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At least 19 recordsLinked to original sources
PubMed2004

The alluring simplicity and complex reality of genetic rescue.

A series of important new theoretical, experimental and observational studies demonstrate that just a few immigrants can have positive immediate impacts on the evolutionary trajectory of local populations. In many cases, a low level of immigration into small populations has produced fitness benefits that are greater than those predicted by theoretical models, resulting in what has been termed 'genetic rescue'. However, the opposite result (reduced fitness) can also be associated with immigration of genetically divergent individuals. Central to our understanding of genetic rescue are complex interactions among fundamental concepts in evolutionary and population biology, including both genetic and non-genetic (environmental, behavioral and demographic) factors. Developing testable models to predict when genetic rescue is likely to occur is a daunting challenge that will require carefully controlled, multi-generation experiments as well as creative use of information from natural 'experiments'.

Journal Article↗
PubMed2001

Restoration of genetic variation lost - the genetic rescue hypothesis.

It has been long known that immigrants from surrounding populations might prevent the extinction of small populations, a process known as the 'rescue effect'. This focuses on the demographic effects of migration through the direct positive influence that immigrants have on abundance of the recipient population. Now, two recent papers have indicated another potentially important way that migration might rescue populations from extinction - replenishing genetic variation and reducing inbreeding depression, or what has been termed 'genetic rescue'.

Journal Article↗
PubMed2003

Enhanced genetic rescue of negative-strand RNA viruses: use of an MVA-T7 RNA polymerase vector and DNA replication inhibitors.

A modified cDNA rescue system that improves recovery of recombinant nonsegmented, negative-strand RNA viruses from cloned DNAs is described. Rescue systems based on vaccinia virus-T7 RNA polymerase vectors have been used to derive many negative-strand viruses; however, some strains can be recalcitrant to rescue possibly because of the simultaneous replication of the vaccinia virus-T7 vector. Our goal was to engineer a system where replication of the vaccinia virus-T7 vector could be blocked, yet allow for sufficient T7 RNA polymerase expression to enable genetic rescue. To that end, a recombinant modified vaccinia virus Ankara (MVA) was engineered that contained the bacteriophage T7 gene-1 under the control of a strong early promoter that would enable T7 RNA polymerase expression in the absence of MVA DNA replication. The new T7 helper, MVAGKT7, was then utilized successfully for the genetic rescue of a measles virus minigenome and full-length cDNAs, in the presence of DNA synthesis inhibitors. In addition to blocking completely MVAGKT7 replication, AraC treatment was found to enhance minigenome-encoded gene expression and the efficiency of measles virus rescue.

Animals↗
PubMed2005

Genetic rescue of a Toxoplasma gondii conditional cell cycle mutant.

Growth rate is a major pathogenesis factor in the parasite Toxoplasma gondii; however, how cell division is controlled in this protozoan is poorly understood. Herein, we show that centrosomal duplication is an indicator of S phase entry while centrosome migration marks mitotic entry. Using the pattern of centrosomal replication, we confirmed that mutant ts11C9 undergoes a bimodal cell cycle arrest that is characterized by two subpopulations containing either single or duplicated centrosomes which correlate with the bipartite genome distribution observed at the non-permissive temperature. Genetic rescue of ts11C9 was performed using a parental RH strain cDNA library, and the cDNA responsible for conferring temperature resistance (growth at 40 degrees C) was recovered by recombination cloning. A single T. gondii gene encoding the protein homologue of XPMC2 was responsible for genetic rescue of the temperature-sensitive defect in ts11C9 parasites. This protein is a known suppressor of mitotic defects, and in tachyzoites, TgXPMC2-YFP localized to the parasite nucleus and nucleolus which is consistent with the expected subcellular localization of critical mitotic factors. Altogether, these results demonstrate that ts11C9 is a conditional mitotic mutant containing a single defect which influences two distinct control points in the T. gondii tachyzoite cell cycle.

Amino Acid Sequence↗
PubMed2005

Genetic rescue in interconnected populations of small and large size of the self-incompatible Ranunculus reptans.

Small populations of our study species Ranunculus reptans have reduced fitness because of inbreeding, genetic load, and reduced mate availability; that is, they suffer from a three-fold genetic Allee effect. Here, we investigate how the effect of interpopulation outbreeding on offspring fitness depends on population size. We performed within- and between-population crosses with plants originating from 15 populations, and measured offspring performance in a common environment. Interpopulation outbreeding led to an increase in population means of clonal performance, which was defined as the number of rooted offspring rosettes produced per maternal ovule. This fitness gain mainly occurred at the life stage of seed set. It was especially pronounced for populations with a long-term history of small size inferred from their low genetic diversity, estimated from eight allozyme loci. We conclude that in a self-incompatible plant such as R. reptans, interpopulation outbreeding can lead to an immediate genetic rescue effect due to increased cross-compatibility and heterosis, and that this rescue effect is increased as population size decreases.

Crosses, Genetic↗
PubMed2004

Role of the midbody matrix in cytokinesis: RNAi and genetic rescue analysis of the mammalian motor protein CHO1.

CHO1 is a kinesin-like motor protein essential for cytokinesis in mammalian cells. To analyze how CHO1 functions, we established RNAi and genetic rescue assays. CHO1-depleted cells reached a late stage of cytokinesis but fused back to form binucleate cells because of the absence of the midbody matrix in the middle of the intercellular bridge. Expression of exogenous CHO1 restored the formation of the midbody matrix and rescued cytokinesis in siRNA-treated cells. By analyzing phenotypes rescued with different constructs, it was shown that both motor and stalk domains function in midbody formation, whereas the tail is essential for completion of cytokinesis after the midbody matrix has formed. During the terminal stage of cytokinesis, different subregions of the tail play distinctive roles in stabilizing the midbody matrix and maintaining an association between the midbody and cell cortex. These results demonstrate that CHO1 consists of functionally differentiated subregions that act in concert to ensure complete cell separation.

Adenosine Triphosphate↗
PubMed1999

Peripheral nervous system defects in erbB2 mutants following genetic rescue of heart development.

The ErbB2 tyrosine kinase functions as coreceptor for the neuregulin receptors ErbB3 and ErbB4 and can participate in signaling of EGF receptor (ErbB1), interleukin receptor gp130, and G-protein coupled receptors. ErbB2(-/-) mice die at midgestation because of heart malformation. Here, we report a genetic rescue of their heart development by myocardial expression of erbB2 cDNA that allows survival of the mutants to birth. In rescued erbB2 mutants, Schwann cells are lacking. Motoneurons form and can project to muscle, but nerves are poorly fasciculated and disorganized. Neuromuscular junctions form, as reflected in clustering of AChR and postsynaptic expression of the genes encoding the alpha-AChR, AChE, epsilon-AChR, and the RI subunit of the cAMP protein kinase. However, a severe loss of motoneurons on cervical and lumbar, but not on thoracic levels occurs. Our results define the roles of Schwann cells during motoneuron and synapse development, and reveal different survival requirements for distinct motoneuron populations.

Alleles↗
PubMed1976

Maternally influenced embryonic lethality: allele specific genetic rescue at a female fertility locus in Drosophila melanogaster.

A new locus, mel(1)R1, with a maternal effect on embryonic development, has been mapped at about 0.5 on the X chromosome of Drosophila melanogaster and localized cytologically between bands 2D6 and 3A1. Genotypically mutant embryos die if produced by homozygous mutant females but survive if produced by heterozygous females. Two mutant alleles have been isolated. One of these is genetically rescuable: when homozygous mutant females are mated to mutant males, all the embryos die, but when these females are mated to normal males, female offspring are produced. The other allele is not rescuable. Genetic rescue is dominant at this locus since females heterozygous for the two mutant alleles produce female offspring in crosses to normal males.

Alleles↗
PubMed2003

Genetic rescue of chondrodysplasia and the perinatal lethal effect of cartilage link protein deficiency.

The targeted disruption of cartilage link protein gene (Crtl1) in homozygous mice resulted in a severe chondrodysplasia and perinatal lethality. This raised the question of whether the abnormalities seen in Crtl1 null mice are all caused by the absence of link protein in cartilage or whether the deficiency of the protein in other tissues and organs contributed to the phenotype. To address this question we have generated transgenic mice overexpressing cartilage link protein under the control of a cartilage-specific promoter, and then these transgenic mice were used for a genetic rescue of abnormalities in Crtl1 null mice. While the overexpression of cartilage link protein resulted in no abnormal phenotype, the cartilage-specific transgene expression of link protein could completely prevent the perinatal mortality of link protein-deficient mice and, depending on the level of the link protein expression, rescue skeletal abnormalities. Although link protein was originally isolated from cartilage, we found and determined Crtl1 transcripts and corresponding proteins in every organ tested from mouse embryos to aging animals. We also identified three additional members of the link protein family, all co-localized with hyaluronic acid-binding proteoglycans in the mouse genome. The ubiquitous presence of link protein suggests a general and systemic function of link protein in the organization of extracellular matrix in a number of tissues, possibly interacting with other proteoglycans, such as versican, brevican, and neurocan.

Animals↗
PubMed1998

Genetic rescue of follicle-stimulating hormone beta-deficient mice.

FSH is an alpha:beta heterodimeric pituitary glycoprotein that shares a common alpha-subunit with LH and TSH. To study the role of FSH in mammalian reproduction, we have previously generated an FSH-deficient mouse model using embryonic stem (ES) cell technology by introducing a null mutation in the unique FSHbeta gene. Male mice deficient in FSH are fertile despite their small testes and reduced sperm number and motility. In contrast, FSH-deficient female mice are infertile due to a block in folliculogenesis at the preantral stage. In this set of experiments, we have rescued the mutant phenotypes of FSHbeta-deficient mice by two genetic strategies. In the type I rescue mice, we introduced into the FSHbeta-deficient background a 10-kb human FSHbeta transgene that is selectively expressed in pituitary gonadotropes. The presence of this transgene [and thus the interspecies hybrid (i.e. mouse alpha:human FSHbeta hormone)] in the background of mouse FSHbeta deficiency completely restored the testis size, sperm number, and motility defects to levels comparable to those seen in control male mice. All of the mouse FSHbeta-deficient female mice carrying this human FSHbeta transgene resumed normal folliculogenesis, were fertile and delivered normal size litters. In the type II rescue mice, human FSH (human alpha:human FSHbeta) was ectopically produced from multiple tissues in the mutant background using a mouse metallothionein-I promoter. Whereas ectopic production of human FSH completely rescued the mouse FSHbeta-deficient male mice, only 3 out of 10 mouse FSHbeta-deficient females bearing these human FSH transgenes were fertile and carried their pregnancies to term and parturition. We conclude that the resultant phenotypes due to a genetic deficiency of mouse FSHbeta can be corrected by appropriate expression of human FSH transgenes and that human FSHbeta gene regulation and function in the mouse pituitary are indistinguishable from the endogenous mouse FSHbeta gene.

Animals↗
PubMed2026

Genetic rescue stabilizes diversity in small isolated populations of Bonneville cutthroat trout.

Genetic diversity loss due to anthropogenic factors is occurring rapidly on a global scale, putting many species at risk of extirpation and extinction. Different management strategies have been developed to slow this loss; however, it is often unknown whether these strategies reach their intended goals. In this study, we evaluate population structure and changes in nucleotide diversity (π) in isolated populations of Bonneville cutthroat trout (Oncorhynchus clarkii utah) from the Snake Range (Nevada, USA). Starting in the 1990s, three of these populations were used to reestablish populations in the Snake Range because many of the historic populations were extirpated. Some populations were stocked using a single-source and others were stocked using multiple-sources. Using low-coverage whole-genome sequencing coupled with historic samples (2003-2010) and contemporary samples (2019-2022), we find that single-source populations lost nucleotide diversity while mixed-source populations maintained nucleotide diversity. Further, source populations used to restore populations throughout the Snake Range lost the most nucleotide diversity over the time span evaluated. Our findings provide insight into how small, isolated populations can be managed to maintain genetic diversity.

Animals↗
PubMed2006

Genetic rescue of an insular population of large mammals.

Natural populations worldwide are increasingly fragmented by habitat loss. Isolation at small population size is thought to reduce individual and population fitness via inbreeding depression. However, little is known about the time-scale over which adverse genetic effects may develop in natural populations or the number and types of traits likely to be affected. The benefits of restoring gene flow to isolates are therefore also largely unknown. In contrast, the potential costs of migration (e.g. disease spread) are readily apparent. Management for ecological connectivity has therefore been controversial and sometimes avoided. Using pedigree and life-history data collected during 25 years of study, we evaluated genetic decline and rescue in a population of bighorn sheep founded by 12 individuals in 1922 and isolated at an average size of 42 animals for 10-12 generations. Immigration was restored experimentally, beginning in 1985. We detected marked improvements in reproduction, survival and five fitness-related traits among descendants of the 15 recent migrants. Trait values were increased by 23-257% in maximally outbred individuals. This is the first demonstration, to our knowledge, of increased male and female fitness attributable to outbreeding realized in a fully competitive natural setting. Our findings suggest that genetic principles deserve broader recognition as practical management tools with near-term consequences for large-mammal conservation.

Animal Migration↗
PubMed1987

Genetic rescue of muscle defects associated with a mutant Drosophila melanogaster tropomyosin allele.

We describe a genetic transformation system which should prove useful for investigating tropomyosin assembly and function. Muscle abnormalities associated with a defective tropomyosin allele were corrected by integrating the wild-type gene into germ line chromosomes. The transformation protocol permits application of directed mutagenesis techniques in investigations of contractile regulatory mechanisms.

Alleles↗
PubMed1995

Lethal alpha-thalassaemia created by gene targeting in mice and its genetic rescue.

Mutations at the alpha-globin locus are the most common class of mutations in humans, with deletion of all four adult alpha-globin genes resulting in the perinatal lethal condition haemoglobin Barts hydrops fetalis. Using gene targeting in mice, we have deleted a 16 kilobase region encompassing both adult alpha-globin genes. Animals homozygous for this deletion become hydropic and die late in gestation mimicking humans with hydrops fetalis. Introduction of a human alpha-globin transgene rescued these animals from perinatal death thus demonstrating the utility of this murine model in the development of cellular and gene based approaches for treating this human genetic disease.

Animals↗
PubMedDate not supplied

Genetic rescue of inviable hybrids between Drosophila melanogaster and its sibling species.

Post-mating mechanisms are central to the establishment of reproductive isolation between different, but closely related, species. Post-mating isolation mechanisms include hybrid breakdown, hybrid sterility and hybrid lethality and may, in some cases, be reinforced by pre-mating mechanisms such as ethological differentiation. In the Drosophila melanogaster species sub-group post-mating reproductive isolation is ensured by both the inviability and the sterility of hybrids. For example when D. melanogaster females are crossed to D. simulans males the hybrid progeny are normally all female; the hybrid males die as third instar larvae. The viable hybrid females are totally sterile. Little is known of the genetic basis for either hybrid sterility or hybrid inviability, although Coyne and others have begun a genetic analysis of the sterility of hybrids within this species sub-group. We have discovered a single gene difference that rescues the otherwise inviable male hybrids from the cross between D. melanogaster females and males of its three closest relatives. The study of this locus may shed light on the genetic control of both speciation and development.

Animals↗
PubMed1994

Survival of steroid 21-hydroxylase-deficient mice without endogenous corticosteroids after neonatal treatment and genetic rescue by transgenesis as a model system for treatment of congenital adrenal hyperplasia in humans.

The genome of mice with the H-2aw18 haplotype has a deletion of approximately 80 kilobases in the H-2 class III region of chromosome 17. Mice that are homozygous for the mutation die soon after birth. A functional form of steroid 21-hydroxylase (21-OHase) is encoded by the deleted DNA fragment, and H-2aw18 homozygotes are deficient in this enzyme. 21-OHase catalyzes the conversion of progesterone to deoxycorticosterone during adrenal steroidogenesis in mice; therefore, H-2aw18 homozygous mice are unable to synthesize corticosteroids. The deleted region also includes the gene for complement component C4, which has a role in the classical pathway of the complement activation cascade. To clarify the cause of the lethality of the mutation, we first administered either an adrenal homogenate or synthetic steroids to newborn mice; as a result, several H-2aw18 homozygotes were rescued. The results demonstrated that the mutant mice die as the result of a defect in adrenal steroidogenesis. The low efficiency of the rescue by treatment of newborns (16.0% by the adrenal homogenate and 14.8% by the synthetic steroids) suggested that mutant mice should be treated prenatally. Moreover, because the 21-OHase gene is expressed before birth, introduction of a gene for 21-OHase should improve the efficiency of rescue. The results of the murine mutation are similar to those of the inherited human disease known as congenital adrenal hyperplasia, which is caused by steroid 21-hydroxylase deficiency. As a model system for treatment of the human disease by genetic therapy, we used transgenic approaches to introduce a recombinant DNA fragment containing the murine genomic gene for 21-OHase into the mutant mice. We produced four lines of transgenic mice, and in all four transgenic lines, the transgene rescued the lethal mutation. The apparent efficiencies of rescue were 80.2%, 80.0%, 68.7%, and 16.7% for the respective lines of transgenic mice. During the course of our experiments, we also found an unexpected property associated with the role of corticosteroids. The H-2aw18 homozygous mice rescued by neonatal treatment survived for a long period without further treatment. This observation indicates that corticosteroids down-stream of 21-OHase in the pathway for adrenal steroidogenesis are not essential for the survival of mice, except during the period immediately after birth.

Adrenal Cortex Hormones↗