On the Interpretation of Mutagenically Induced Mosaicism in Drosophila

This paper draws attention to the formal parallelism that exists between chromosomal-loss mosaicism and mutagenically induced mosaicism in Drosophila and suggests that, although the underlying processes by which these two types of genetic mosaics are generated are very different, the more refined methodology employed in developmental analyses of genetically induced chromosomal-loss mosaics may be profitably extrapolated to mutagenesis studies. Results obtained from various studies of genetically induced mosaics and from a previous EMS mutation induction experiment at the yellow locus are utilized to illustrate this methodology and to estimate the total mutagenicity rates of EMS.-The following are some of the tentative conclusions that have been drawn in this report regarding an EMS concentration that produced 31% F(2) lethals in the standard X-linked recessive lethal test: (1) The frequency of cuticular mosaics is at least 5 times that of F(3) lethals. (2) At least 60% of all cuticular mosaics go undetected in the standard X -linked recessive lethal test since their mutant tissue does not extend into the germ line. (3) The frequency of EMS-induced cryptic mosaics is probably less than 10% the frequency of cuticular mosaics. (4) Some EMS-induced mutations are probably bona fide completes; if confirmed, this inference must be taken into consideration in estimating the total mutagenicity rates of this agent and in molecular interpretations of its mechanism of action. (5) The fact that the proportion of mutant tissue in EMS-induced mosaics is greater than 25% is consistent with the suggestion that the action of EMS is occasionally delayed until after the first cleavage division of the embryo. (6) Such an EMS concentration causes on the average more than 5 independent genetic alterations in the entire haploid genome of an X-bearing sperm.-This report clarifies the experimental evidence that must be generated, and the methodology that can be used to analyze this evidence, if it is of interest to render these and related conclusions regarding the effect of EMS on D. melanogaster more accurate, or if it is of interest to conduct a similar analysis for other mutagens that cause a significant degree of mosaicism.     

Somatic mosaicism in cases with small supernumerary marker chromosomes

Somatic mosaicism is something that is observed in everyday lives of cytogeneticists. Chromosome instability is one of the leading causes of large-scale genome variation analyzable since the correct human chromosome number was established in 1956. Somatic mosaicism is also a well-known fact to be present in cases with small supernumerary marker chromosomes (sSMC), i.e. karyotypes of 47,+mar/46. In this study, the data available in the literature were collected concerning the frequency mosaicism in different subgroups of patients with sSMC. Of 3124 cases with sSMC 1626 (52%) present with somatic mosaicism. Some groups like patients with Emanuel-, cat-eye- or i(18p)- syndrome only tend rarely to develop mosaicism, while in Pallister-Killian syndrome every patient is mosaic. In general, acrocentric and non-acrocentric derived sSMCs are differently susceptible to mosaicism; non-acrocentric derived ones are hereby the less stable ones. Even though, in the overwhelming majority of the cases, somatic mosaicism does not have any detectable clinical effects, there are rare cases with altered clinical outcomes due to mosaicism. This is extremely important for prenatal genetic counseling. Overall, as mosaicism is something to be considered in at least every second sSMC case, array-CGH studies cannot be offered as a screening test to reliably detect this kind of chromosomal aberration, as low level mosaic cases and cryptic mosaics are missed by that.     

Widespread genetic mosaicism in the marine angiosperm <Emphasis Type="Italic">Zostera marina</Emphasis> is correlated with clonal reproduction

Somatic mutations are an underappreciated source of genetic variation within multi-cellular organisms. The resulting genetic mosaicism should be particularly abundant in large clones of vegetatively propagating angiosperms. Little is known on the abundance and ecological correlates of genetic mosaicism in field populations, despite its potential evolutionary significance. Because sexual reproduction restores genetic homogeneity, we predicted that in facultatively clonally reproducing organisms, the prevalence of genetic mosaicism increases with increasing clonality. This was tested among 33 coastal locations colonized by the ecologically important marine angiosperm Zostera marina, ranging from Portugal to Finland. Genetic mosaics were detectable as complex microsatellite genotypes at two hypervariable loci that revealed additional mosaic alleles, suggesting the presence of one or more divergent cell lineages within the same ramet. The proportions of non-mosaic genotypes in a population sharply decreased below a clonal richness of 0.2. Accordingly, more genetic mosaics were found at the southern and northern limit of the distribution of Z. marina in Europe where sexual reproduction is rare or absent. The genetic mosaics observed at neutral microsatellite markers suggest the possibility of within-clone variation at selectively relevant loci and supports the notion that members of clones are seldom genetically identical.     

Somatic Mosaicism in Hemophilia A: A Fairly Common Event

Mutations in the large gene of clotting factor VIII (FVIII) are the most common events leading to severe human bleeding disorder. The high proportion of de novo mutations observed in this gene raises the possibility that a significant proportion of such mutations does not derive from a single germ cell but instead should be attributed to a germline or somatic mosaic originating from a mutation during early embryogenesis. The present study explores this hypothesis by using allele-specific PCR to analyze 61 families that included members who had sporadic severe hemophilia A and known FVIII gene defects. The presence of somatic mosaicisms of varying degrees (0.2%-25%) could be shown in 8 (13%) of the 61 families and has been confirmed by a mutation-enrichment procedure. All mosaics were found in families with point mutations (8 [25%] of 32 families). In the subgroup of 8 families with CpG transitions, the percentage with mosaicism increased to 50% (4 of 8 families). In contrast, no mosaics were observed in 13 families with small deletions/insertions or in 16 families with intron 22 inversions. Our data suggest that mosaicism may represent a fairly common event in hemophilia A. As a consequence, risk assessment in genetic counseling should include consideration of the possibility of somatic mosaicism in families with apparently de novo mutations, especially families with the subtype of point mutations.     

Dermatoglyphic studies in the parents of trisomy 21 children I. Distribution of dermatoglyphic discriminants

A sample of 312 parents of a child with complete trisomy 21 (168 mothers and 144 fathers) has been compared with 295 parents of non-mongol children (61 mothers and 134 fathers) with respect to distribution of individual dermatoglyphic discriminant scores. Selection of dermatoglyphic traits as well a weightings have been based on the discriminant function, constructed for normal controls against cytogenetically diagnosed trisomy 21 mosaics. The results indicate that the proportion of individuals with an increased chance of mosaicism is appreciably greater in a sample of both the mothers and the fathers of mongol children, as compared with the parents of non-mongol children. For D greater than + 3.00, including also the overlap range values, it is, on the average, twice as high as in the control parents, while for the D values greater than + 4.00, strongly indicative of mosaicism, it is about five times higher than in control parents. This is so in spite of the fact that all parents, who had previously been cytogenetically tested and diagnosed as mosaics, were not included in this sample. Although the meaning of these results cannot yet be completely understood, they justify the extension of the use of dermatoglyphic discriminants in studies on parental mosaicism in trisomy 21.     

Supernumerary chromosomes, mosaicism, and dynamics in two populations of Eastern-Asian wood mouse (Apodemus peninsulae, Rodentia) from Primorski? Krai at various seasons of the year]

Karyotypes of 47 individuals of the wood mice Apodemus peninsulae from two reserves in Primorskii krai (Kedrovaya Pad' and Ussuriiskii) were studied during spring, summer, and autumn. In each population, variation in the number of B-chromosomes (2n = 48 + 0-5B) as well as the intratissue mosaicism determined by variation of the number, size and morphology of supernumerary chromosomes were described. Animals that have one dotlike B-chromosome were first described in both populations as rare variants. Individuals that have bone-marrow cell clones with two or three B-chromosomes were found to be predominant in the populations of Primorskii krai. The number of clones varied from one to three per animal. The frequency of mosaics showed seasonal variation. In the population of the Ussuriiskii reserve, a sharp increase in the frequency of animals with a stable karyotype was detected in autumn, at the phase of increased numbers. The variation for mosaicism was suggested to correlate with the population numbers in mice and to indicate the genetic differences between generations of the population.     

Polymorphism and mosaicism of B chromosome number in Korean field mouse <Emphasis Type="Italic">Apodemus peninsulae</Emphasis> (Rodentia) in the Russian Far East

A karyotype analysis of the Apodemus peninsulae (n = 355) from 41 trapping points from the Russian Far East has allowed us to identify B chromosomes in 87.9% of the animals, 61.7% of which are mosaics. Different levels of variability in the B chromosome numbers have been studied, including both the inter- and intrapopulational, as well as intraindividual variability (mosaicism). It was found that the frequencies of the occurrence of individuals with B chromosomes and mosaicism between different population samples were not constant. The range of the modal B chromosome number variability and variation of the xB index (zero to four; on average, the xB amounted to 1.67) were studied for the first time in different samples and populations of this species. Individuals with the predominant numbers of B chromosome (as a rule, zero to two) were revealed in both groups of animals (with stable and mosaic karyotypes), but the frequency was different in geographical regions. The spectra of B chromosome variability were wider in mosaics (zero to seven) compared to animals with stable karyotypes (zero to four). The importance of this for species of the high frequency of individuals with B chromosomes and with mosaicism has been discussed. The adaptive role of the low number of B chromosomes (one to two), as well as the imbalance of the B chromosome system for the species as a whole is assumed.     

Chromosomale Mosaike in der klinischen Zytogenetik

In contrast to molecular genetics, in cytogenetic analyses single cells are analyzed individually. This affords an opportunity to detect cells with chromosomal mosaicism. This article provides an overview on problems arising in the detection and interpretation of chromosomal mosaicism in cytogenetic diagnostics. A particular challenge in the diagnostics is to distinguish between clinically relevant genuine mosaicism on the one hand and cultured artifacts, pseudomosaics, age effects, maternal contamination and chimerism on the other. The probability of overlooking mosaicism in cytogenetic routine diagnostics is very high, as on average only 15 of the 10¹² cells in the body are examined and usually only a single tissue is analyzed. However, some cytogenetic mosaics are typical for certain syndromes, such as Pallister-Killian syndrome, cat eye syndrome or Ullrich-Turner syndrome and others are characteristic for certain disorders including some hematological malignancies.     

Value of molecular-genetic examination of patients with the Shereshevsky-Terner syndrome and married couples with disorders of reproductive function]

The molecular-cytogenetic investigation gives a significant opportunity for diagnosis of gonosome mosaics. Due to the molecular-cytogenetic method additional chromosomes in karyotypes in 4 of 13 patients are determined. A significant spreading of mosaicism type 45, XO/46, X among women with early spontaneous abortions is revealed.     

Chromosome mosaicism in a population sample.

An analysis has been made of mosaicism found in the different types of chromosome abnormalities among the 19000 persons examined at the Cytogenetic Laboratory, Risskov. The percentage with mosaicism was 36 in both triple-X and Turner's syndrome, it was 7 and 11% in XYY and Klinefelter's syndrome, respectively, and 2 in autosomal abnormalities. We found a mosaicism frequency of 11% in population studies with 5 cells analyzed primarily compared with 7% in other studies, in which 10-50 cells were analyzed primarily. (The difference is not significant.) The total frequency of mosaicism was 8%. The first cell with the chromosome aberration establishing the mosaicism was found among the first 5 cells in 40 of the 44 cases with mosaicism, and all but one of the 44 cases would have been established as mosaics, if the guidlines indicated by Bochkov et al. (1974) had been followed; that is 11 cells analyzed primarily, and if one of these cells has a chromosome aberration, the number of cells analyzed is increased to 17; if 2 cells have the same chromosome aberration, the number of cells analyzed is extended to 23, and if 3 cells with the same chromosome aberration is found among these 23 cells, the mosaicism is established. Aneuploid or structural chromosome abnormalities present in all cells may be detected by analysis of 2-3 cells of good quality. Mosaicism with 2 or more cell clones with different chromosome patterns are extremely difficult to detect, if the percentage of cell clones with chromosome aberration is low. The incidence of chromosome abnormalities found in all cells in newborn children in the different studies is very similar as shown in a recent survey of 6 different studies by Jacobs et al. (1974). The incidence of mosaicism varies according to the frequency of artefactual aneuploidy, the variety of tissue studied, number of cells analyzed from each tissue as well as the acuity of the observer and the checking procedures.     

Intra individual variation in the number of B chromosomes in the yellow-necked mouse, Apodemus flavicollis (Mammalia, Rodentia)

The yellow-necked mouse, Apodemus flavicollis, is characterized by a frequent occurrence of B chromosomes. The frequency of intra individual mosaicism of Bs was studied in 995 animals collected at six localities in Serbia. It was found that 329 (33.06%) possessed B chromosomes. Among these, 87 animals (26.44%) were mosaics. A total of 32 mosaic animals with more than one B chromosome were analyzed for distribution of Bs which was found to be quite different between groups of animals with different numbers of Bs and increases with their number. The frequency of mosaics differs between localities and ranges from 0.22 to 0.55.     

XO/XY mosaicism and non-fluorescing Y chromosome in a male

Summary An adult male of short stature and with underdeveloped external genitalia is described, who carried out a number of sexual assaults on young women. He proved to have XO/XY mosaicism and a non-fluorescing Y chromosome. It was considered to be a terminal deletion on morphological grounds. It is suggested, on the evidence of the small number of XO/XY mosaics examined by appropriate staining methods, that an abnormal Y chromosome, whether terminally deleted or non-fluorescing owing to an altered chemical state, predisposes to anaphase lagging and non-disjunction.Of eleven reported cases of XO/XY mosaicism with a non-fluorescing Y chromosome, this is the fifth of male phenotype. The severe behaviour disturbance of early onset is considered to be probably causally associated with the chromosome anomaly.     

Sectorial mosaics in the domestic pigeion: 25 more years.

The hypothesis of bipaternity--incorporation of tissue derived from supernumerary sperms into an embryo--to explain the origin of sectorial mosaicism in pigeons was advanced in 1949. Since then, 182 additional examples have come to my attention. Only one was reported to be a gynandromorph; sex ratios generally have been near 1 : 1. No environmental variable has shown significant relation to the origin of the mosaics, and only a slight familial tendency has been indicated. At least 15 color and pattern mutants have been involved, usually contrasting only two alleles. The frequency and its use in crosses. Complex mosaics, involving two or more loci in the contrasts numbered at least 38 cases, of which 11 are examined in more detail, and 6 shown in photographs. Several instances of germinal as well as somatic mosaicism were demonstrated by progeny tests. The bipaternity hypothesis has not been ruled out by evidence in any case.     

Somatic and germline mosaic mutations in the doublecortin gene are associated with variable phenotypes

Mutations in the X-linked gene doublecortin lead to "double cortex" syndrome (DC) in females and to X-linked lissencephaly (XLIS) in males. Because most patients with DC and XLIS are sporadic, representing de novo doublecortin mutations, we considered that some of these patients could be somatic or germline mosaics. Among a population of 20 patients and their families, we found evidence for mosaic doublecortin mutations in 6 individuals. Germline mosaicism was identified in two unaffected women, each with two affected children. Additionally, one affected male with DC was found to be a somatic mosaic, which presumably spared him from the more severe phenotype of lissencephaly. The high rate of mosaicism indicates that there may be a significant recurrence risk for DC/XLIS in families at risk, even when the mother is unaffected.     

Molecular studies of parental origin and mosaicism in 45,X conceptuses

Summary The present report summarizes molecular studies of parental origin and sex chromosome mosaicism in forty-one 45,X conceptuses, consisting of 29 spontaneous abortions and 12 liveborn individuals with Turner syndrome. Our studies indicate that most 45,X conceptuses have a single, maternally derived X chromosome, regardless of whether the conceptus is liveborn or spontaneously aborted. In studies of mosaicism, our identification of X- and Y-chromosome mosaics among 45,X spontaneous abortions indicates that mosaicism does not ensure survival to term of 45,X fetuses. However, the incidence of sex chromosmome mosaicism is substantially higher in liveborn than in aborted 45,X conceptuses, indicating that the presence of a second cell line increases the likelihood of survival to term.     

Genetic analysis of mitomycin C-induced interchange in Drosophila melanogaster females

A genetic analysis of an array of mitomycin-induced rearrangements in immature Drosophila oocytes is reported. Induced aberrations were recovered representing detachments of the compound-X chromosome, Y chromosome fragments, X chromosome loss and mosaicism. The spectrum of rearrangements induced by mitomycin C was very similar to that induced by X-ray treatment of immature oocytes. This work suggests that mitomycin C has two modes of action. The drug is radiomimetic for it induces the types of aberrations recovered after X-irradiation. Mitomycin C also seems to have a delayed effect which is reflected in the relatively high recovery of mosaics.     

Transcriptome Sequencing of Two Phenotypic Mosaic Eucalyptus Trees Reveals Large Scale Transcriptome Re-Modelling

Phenotypic mosaic trees offer an ideal system for studying differential gene expression. We have investigated two mosaic eucalypt trees from two closely related species (Eucalyptus melliodora and E. sideroxylon), which each support two types of leaves: one part of the canopy is resistant to insect herbivory and the remaining leaves are susceptible. Driving this ecological distinction are differences in plant secondary metabolites. We used these phenotypic mosaics to investigate genome wide patterns of foliar gene expression with the aim of identifying patterns of differential gene expression and the somatic mutation(s) that lead to this phenotypic mosaicism. We sequenced the mRNA pool from leaves of the resistant and susceptible ecotypes from both mosaic eucalypts using the Illumina HiSeq 2000 platform. We found large differences in pathway regulation and gene expression between the ecotypes of each mosaic. The expression of the genes in the MVA and MEP pathways is reflected by variation in leaf chemistry, however this is not the case for the terpene synthases. Apart from the terpene biosynthetic pathway, there are several other metabolic pathways that are differentially regulated between the two ecotypes, suggesting there is much more phenotypic diversity than has been described. Despite the close relationship between the two species, they show large differences in the global patterns of gene and pathway regulation.     

Principles of organization of tissue mosaics of simple squamous epithelia

With the aim to study general principles on organization of tissue mosaics of various types of simple squamous epithelii, a quantitative topological analysis has been performed in the frog mesothelial mosaics, in the posterior epithelium of the rabbit cornea and in the rat aortal endothelium after Lewis method. To all the types of simple squamous epithelii studied the histological law of Lewis can be applied. As demonstrates the qualitative analysis of the mosaics, the mesothelium and the posterior epithelium of the cornea are typical isotropic mosaics, while the mosaic of the aortal endothelium is nearer to the polystichous one. The possibilities of qualitative and quantitative topological analysis of the biological mosaics after Lewis method for studying their organization, degree of regularity, histogenesis and proliferative properties are discussed.     

Mechanisms of aneuploidy induction in human oogenesis and early embryogenesis

The mechanisms of aneuploidy induction in human oogenesis mainly involve nondisjunction arising during the first and second meiotic divisions. Nondisjunction equally affects both whole chromosomes and chromatids, in the latter case it is facilitated by "predivision" or precocious centromere division. Karyotyping and CGH studies show an excess of hypohaploidy, which is confirmed in studies of preimplantation embryos, providing evidence in favour of anaphase lag as a mechanism. Preferential involvement of the smaller autosomes has been clearly shown but the largest chromosomes are also abnormal in many cases. Overall, the rate of chromosomal imbalance in oocytes from women aged between 30 and 35 has been estimated at 11% from recent karyotyping data but accruing CGH results suggest that the true figure should be considerably higher. Clear evidence has been obtained in favour of germinal or gonadal mosaicism as a predisposing factor. Constitutional aneuploidy in embryos is most frequent for chromosomes 22, 16, 21 and 15; least frequently involved are chromosomes 14, X and Y, and 6. However, embryos of women under 37 are far more likely to be affected by mosaic aneuploidy, which is present in over 50% of 3-day-old embryos. There are two main types, diploid/aneuploid and chaotic mosaics. Chaotic mosaics arise independently of maternal age and may be related to centrosome anomalies and hence of male origin. Aneuploid mosaics most commonly arise by chromosome loss, followed by chromosome gain and least frequently by mitotic nondisjunction. All may be related to maternal age as well as to lack of specific gene products in the embryo. Partial aneuploidy as a result of chromosome breakage affects a minimum of 10% of embryos.