THE GENETICS OF ADAPTATION: THE GENETIC BASIS OF RESISTANCE TO WASP PARASITISM IN DROSOPHILA MELANOGASTER.

There have been very few genetic analyses of "natural" adaptations, that is, those not involving artificial selection or responses to human disturbance. Here we analyze the genetic basis of geographic variation in Drosophila melanogaster's resistance to parasitism by a wasp, Asobara tabida. Our results suggest that population differences in ability to encapsulate parasitoid eggs have a fairly simple genetic basis: 60% of the D.

The cerebellar leucine-rich acidic nuclear protein interacts with ataxin-1.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder characterized by ataxia, progressive motor deterioration, and loss of cerebellar Purkinje cells. SCA1 belongs to a growing group of neurodegenerative disorders caused by expansion of CAG repeats, which encode glutamine. Although the proteins containing these repeats are widely expressed, the neurodegeneration in SCA1 and other polyglutamine diseases selectively involves a few neuronal subtypes.

Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures.

Spinocerebellar ataxia type 1 (SCA1) is one of several neurodegenerative disorders caused by an expansion of a polyglutamine tract. It is characterized by ataxia, progressive motor deterioration, and loss of cerebellar Purkinje cells. To understand the pathogenesis of SCA1, we examined the subcellular localization of wild-type human ataxin-1 (the protein encoded by the SCA1 gene) and mutant ataxin-1 in the Purkinje cells of transgenic mice.

Increased trinucleotide repeat instability with advanced maternal age.

Nucleotide repeat instability is associated with an increasing number of cancers and neurological disorders. The mechanisms that govern repeat instability in these biological disorders are not well understood. To examine genetic aspects of repeat instability we have introduced an expanded CAG trinucleotide repeat into transgenic mice.

Purkinje cell expression of a mutant allele of SCA1 in transgenic mice leads to disparate effects on motor behaviors, followed by a progressive cerebellar dysfunction and histological alterations.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurological disorder caused by the expansion of a CAG repeat encoding a polyglutamine tract. Work presented here describes the behavioral and neuropathological course seen in mutant SCA1 transgenic mice. Behavioral tests indicate that at 5 weeks of age mutant mice have an impaired performance on the rotating rod in the absence of deficits in balance and coordination.

Cytotoxic T lymphocyte recognition of HLA-G in mice.

Several features of HLA-G's sequence and expression pattern distinguish HLA-G from its classical counterparts. These features, including HLA-G's limited polymorphism and its expression at the maternal-fetal interface, have been used as a basis for suggesting a distinct functional role for this nonclassical class I HLA molecule. On the other hand, published data do demonstrate that HLA-G has much in common with its classical counterparts.

Mouse models of human CAG repeat disorders.

Expansions of CAG trinucleotide repeats encoding glutamine have been found to be the causative mutations of seven human neurodegenerative diseases. Similarities in the clinical, genetic, and molecular features of these disorders suggest they share a common mechanism of pathogenesis. Recent progress in the generation and characterization of transgenic mice expressing the genes containing expanded repeats associated with spinal and bulbar muscular atrophy (SBMA), spinocerebellar ataxia type 1 (SCA1), Machado-Joseph disease (MJD/SCA3), and Huntington's disease (HD) is beginning to provide insight into the underlying mechanisms of these neurodegenerative disorders.

Identification of a self-association region within the SCA1 gene product, ataxin-1.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of a polyglutamine tract within the SCA1 gene product, ataxin-1. Expansion of this tract is believed to result in a gain of function by the mutant protein, perhaps through altered self-associations or interactions with other cellular proteins. We have used the yeast two hybrid system to determine if ataxin-1 is capable of multimerization.

The developmental genetics of hybrid inviability: a mitotic defect in Drosophila hybrids.

We report studies of the developmental basis of hybrid inviability in the Drosophila melanogaster complex. The pathology of these hybrids closely resembles that of mitotic mutants in D. melanogaster.

Susceptibility to cell death induced by mutant SV40 T-antigen correlates with Purkinje neuron functional development.

Purkinje cells are uniquely susceptible to a number of physical, chemical, and genetic insults both during development and in the mature state. We have previously shown that when the postmitotic state of murine Purkinje cells is altered by inactivation of the retinoblastoma tumor susceptibility protein (pRb), immature as well as mature Purkinje cells undergo apoptosis. DNA synthesis and neuronal loss are induced in postmitotic Purkinje cells dependent upon the pRb-binding portion of SV40 large T antigen (T-ag).

WAITING FOR SPECIATION: THE EFFECT OF POPULATION SUBDIVISION ON THE TIME TO SPECIATION.

We study the time required for speciation in a species that is divided into small versus large populations. Following Dobzhansky and Muller, we assume that hybrid sterility or inviability is caused by "complementary genes," that is, by the accumulation of genes that cause sterility or inviability when brought together in hybrids but that have no deleterious effect on their normal species genetic background. When divergence between populations is caused by genetic drift, we show that the time to speciation is independent of population subdivision: speciation occurs just as quickly in a species split into a few large populations as into many small populations.

Spinocerebellar ataxia type-1 and spinobulbar muscular atrophy gene products interact with glyceraldehyde-3-phosphate dehydrogenase.

Spinocerebellar ataxia type1 (SCA1) is one of several neurodegenerative disorders caused by expansions of translated CAG trinucleotide repeats which code for polyglutamine in the respective proteins. Most hypotheses about the molecular defect in these disorders suggest a gain of function, which may involve interactions with other proteins via the expanded polyglutamine tract. In this study we used ataxin-1, the SCA1 gene product, as a bait in the yeast two-hybrid system and identified the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase as an ataxin-1 interacting protein.

Familial cerebral cavernous angioma: a gene localized to a 15-cM interval on chromosome 7q.

Cerebral cavernous angiomas are collections of closely clustered vessels without intervening normal brain parenchyma, with microscopic evidence of hemorrhage, frequently multiple; they are best visualized with magnetic resonance imaging. Familial cerebral cavernous angioma occurs as an autosomal dominant disorder, although carriers of the gene are often asymptomatic. Recently, a gene responsible for familial cerebral cavernous angioma in a large Hispanic kindred was mapped to human chromosome 7q11-22, representing a large segment of DNA containing approximately 33 cM (about 33 million base pairs).

Isolation, characterization and in vivo analysis of the murine calbindin-D28K upstream regulatory region.

The genomic locus containing the murine calbindin-D28K gene has been isolated and partially characterized. Genomic cloning revealed an exon/intron chromosomal structure very similar to the avian gene previously described. The ability of the calbindin-D28K upstream region to direct cell-specific expression was tested in vivo.

The unexpected recovery of hybrids in a Drosophila species cross: a genetic analysis.

The species cross between Drosophila melanogaster and D. simulans was first described by Sturtevant in the 1920s. According to his description, the hybridization of D.

Cloning and developmental expression analysis of the murine homolog of the spinocerebellar ataxia type 1 gene (Sca1).

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat which encodes glutamine in the novel protein ataxin-1. In order to characterize the developmental expression pattern of SCA1 and to identify putative functional domains in ataxin-1, the murine homolog (Sca1) was isolated. Cloning and characterization of the murine Sca1 gene revealed that the gene organization is similar to that of the human gene.

Refined localization of the cerebral cavernous malformation gene (CCM1) to a 4-cM interval of chromosome 7q contained in a well-defined YAC contig.

Cerebral cavernous malformations (CCM) are vascular lesions present in some 20 million people worldwide that are responsible for seizures, migraine, hemorrhage, and other neurologic problems. Familial cases ofCCM can be inherited as an autosomal dominant disorder with variable expression. A gene for CCM (CCM/)was recently mapped to a 33-cM segment of chromosome 7q in a large Hispanic family (Dubovsky et al.

HLA-G transgenic mice: a model for studying expression and function at the maternal/fetal interface.

Experiments designed to identify all HLA class I genes led to the cloning of the HLA-G gene (Geraghty et al. 1987). Very low levels of HLA-G mRNA expression have been demonstrated in the eye, thymus, peripheral blood lymphocytes and in keratinocytes (Shukla et al.

SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant inherited disorder characterized by degeneration of cerebellar Purkinje cells, spinocerebellar tracts, and selective brainstem neurons owing to the expansion of an unstable CAG trinucleotide repeat. To gain insight into the pathogenesis of the SCA1 mutation and the intergenerational stability of trinucleotide repeats in mice, we have generated transgenic mice expressing the human SCA1 gene with either a normal or an expanded CAG tract. Both transgenes were stable in parent to offspring transmissions.

Spinocerebellar ataxia type 1 and Machado-Joseph disease: incidence of CAG expansions among adult-onset ataxia patients from 311 families with dominant, recessive, or sporadic ataxia.

The ataxias are a complex group of diseases with both environmental and genetic causes. Among the autosomal dominant forms of ataxia the genes for two, spinocerebellar ataxia type 1 (SCA1) and Machado-Joseph disease (MJD), have been isolated. In both of these disorders the molecular basis of disease is the expansion of an unstable CAG trinucleotide repeat.