Genetic variability of the tumorous-head maternal effect in Drosophila melanogaster

Summary The tumorous-head maternal effect in Drosophila melanogaster is produced by a recessive gene (tuh-1) in chromosome 1. Polymorphism exists at this locus. This maternal effect, which is part of the normal variation found in this species, is detected with the aid of a mutant gene. In the presence of the maternal effect, a semi-dominant mutant gene (tuh-3) causes homoeotic changes in the eye-antennal imaginal discs. The phenotype in the adult is known as the tumorous-head abnormality. The mutant gene, which is located in the right arm of chromosome 3, is characterized by reduced penetrance. Using the penetrance of the mutant gene as the criterion, the results of these experiments show that the level of the maternal effect activity is influenced remarkably by modifiers present in wild type strains. The assay is to mate females homozygous for tuh-1 with males homozygous for tuh-3 and to determine the percent of the offspring showing the tumorous head abnormality. Using this procedure, it was observed that parental females with various combinations of chromosomes 1 and 3 from Lausanne and Stephenville wild type strains show great variability in the level of maternal effect activity. Modifiers in chromosome 1 and 3 from the Stephenville strain increase the level of the maternal effect activity. The level is reduced if these chromosomes are replaced by those from the Lausanne strain. A major locus in chromosome 3 is in the same region occupied by clusters of functionally related genes with regulating action. These results demonstrate that the penetrance of a mutant gene, which acts during embryogenesis, is influenced by modifiers which act during oogenesis.This investigation was supported by Public Health Service Research Grant GM 18664 to Arizona State University from the National Institute of General Medical Sciences     

Two Closely Linked Mutations in DROSOPHILA MELANOGASTER That Are Lethal to opposite Sexes and Interact with Daughterless

A new spontaneous mutation named Sex-lethal, Male-specific No. 1 (SxlM1) is described that is lethal to males, even in the presence of an Sxl+ duplication. Females homozygous for SxlM1 are fully viable. This dominant, male-specific lethal mutation is on the X chromosome approximately 0.007 map units to the right of a previously isolated female-specific mutation, Female-lethal, here renamed Sex-lethal, Female-specific No. 1 (SxlF1). SxlM1 and SxlF1 are opposite in nearly every repect, particularly with regard to their interaction with maternal effect of the autosomal mutation, daughterless (da). Females that are homozygous for da produce defective eggs that cannot support female (XX) development. A single dose of SxlM1 enables daughters to survive this da female-specific lethal maternal effect. A duplication of the Sxl locus weakly mimics this action of SxlM1. In contrast, SxlF1 and a deficiency for Sxl, strongly enhance the female-lethal effects of da. The actions of SxlM1 and SxlF1 are explained by a model in which expression of the Sxl locus is essential for females, lethal for males, and under the control of a product of the da locus. It is suggested that SxlM1 is a constitutive mutation at the Sxl locus.     

Characterisation of a new tumorous-head mutant of Drosophila melanogaster

Summary A new homoeotic mutant, I127, showing abnormal growths in the head region including homoeotic transformation of eye to genitalia and antenna to leg, was isolated in a screen designed to find new alleles of the tumorous head (tuh-3), mutation. Similarities in the phenotype and genetics of the mutant, and complementation studies with tuh-1; tuh-3, suggest that I127 is indeed an allele of tuh-3. In combination with the first chromosome modifier tuh-1, the mutant is temperature-sensitive during the third larval instar, giving an increased penetrance of the tumorous head phenotype when reared at 25° C as opposed to 18° C. The isolation of further alleles at the tumorous-head locus are essential. The types of morphological defects which can result from mutations at this locus would enable us to establish if this is a complex locus, and if null mutations are lethal during development. The interactions of the tumorous-head gene with first chromosome modifiers and other homoeotic mutations will only be understood if we able to induce a number of mutations at this locus, and as a consequence begin to elucidate the role of the wild-type gene product in normal development.     

The Genetic Factors Altered in Homozygous abo Stocks of DROSOPHILA MELANOGASTER

Females homozygous for the maternal-effect mutation abo (2-44.0) produce a large fraction of eggs which arrest during embryogenesis. Increasing doses of defined heterochromatic regions inherited by offspring of abo mothers from their fathers function zygotically to bring about a partial rescue of the abo-induced embryonic lethality. Another property of the abo mutation is that the severity of the maternal effect decreases when an abo stock is maintained in homozygous condition for a number of generations. Here, we show that the factors which change in homozygous abo stocks to result in the decrease in maternally induced embryonic lethality, act zygotically, dominantly and additively. More importantly, we show that the X and second chromosomes, but not the Y and third chromosomes, derived from homozygous abo stocks are, when inherited from males, more effective in promoting zygotic rescue of the abo-induced lethality than are the equivalent chromosomes derived from an abo stock maintained in heterozygous condition. The chromosomal locations of the factors maintained in the homozygous condition. The chromosomal locations of the factors altered in homozygous stock, as well as their behavior, strongly suggest that the same heterochromatic elements that are responsible for rescuing embryos from the abo-induced maternal effect are altered in homozygous abo flies in such a way that the maternal effect itself is less severe.     

A pupal lethal mutation with a paternally influenced maternal effect on embryonic development in Drosophila melanogaster

The maternal effect and zygotic phenotype of l(1)pole hole (l(1)ph) is described. l(1)ph is a zygotic lethal mutation which affects cell division of adult precursor cells in Drosophila larvae. The locus is located in 2F6 on the salivary gland chromosome map and four alleles have been characterized. Germ-line clonal analysis of amorphic alleles indicates that l(1)ph has a maternal effect lethal phenotype. Two lethal phenotypes are observed among embryos derived from female germ-line clones homozygous for amorphic alleles dependent upon the zygotic activity of l(1)ph⁺ introduced via the sperm. Class 1: If no wild-type dose of the gene is introduced, embryos form abnormal blastoderms in which nuclear migration and cell formation is disrupted leading to an ill-defined cuticular pattern. Class 2: If a wild-type copy of the gene is introduced, blastoderm cells do not form beneath the pole cells (the pole hole phenotype); subsequently such embryos are missing cuticular structures posterior to the seventh abdominal segment (the torso phenotype). When the zygotic activity l(1)ph⁺ is modulated using position effect variegation a new phenotype is observed among class 2 embryos in which torso embryos are twisted along their longitudinal axis.     

Multiple functions of segment polarity genes in Drosophila

l(1)dishevelled (l(1)dsh) is a late zygotic lethal mutation that exhibits a rescuable maternal effect lethal phenotype. l(1)dsh/Y embryos, derived from females possessing a homozygous l(1)dsh germline clone, exhibit a segment polarity embryonic phenotype. Analysis of the development of these embryos indicates: (1) that segmental boundaries do not form although the correct number of tracheal pits is formed; (2) that pockets of cell death occur between the tracheal pits; and (3) that engrailed expression becomes abnormal during germ band shortening. We propose that, in the absence of both maternal and zygotic expression of l(1)dsh+, cells from each posterior compartment die. Subsequently, cells from the anterior compartment must rearrange their positional values to generate the segment polarity phenotype. We have compared the phenotype of five other segment polarity loci: four embryonic lethals [l(1)armadillo, l(2)gooseberry, l(2)wingless, and l(3)hedgehog]; and the late zygotic lethal, l(1)fused. Only l(2)wingless embryos exhibit early segmentation defects similar to those found in l(1)dsh/Y embryos derived from homozygous germline clones. In contrast, segmentation is essentially normal in l(1)armadillo, l(2)gooseberry, l(3)hedgehog, and l(1)fused embryos. The respective maternal and zygotic contribution and the roles of the segment polarity loci for the patterning of the embryo and the adult are discussed.     

Linkage disequilibrium mapping of molecular polymorphisms at the scabrous locus associated with naturally occurring variation in bristle number in Drosophila melanogaster

We evaluated the hypothesis that the Drosophila melanogaster second chromosome gene scabrous (sca), a candidate sensory bristle number quantitative trait locus (QTL), contributes to naturally occurring variation in bristle number. Variation in abdominal and sternopleural bristle number was quantified for wild-derived sca alleles in seven genetic backgrounds: as homozygous second chromosomes (C2) in an isogenic background, homozygous lines in which approximately 20 cM including the sca locus had been introgressed into the isogenic background (sca BC), as C2 and sca BC heterozygotes and hemizygotes against a P element insertional sca allele and a P-induced sca deficiency in the same isogenic background, and as sca BC heterozygotes against the wild-type sca allele of isogenic strain. Molecular restriction map variation was determined for a 45 kb region including the sca locus, and single-stranded conformational polymorphism (SSCP) was examined for the third intron and parts of the third and fourth exons. Associations between each of the 27 molecular polymorphisms and bristle number were evaluated within each genotype and on the first principal component score determined from all seven genotypes, separately for each sex and bristle trait. Permutation tests were used to assess the empirical significance thresholds, accounting for multiple, correlated tests, and correlated markers. Three sites in regulatory regions were associated with female-specific variation in abdominal bristle number, one of which was an SSCP site in the region of the gene associated with regulation of sca in embryonic abdominal segments.     

Dosage of the Maternal Effect Gene Associated with the Tumorous-Head Abnormality in DROSOPHILA MELANOGASTER

The penetrance of tuh-3 observed in the progeny of triploids with two doses of tuh-1 was not statistically different from that occurring in the progeny of their diploid sisters with two doses. A higher penetrance was observed in the progeny of triploids with three doses of tuh-1 than in the progeny of their diploid sisters with two doses. These observations suggest that the maternal effect responsible for increasing the penetrance of tuh-3, the gene causing the tumorous-head abnormality, is caused by a specific gene product of tuh-1, the maternal-effect allele. In addition there is probably a maternal-effect threshold, lying between amounts produced by one and two doses of tuh-1, below which no increased penetrance of tuh-3 is observed.     

Paternal Imprinting of Inversion Uab(1) Causes Homeotic Transformations in Drosophila

Paternal transmission of the bithorax-complex (BX-C) rearrangement, inversion Uab(1), causes a specific dominant gain of function phenotype in most abdominal segments. This represents a case of paternal imprinting since the mutant phenotype will occur only if inversion Uab(1) is paternally transmitted. The transformations in males are toward genital arch tissue. For females the transformations are to tissue found on abdominal segment 7 (Ab7) and to structures normally restricted to the genital disc. Ninety-six percent of transformed areas appear on Ab5 and Ab6 in both sexes and on Ab7 in females, coinciding with the Abd-B domain. Four percent of the transformations occurred on Ab1 through Ab4, coinciding with the abd-A domain. The mutant phenotype can be dramatically enhanced by modifying genes such as the posterior BX-C mutant tuh-3. Expressivity is modulated by maternal effect alleles interacting with tuh-3. A region of function within inversion Uab(1) appears to be programmed during spermatogenesis to function in a legacy dependent manner during embryogenesis.     

Localized defects of blastoderm formation in maternal effect mutants of Drosophila

In the three maternal effect lethal mutant strains of D. melanogaster described in this report, the homozygous mutant females produce defective eggs that cannot support normal embryonic development. The embryos from these eggs begin to develop for the first 2 hr after fertilization in an apparently normal way, forming a blastula containing a cluster of pole cells at the posterior end and a layer of syncytial blastoderm nuclei. During the subsequent transition from a syncytial to a cellular blastoderm, cell formation in the blastoderm is either partially or totally blocked. In mutant mat(3)1 no blastoderm cells are formed, indicating that there are separate genetic controls for pole cells and blastoderm cells. The other two mutants form an incomplete cellular blastoderm in which certain regions of the blastoderm remain noncellular. The noncellular region in mutant mat(3)3 is on the posterior-dorsal surface, covering about 30% of the total blastoderm. In mutant mat(3)6 blastoderm cells are formed only at the anterior and posterior ends, separated by a noncellular region that covers about 70% of the total blastoderm. The selective effects on blastoderm cell formation in the three mutants emphasize the importance of components present in the egg before fertilization for the transition from a syncytial to a cellular blastoderm.The genes defective in the three mutants are essential only for oogenesis and not for any other period of development, as indicated by a strict dependence of the lethal phenotypes on the maternal genotypes. Heterozygous embryos from the eggs of homozygous mutant females die, whereas homozygous mutant embryos from the eggs of heterozygous females develop into viable adults.One of the mutants, mat(3)3, has a temperature-sensitive phenotype. Homozygous mat(3)3 females maintained at a restrictive temperature of 29°C show the lethal maternal effect. However, at a permissive temperature of 20°C the females produce viable adult progeny. The temperature-sensitive period in mat(3)3 females occurs during the last 12 hr of oogenesis, consistent with the maternal effect phenotype of the mutant.     

QTL on mouse chromosomes 1 and 4 causing sperm-head morphological abnormality and male subfertility

The B10.M mouse strain represents a model for male subfertility as it produces a significantly low number of offspring. The only known male reproductive phenotype of this strain is its high frequency of sperm-head morphological abnormalities (44.7 ± 2.4 %). We previously reported that this phenotype was the product of two recessive loci. In this study we mapped the loci causing the high frequency of sperm-head morphological abnormalities in this strain using F2 animals produced by crossing B10.M and C3H mice. Quantitative trait loci (QTL) analysis (n = 178) identified two recessive genes, one on Chromosome (Chr) 1 (LOD score = 30.585) and one on Chr 4 (LOD score = 4.532). Further analysis (n = 854) mapped the locus on Chr 1 between Ercc5 (23.55 cM) and D1Mit528 (25.95 cM) and the locus on Chr 4 between D4Mit148 (69.48 cM) and D4Mit170 (70.47 cM). It was also found that the effects of these two loci were not independent. The major locus on Chr 1 determines the expression of sperm-head abnormalities, while the locus on Chr 4 enhances the frequency of abnormalities only when the genotype of the Chr 1 locus is homozygous for the B10.M allele. The major locus on Chr 1 was named sperm-head morphology 1 (Shm1), while the modifier locus on Chr 4 was named sperm-head morphology 2 (Shm2).     

Acute corticosterone treatment prior to ovulation biases offspring sex ratios towards males in zebra finches Taeniopygia guttata

Researchers have documented significant skews in the primary sex ratios of avian offspring in relation to a variety of environmental and social cues. Zebra finches Taeniopygia guttata, in particular, adjust offspring sex ratio according to both the quality and quantity of available food, as well as male attractiveness. The mechanisms behind such manipulation of offspring sex remain elusive. Recent studies suggest that females with chronically elevated corticosterone levels (both naturally and artificially) produce significantly female biased offspring sex ratios. We tested the effects of a pharmacological dose of corticosterone or progesterone administered at the time of sex chromosome segregation on the primary sex ratio of zebra finch offspring to determine whether one or both hormones act on offspring sex at this critical period. Females were injected with 20 μg of corticosterone or 20 μg of progesterone five hours prior to the predicted time of ovulation of the 3^rd or 4th ovulating follicle. A third group of females were unmanipulated. The corticosterone treated group produced 72% males while the control group produced 37.5% in the 3rd or 4th ovulation of the sequence. Progesterone injections disrupted ovulation and oviposition in 90% of females. Corticosterone administration did not adversely affect oviposition or ovulation. Females injected with corticosterone had significantly elevated levels of corticosterone 20 min, 1 h and 2.5 h post‐injection and produced significantly more males compared to untreated females. Our results suggest that offspring sex ratios may be influenced at the time of meiotic division by acute exposure to corticosterone and provides evidence for the timing of this effect.     

Developmental Genetics of the 2e-F Region of the Drosophila X Chromosome: A Region Rich in "Developmentally Important" Genes

We have analyzed the 2E1-3A1 area of the X chromosome with special attention to loci related to embryogenesis. Published maps indicate that this chromosomal segment contains ten bands. Our genetic analysis has identified 11 complementation groups: one recessive visible (prune), two female steriles and eight lethals. One of the female sterile loci is fs(1)k10 for which homozygous females produce both egg chambers and embryos with a dorsalized morphology. The second female sterile is the paternally rescuable fs(1)pecanex in which unrescued embryos have a hypertrophic nervous system. Of the eight lethal complementation groups two are recessive embryonic lethals: hemizygous giant (gt) embryos possess segmental defects, and hemizygous crooked neck (crn) embryos exhibit a twisted phenotype. Analysis of these mutations in the female germ line indicates that gt does not show a maternal effect, whereas normal activity of crn is required for germ cell viability. Analysis of the maternal effect in germ line clones of the remaining six recessive lethal complementation groups indicates that four are required for germ cell viability and one produces ambiguous results for survival of the germ cells. The remaining, l(1)pole hole, is a recessive early pupal lethal in which embryos derived from germ line clones and lacking wild-type gene activity exhibit the "torso" or "pole hole" phenotype.     

Cytological localization of the maternal effect gene, tuh-1, in Drosophila melanogaster

Summary The sex-linked gene, tuh-1, produces a maternal effect that is associated with the tumorous head abnormality in Drosophila melanogaster. With the aid of various known deletions, tuh-1 has been localized to band 20A1-2 on the salivary chromosome map of the X.Work supported by grant GM 18664-01 from the National Institute of Health, U.S. Public Health Service     

Effects of P Element Insertions on Quantitative Traits in Drosophila Melanogaster

P element mutagenesis was used to construct 94 third chromosome lines of Drosophila melanogaster which contained on average 3.1 stable P element inserts, in an inbred host strain background previously free of P elements. The homozygous and heterozygous effects of the inserts on viability and abdominal and sternopleural bristle number were ascertained by comparing the chromosome lines with inserts to insert-free control lines of the inbred host strain. P elements reduced average homozygous viability by 12.2% per insert and average heterozygous viability by 5.5% per insert, and induced recessive lethal mutations at a rate of 3.8% per insert. Mutational variation for the bristle traits averaged over both sexes was 0.03Ve per homozygous P insert and 0.003Ve per heterozygous P insert, where Ve is the environmental variance. Mutational variation was greater for the sexes considered separately because inserts had large pleiotropic effects on sex dimorphism of bristle characters. The distributions of homozygous effects of inserts on the bristle traits were asymmetrical, with the largest effects in the direction of reducing bristle number; and highly leptokurtic, with most of the increase in variance contributed by a few lines with large effects. The inserts had partially recessive effects on the bristle traits. Insert lines with extreme bristle effects had on average greatly reduced viability.     

Is There a Gene Regulating the Scute Locus on the Third Chromosome of D. MELANOGASTER?

A section of the third chromosome of D. melanogaster some 25 to 40 centimorgans long including sr was transferred from a wild-type stock selected by Latter for high scutellar bristle number into a scute stock with a large number of scutellar bristles. This segment is shown to have a large effect on the bristle numbers of wild-type flies, to reduce the strength of canalization of the scute phenotype at 4 bristles, to have little, if any, effect on bristle numbers of scute flies with less than 4 bristles but to increase the number of flies with 5 and 6 scutellar bristles in scute stocks that normally have a large number of flies with 4 bristles. It is suggested that this segment in unselected chromosomes contains a gene that regulates bristle number by repressing the scute locus and that Latter has selected a mutant of the regulator which fails to repress the action of the scute locus.     

The thrifty phenotype as an adaptive maternal effect

Human diseases in adulthood are increasingly associated with growth patterns in early life, implicating early-life nutrition as the underlying mechanism. The thrifty phenotype hypothesis proposed that early-life metabolic adaptations promote survival, with the developing organism responding to cues of environmental quality by selecting an appropriate trajectory of growth. Recently, some authors have proposed that the thrifty phenotype is also adaptive in the longer-term, by preparing the organism for its likely adult environment. However, windows of plasticity close early during human development, and subsequent environmental changes may result in the selected trajectory becoming inappropriate, leading to adverse effects on health. This paradox generates uncertainty as to whether the thrifty phenotype is indeed adaptive for the offspring in humans. The thrifty phenotype should not be considered a dichotomous concept, rather it refers to the capacity of all offspring to respond to environmental information during early ontogenetic development. This article argues that the thrifty phenotype is the consequence of three different adaptive processes - niche construction, maternal effects, and developmental plasticity - all of which in humans are influenced by our large brains. While developmental plasticity represents an adaptation by the offspring, both niche construction and parental effects are subject to selection on parental rather than offspring fitness. The three processes also operate at different paces. Human offspring do not become net calories-producers until around 18 years of age, such that the high energy costs of the human brain are paid primarily by the mother, even after weaning. The evolutionary expansion of human brain volume occurred in environments characterised by high volatility, inducing strong selective pressure on maternal capacity to provision multiple offspring simultaneously. The thrifty phenotype is therefore best considered as a manipulation of offspring phenotype for the benefit of maternal fitness. The information that enters offspring phenotype during early development does not predict the likely future environment of the offspring, but rather reflects the mother's own developmental experience and the quality of the environment during her own maturation. Offspring growth trajectory thus becomes aligned with long-term maternal capacity to provision. In contemporary populations, the sensitivity of offspring development to maternal phenotype exposes the offspring to adverse effects, through four distinct pathways. The offspring may be exposed to (1) poor maternal metabolic control (e.g. gestational diabetes), (2) maternally derived toxins (e.g. maternal smoking), or (3) low maternal social status (e.g. small size). Adverse consequences of these effects may then be exacerbated by (4) exposure either to the "toxic" western environment in postnatal life, in which diet and physical activity levels are mismatched with metabolic experience in utero, or at the other extreme to famine. The rapid emergence of the epidemic of the metabolic syndrome in the 20th Century reflects the rapid acceleration in the pace of niche construction relative to the slower physiological combination of developmental plasticity and parental effects.     

A genetic maternal effect on egg surface in Tribolium castaneum.

Females homozygous for an autosomal recessive gene, wd, produce "weird" eggs that are dry when laid. The wd gene has some important population consequences and also provides a very useful example of a genetic maternal effect for laboratory courses.