Mechanism of gene conversion in Ascobolus immersus. II. The relationships between the genetic alterations in b 1 or b 2 mutants and their conversion spectrum

Summary In order to establish a relationship between the type of genetic alteration occurring in the mutant and the conversion spectrum which is associated with it, an attempt was made to characterize the genetic alterations in a sample of five spore colour mutants by specific reversion.All the mutants revert by back-mutation. Reversion of one of them is possible by mutation in external suppressor gene: at least two of the external suppressors behave like super-suppressors. Reversion of two other mutants by intragenic second-site mutation and study of the intragenic suppressors indicate that they are of the frameshift type. One of the frameshift mutants (ICR₁₇₀ induced) reverts by two alkylating agents suggesting that it originates from base(s) addition. The inhability of ICR₁₇₀ to induce reversion of this mutant suggests the preferential occurrence of base addition in ICR₁₇₀ mutagenesis. Conversly the other frameshift mutant (induced by ethyl methanesulfonate) reverts strongly by ICR₁₇₀. Thus it is concluded that it originates from deletion.These two frameshift mutants and all the ICR₁₇₀ induced mutants give no or very few asci with postmeiotic segregation and either an excess of conversion towards the mutant type allele (addition type mutant) or towards the wild type allele (deletion type mutant).Evidence supports the hypothesis that mutants which give many asci with postmeiotic segregation originate from substitution.These data imply differential recognition of non-pairing and mispairing of bases and in the case of non-pairing, that the direction of conversion is determined by the non-pairing itself.     

Estimating meiotic gene conversion rates from population genetic data

Gene conversion plays an important part in shaping genetic diversity in populations, yet estimating the rate at which it occurs is difficult because of the short lengths of DNA involved. We have developed a new statistical approach to estimating gene conversion rates from genetic variation, by extending an existing model for haplotype data in the presence of crossover events. We show, by simulation, that when the rate of gene conversion events is at least comparable to the rate of crossover events, the method provides a powerful approach to the detection of gene conversion and estimation of its rate. Application of the method to data from the telomeric X chromosome of Drosophila melanogaster, in which crossover activity is suppressed, indicates that gene conversion occurs approximately 400 times more often than crossover events. We also extend the method to estimating variable crossover and gene conversion rates and estimate the rate of gene conversion to be approximately 1.5 times higher than the crossover rate in a region of human chromosome 1 with known recombination hotspots.     

The conversion of the Chumash Indians: An ecological interpretation

A 17-year period during which interaction occurred between the Chumash and Spanish colonizers is the focus of the study. Significant variation in subsistence and interactive patterns during this period is identified. The baptismal rite that marked the transition from native villager to mission Indian is interpreted in relation to the environmental and subsistence realities faced by both the Chumash and Spanish.     

The coalescent with gene conversion

In this article we develop a coalescent model with intralocus gene conversion. The distribution of the tract length is geometric in concordance with results published in the literature. We derive a simulation scheme and deduce a number of analytical results for this coalescent with gene conversion. We compare patterns of variability in samples simulated according to the coalescent with recombination with similar patterns simulated according to the coalescent with gene conversion alone. Further, an expression for the expected number of topology shifts in a sample of present-day sequences caused by gene conversion events is derived.     

The natural history of class I primate alcohol dehydrogenases includes gene duplication, gene loss, and gene conversion

Background

Gene duplication is a source of molecular innovation throughout evolution. However, even with massive amounts of genome sequence data, correlating gene duplication with speciation and other events in natural history can be difficult. This is especially true in its most interesting cases, where rapid and multiple duplications are likely to reflect adaptation to rapidly changing environments and life styles. This may be so for Class I of alcohol dehydrogenases (ADH1s), where multiple duplications occurred in primate lineages in Old and New World monkeys (OWMs and NWMs) and hominoids.

Methodology/Principal Findings

To build a preferred model for the natural history of ADH1s, we determined the sequences of nine new ADH1 genes, finding for the first time multiple paralogs in various prosimians (lemurs, strepsirhines). Database mining then identified novel ADH1 paralogs in both macaque (an OWM) and marmoset (a NWM). These were used with the previously identified human paralogs to resolve controversies relating to dates of duplication and gene conversion in the ADH1 family. Central to these controversies are differences in the topologies of trees generated from exonic (coding) sequences and intronic sequences.

Conclusions/Significance

We provide evidence that gene conversions are the primary source of difference, using molecular clock dating of duplications and analyses of microinsertions and deletions (micro-indels). The tree topology inferred from intron sequences appear to more correctly represent the natural history of ADH1s, with the ADH1 paralogs in platyrrhines (NWMs) and catarrhines (OWMs and hominoids) having arisen by duplications shortly predating the divergence of OWMs and NWMs. We also conclude that paralogs in lemurs arose independently. Finally, we identify errors in database interpretation as the source of controversies concerning gene conversion. These analyses provide a model for the natural history of ADH1s that posits four ADH1 paralogs in the ancestor of Catarrhine and Platyrrhine primates, followed by the loss of an ADH1 paralog in the human lineage.     

Problems in the definition, interpretation, and evaluation of genetic heterogeneity

Suppose that we wish to classify families with multiple cases of disease into one of three categories: those that segregate mutations of a gene of interest, those which segregate mutations of other genes, and those whose disease is due to nonhereditary factors or chance. Among families in the first two categories (the hereditary families), we wish to estimate the proportion, p, of families that segregate mutations of the gene of interest. Although this proportion is a commonly accepted concept, it is well defined only with an unambiguous definition of "family." Even then, extraneous factors such as family sizes and structures can cause p to vary across different populations and, within a population, to be estimated differently by different studies. Restrictive assumptions about the disease are needed, in order to avoid this undesirable variation. The assumptions require that mutations of all disease-causing genes (i) have no effect on family size, (ii) have very low frequencies, and (iii) have penetrances that satisfy certain constraints. Despite the unverifiability of these assumptions, linkage studies often invoke them to estimate p, using the admixture likelihood introduced by Smith and discussed by Ott. We argue against this common practice, because (1) it also requires the stronger assumption of equal penetrances for all etiologically relevant genes; (2) even if all assumptions are met, estimates of p are sensitive to misspecification of the unknown phenocopy rate; (3) even if all the necessary assumptions are met and the phenocopy rate is correctly specified, estimates of p that are obtained by linkage programs such as HOMOG and GENEHUNTER are based on the wrong likelihood and therefore are biased in the presence of phenocopies. We show how to correct these estimates; but, nevertheless, we do not recommend the use of parametric heterogeneity models in linkage analysis, even merely as a tool for increasing the statistical power to detect linkage. This is because the assumptions required by these models cannot be verified, and their violation could actually decrease power. Instead, we suggest that estimation of p be postponed until the relevant genes have been identified. Then their frequencies and penetrances can be estimated on the basis of population-based samples and can be used to obtain more-robust estimates of p for specific populations.     

The amino-acid mutational spectrum of human genetic disease

Background  

Nonsynonymous mutations in the coding regions of human genes are responsible for phenotypic differences between humans and for susceptibility to genetic disease. Computational methods were recently used to predict deleterious effects of nonsynonymous human mutations and polymorphisms. Here we focus on understanding the amino-acid mutation spectrum of human genetic disease. We compare the disease spectrum to the spectra of mutual amino-acid mutation frequencies, non-disease polymorphisms in human genes, and substitutions fixed between species.     

The functional interchangeability of enterobacterial and staphylococcal iron chelators

The functional interchangeability of staphylococcal and enterobacterial iron chelators was investigated with an indicator system in which minimally effective concentrations of ethylene diamine di-ortho-hydroxyphenyl acetic acid (EDDA) were used to inhibit the growth of indicator strains in the depth of simple agar media by making the iron unavailable. Test colonies were then applied to the surface of the media to determine whether the indicator organisms, by utilising chelators from the test colony could obtain the required iron for growth, in its vicinity.Approximately 50% of staphylococcal strains, both S. aureus and S. epidermidis, reversed the inhibition of enterobacterial indicators, whereas almost all enterobacterial test strains, representing five genera, reversed the inhibition of the staphylococcal indicators. A purified preparation of the enterobacterial iron chelator enterochelin also reversed the inhibition of four out of the five staphylococcal indicator strains.     

Recombination, gene conversion, and identity-by-descent at three loci

We investigate the probabilities of identity-by-descent at three loci in order to find a signature which differentiates between the two types of crossing over events: recombination and gene conversion. We use a Markov chain to model coalescence, recombination, gene conversion and mutation in a sample of size two. Using numerical analysis, we calculate the total probability of identity-by-descent at the three loci, and partition these probabilities based on a partial ordering of coalescent events at the three loci. We use these results to compute the probabilities of four different patterns of conditional identity and non-identity at the three loci under recombination and gene conversion. Although recombination and gene conversion do make different predictions, the differences are not likely to be useful in distinguishing between them using three locus patterns between pairs of DNA sequences. This implies that measures of genetic identity in larger samples will be needed to distinguish between gene conversion and recombination.     

Integrative gene network analysis provides novel regulatory relationships, genetic contributions and susceptible targets in autism spectrum disorders

Autism spectrum disorders (ASDs) are a group of diseases exhibiting impairment in social drive, communication/language skills and stereotyped behaviors. Though an increased number of candidate genes and molecular interactions have been identified by various approaches, the pathogenesis remains elusive. Based on clinical observations, data from accessible GWAS and expression datasets we identified ASDs gene candidates. Integrative gene network and a novel CNV-centric Node Network (CNN) analysis method highlighted ASDs-associated key elements and biological processes. Functional analysis identified neurological functions including synaptic cholinergic receptor (CHRNA) families, dopamine receptor (DRD2), and correlations between social behavior and oxytocin related pathways. CNN analysis of genome-wide genetic and expression data identified inheritance-related clusters related to PTEN/TSC1/FMR1 and mTor/PI3K regulation. Integrative analysis identified potential regulators of networks, specifically TNF and beta-estradiol, suggesting a potential central role in ASDs. Our data provide information on potential disease mechanisms, and key regulators that may generate novel postulations, and diagnostic molecular biomarkers.     

The interchangeability of siderophores in the Enterococcus genus

The functional interchangeability of siderophores was tested among 62 strais belonging to 12 species of genus Enterococcus. Most investigated strains were from E. faecalis and E. faecium species. The majority of examined enterococcal strains appeared highly resistant to EDDA (ethylene-di-amine-di-ortho-hydroxyphenylacetic acid), therefore the group of sensitive strains involved only 11 used as indicator strains. The determination of interchangeability of siderophores within enterococcal strains was performed using EDDA-agar media into which the indicator strains were included. Test colonies (donor strains) were applied to the surface of the media to determine whether the indicator organisms could obtain the required iron for growth by utilizing chelators from the test colony. Only two strains: E. solitarius DSM 5634 and E. pseudoavium DSM 5632 did not demonstrate the ability to utilize siderophores synthesized by all investigated strains. The other tested indicator strains appeared to be recipients of siderophores from 20-52 donor enterococcal strains. The ability to exchange siderophores in enterococci was found as the feature characterizing individual strains.     

The nine-parameter gene conversion model: simpler equations, validity tests, and multiple fits

Lamb and Zwolinski (1992, 1993) provided equations and a method for finding nine parameter values for gene conversion between two alleles at one locus, to study mechanisms for homologous meiotic recombination. Simpler, shorter, and easier-to-use equations have been given here, and the accuracy of the parameter values found has been analysed. Fincham's (1994) criticisms of this method have been tested in several ways and shown to be incorrect. The model's validity has been tested directly: sets of arbitrarily chosen parameter values were used to work out the numbers expected in each segregation class for a sample of 100,000 octads. People not knowing the chosen parameter values used those octad class numbers in computer programs based on the Lamb-Zwolinski method. The best-fitting sets of parameter values obtained corresponded exactly to those initially set. The occurrence of multiple fits has been demonstrated and discussed; when multiple fits occurred, the parameter values in different best fits were fairly similar in absolute values and very similar in relative values.     

The processive kinetics of gene conversion in bacteria

Gene conversion, non‐reciprocal transfer from one homologous sequence to another, is a major force in evolutionary dynamics, promoting co‐evolution in gene families and maintaining similarities between repeated genes. However, the properties of the transfer – where it initiates, how far it proceeds and how the resulting conversion tracts are affected by mismatch repair – are not well understood. Here, we use the duplicate tuf genes in Salmonella as a quantitatively tractable model system for gene conversion. We selected for conversion in multiple different positions of tuf, and examined the resulting distributions of conversion tracts in mismatch repair‐deficient and mismatch repair‐proficient strains. A simple stochastic model accounting for the essential steps of conversion showed excellent agreement with the data for all selection points using the same value of the conversion processivity, which is the only kinetic parameter of the model. The analysis suggests that gene conversion effectively initiates uniformly at any position within a tuf gene, and proceeds with an effectively uniform conversion processivity in either direction limited by the bounds of the gene.     

Interspecific genetic linkage map, segregation distortion and genetic conversion in coffee (Coffea sp.)

An interspecific partial genetic linkage map of Coffea sp. based on 62 backcross hybrids is presented. F₁ hybrids were generated by a cross between the wild C. pseudozanguebariae and the anciently cultivated C. liberica var. dewevrei (DEW); progeny were then derived from a backcross between F₁ hybrid and DEW. The map construction consisted of a two-step strategy using 5.5 and 3.1 LOD scores revealed by simulation file. The map consisted of 181 loci: 167 amplified fragment length polymorphism (AFLP) and 13 random fragment length polymorphism (RFLP) loci. The markers were assembled into 14 linkage groups, each with 4–31 markers covering 1,144 cM. Segregation distortion was observed for 30% of all loci, in particular 3:1 and 1:3 ratios equally favouring each of the two parents. The existence of such ratios suggests genetic conversion events. This map also represents an initial step towards the detection of quantitative trait loci. Received: 4 Janaury 2000 / Accepted: 17 January 2000     

Intrachromosomal gene conversion, linkage, and the evolution of multigene families

The evolution of the probabilities of genetic identity within and between tandemly repeated loci of a multigene family is investigated analytically and numerically. Unbiased intrachromosomal gene conversion, equal crossing over, random genetic drift, and mutation to new alleles are incorporated. Generations are discrete and nonoverlapping; the diploid, monoecious population mates at random. Under the restriction that there is at most one crossover in the multigene family per individual per generation, the dependence on location of the probabilities of identity is treated exactly. In the "homogeneous" approximation to this "exact" model, end effects are disregarded; in the "exchangeable" approximation, to which all previous work was confined, all position dependence is neglected. Numerical results indicate that the exchangeable and homogeneous models are both qualitatively correct, the exchangeable model is sometimes too inaccurate for quantitative conclusions, and the homogeneous model is always more accurate than the exchangeable one and is always sufficiently accurate for quantitative conclusions.     

基因转换的生物学意义及分子机制

基因转换是指同源序列之间遗传信息的非交互的传递.该现象最早是在真菌上发现的.近年来,随着研究的不断深入,发现它普遍存在于所有的生物类群中.目前有关它的分子机制已有较多研究并提出了多种分子模型,其中以DSBR模型和SDSA模型具有较强说服力被较普遍认可.本文对近些年来的这些新进展傲一综述,并对该领域的研究进行了分析和展望.     

A genetic interpretation of ecologically dependent isolation

Hybrids may suffer a reduced fitness both because they fall between ecological niches (ecologically dependent isolation) and as a result of intrinsic genetic incompatibilities between the parental genomes (ecologically independent isolation). Whereas genetic incompatibilities are common to all theories of speciation, ecologically dependent isolation is a unique prediction of the ecological model of speciation. This prediction can be tested using reciprocal transplants in which the fitness of various genotypes is evaluated in both parental habitats. Here we expand a quantitative genetic model of Lynch (1991) to include two parental environments. We ask whether a sufficient experimental design exists for detecting ecologically dependent isolation. Analysis of the model reveals that by using both backcrosses in both parental environments, environment-specific additive genetic effects can be estimated while correcting for any intrinsic genetic isolation. Environment-specific dominance effects can also be estimated by including the F1 and F2 in the reciprocal transplant. In contrast, a reciprocal transplant comparing only F1s or F2s to the parental species cannot separate ecologically dependent from intrinsic genetic isolation. Thus, a reduced fitness of F1 or F2 hybrids relative to the parental species is not sufficient to demonstrate ecological speciation. The model highlights the importance of determining the contribution of genetic and ecological mechanisms to hybrid fitness if inferences concerning speciation mechanisms are to be made.