark A , Stoneking Mark
Published: January 2021

There are estimated to be ~1000 members of the Ya5 Alu subfamily of retroposons in humans. This Subfamily has a distribution restricted to humans, with a few copies in gorillas and chimpanzees. Fifty-seven Ya5 elements were previously cloned from a HeLaderived randomly sheared total genomic library, sequenced, and screened for polymorphism in a panel of 120 unrelated humans. Forty-four of the 57 cloned Alu repeats were monomorphic in the sample and 13 Alu repeats were dimorphic for insertion presence/absence. The observed distribution of sample frequencies of the 13 dimorphic elements is consistent with the theoretical expectation for elements ascertained in a single diploid cell line. Coalescence theory is used to compute expected total pedigree branch lengths for monomorphic and dimorphic elements, leading to an estimate of human effective population size of ~18,000 during the last one to two million years.
Architectural Mediator subunits are differentially essential for global transcription in Saccharomyces cerevisiae
Authors: Tourigny Jason P , Schumacher Kenny , Saleh Moustafa M , Devys Didier , Zentner Gabriel E
Published: January 2021

Mediator is a modular coactivator complex involved in the transcription of the majority of RNA polymerase II-regulated genes. However, the degrees to which individual core subunits of Mediator contribute to its activity have been unclear. Here, we investigate the contribution of two essential architectural subunits of Mediator to transcription in Saccharomyces cerevisiae. We show that acute depletion of the main complex scaffold Med14 or the head module nucleator Med17 is lethal and results in global transcriptional downregulation, though Med17 removal has a markedly greater negative effect. Consistent with this, Med17 depletion impairs preinitiation complex (PIC) assembly to a greater extent than Med14 removal. Co-depletion of Med14 and Med17 reduced transcription and TFIIB promoter occupancy similarly to Med17 ablation alone, indicating that the contributions of Med14 and Med17 to Mediator function are not additive. We propose that, while the structural integrity of complete Mediator and the head module are both important for PIC assembly and transcription, the head module plays a greater role in this process and is thus the key functional module of Mediator in this regard.
Induced polarization of volcanic rocks. 4. Large-scale induced polarization imaging
Authors: Gross L , Soueid Ahmed A , Revil A
Published: January 2021

Thanks to the emergence of new technologies developed with the goal of performing large-scale galvanometric induced polarization surveys and thanks a better understanding of the underlying physics of induced polarization, this geophysical method can now be applied in the field of volcanology and geothermal resources assessment. A new approach is developed here for directly inverting the primary and secondary electric fields recorded at a set of independent stations when injecting a primary current. The use of independent stations to measure the primary and secondary electrical fields improves the quality of the data by reducing the capacitive coupling effects inherent to systems based on long cables. It avoids issues associated with using the same electrodes for both current injection and voltage measurements and negative apparent resistivity and chargeability values. With such acquisitions, we can perform true 3-D surveys in areas characterized by complex topography such as volcanoes. The numerical scheme we developed returns as output the electrical conductivity and chargeability fields. The implemented methodology presents several advantages. The first is the use of data types at the stations, for example the electric field intensity, that are independent from the local geometrical station parameters such as electrode spacing and dipole orientation. The second advantage lies in the suitability of the proposed approach to perform large-scale applications since we use a matrix-free approach that does not require the assembly of the Jacobian matrices. The third concerns the possibility of performing the inversion on complex geometries through a consistent use of the finite element method on unstructured meshes in combination with algebraic multigrid preconditioning for the regularization and the solution of the forward and adjoint problems. The computation of 3-D sensitivity maps can also be a real asset in survey design. After validating our approach with a benchmark synthetic case study, we test it on a large-scale induced polarization survey that mimic true field conditions on a volcanic environment with rough topography. Our tests demonstrate the high potential of this electric field approach in volcanology especially for deep (3 km) imagining of the internal structure of volcanoes, which in turn could improve our understanding of hydrothermal systems and allow the monitoring of active volcanoes and the potential risk of collapse.
Linking health information seeking to patient-centered communication and healthy lifestyles: an exploratory study in China
Authors: Zhang Lianshan , Jiang Shaohai
Published: January 2021

The existing research routinely measures the influence of health information-seeking behavior (HISB) as a whole, which does not capture the complexity and diversity of media channel usage in HISB. The influence of HISB on patient’s lifestyle behaviors and the mediation process through patient-centered communication (PCC) in medical encounters has been understudied in previous literature. Drawing from Street’s three-stage model, this study conducted a secondary analysis of the Health Information National Trends Survey in China to investigate the influences of HISB across five different media outlets (e.g. information-oriented media, entertainment-oriented media, search engines, social media and mobile health applications) on two types of healthy lifestyles (e.g. physical activity, fruit and vegetable consumption), by the mediation of PCC. PROCESS path-analysis with bootstrapping estimation was used to test the hypothesized relationships. The results revealed that HISB is positively related to PCC, and PCC positively predicts frequent engagement in healthy lifestyles. Moreover, PCC partially mediates the effect of information-oriented media HISB on healthy lifestyles and fully mediates the effect of HISB through the other four media sources. This study highlights the essential stage of PCC transferring HISB to engagement in healthy lifestyles and draws attention to the varying influences of media channels carrying different characteristics.
Exploring the social and emotional representations used by students from the University of the Basque Country to face the first outbreak of COVID-19 pandemic
Authors: Idoiaga Mondragon Nahia , Berasategi Sancho Naiara , Eiguren Munitis Amaia , Dosil Santamaria Maria
Published: January 2021

In 2020, COVID-19, a new emerging infectious disease (EID), was spread throughout the world, including Europe. Spain, in particular, witnessed a significant outbreak of the pandemic. In consequence, all classes were cancelled and the Government declared a state of emergency, ordering the lockdown of the entire population from March to May. The aim of this research is to explore the impact of the COVID-19 outbreak on the representations of young university students from the University of the Basque Country and their emotional response when the crisis started. A free-association exercise was completed by 503 students from the University of the Basque Country (UPV/EHU) (Northern Spain). To analyze the content, the Reinert method was used with the Iramuteq software for lexical analysis. The results showed that students placed COVID-19 at a distance from the self, pointing out issues related to social response and disinformation, while showing concerns for self-related issues that are linked to negative emotions, academic consequences, and potentially close victims. The students’ concerns were categorized at four main levels: the communicative-informative level, health-emotional level, community-social level, and academic level. All of this has created overwhelming feelings of nervousness, along with anger and emotional fatigue. These results indicate the necessity for universities to work from a holistic standpoint, not only in terms of responding to academic needs but also from psychological, communicative, social, health, and well-being perspectives.
Occurrence of Colorectal Cancer and the Influence of Medical Treatment in Patients With Inflammatory Bowel Disease: A Danish Nationwide Cohort Study, 1997 to 2015
Authors: Weimers Petra , Ankersen Dorit Vedel , Løkkegaard Ellen Christine Leth , Burisch Johan , Munkholm Pia
Published: January 2021

Background

The risk of colorectal cancer (CRC) for patients with inflammatory bowel disease (IBD) has previously been investigated with conflicting results. We aimed to investigate the incidence and risk of CRC in IBD, focusing on its modification by treatment.

Methods

All patients with incident IBD (n = 35,908) recorded in the Danish National Patient Register between 1997 and 2015 (ulcerative colitis: n = 24,102; Crohn’s disease: n = 9739; IBD unclassified: n = 2067) were matched to approximately 50 reference individuals (n = 1,688,877). CRC occurring after the index date was captured from the Danish Cancer Registry. Exposure to medical treatment was divided into categories including none, systemic 5-aminosalicylates, immunomodulators, and biologic treatment. The association between IBD and subsequent CRC was investigated by Cox regression and Kaplan-Meier estimates.

Results

Of the IBD patients, 330 were diagnosed with CRC, resulting in a hazard ratio (HR) of 1.15 (95% confidence interval [CI], 1.03-1.28) as compared with the reference individuals. However, when excluding patients diagnosed with CRC within 6 months of their IBD diagnosis, the HR decreased to 0.80 (95% CI, 0.71-0.92). Patients with ulcerative colitis receiving any medical treatment were at significantly higher risk of developing CRC than patients with ulcerative colitis who were not given medical treatment (HR, 1.35; 95% CI, 1.01-1.81), whereas a similar effect of medical treatment was not observed in patients with Crohn’s disease or IBD unclassified.

Conclusions

Medical treatment does not appear to affect the risk of CRC in patients with IBD. The overall risk of developing CRC is significantly increased in patients with IBD as compared with the general population. However, when excluding patients diagnosed with CRC within 6 months of their IBD diagnosis, the elevated risk disappears.
Animate the cluster or subsidize collaborative R&D? A multiple overlapping treatments approach to assess the impacts of the French cluster policy
Authors: Mar Modou , Massard Nadine
Published: January 2021

This article examines the effectiveness of the French cluster policy on R&D and innovation in terms of the economic performance of participating SMEs. Based on an original dataset, we built different measures of treatment and extended the DiD methodology to a multiple overlapping treatments approach. Joining a cluster’s association allows firms to benefit from low-cost animation actions and common services, while participating in R&D projects offers substantial financial support. Our findings indicate a complementarity between the two types of instruments since the policy is most effective when the two treatments are simultaneously used. Interestingly, they also show that belonging to a cluster alone induces much stronger positive impacts on R&D spending and on both the R&D and total employment of SMEs than participating in R&D collaborative projects alone. Therefore, to achieve its impact on SMEs, the cluster policy should not overlook low-cost instruments such as animation actions and common services, both as a standalone instrument and as an effective complement to subsidy policies for collaborative R&D projects.