Conserved Genes Act as Modifiers of Invertebrate SMN Loss of Function Defects

Spinal Muscular Atrophy (SMA) is caused by diminished function of the Survival of Motor Neuron (SMN) protein, but the molecular pathways critical for SMA pathology remain elusive. We have used genetic approaches in invertebrate models to identify conserved SMN loss of function modifier genes. Drosophila melanogaster and Caenorhabditis elegans each have a single gene encoding a protein orthologous to human SMN; diminished function of these invertebrate genes causes lethality and neuromuscular defects. To find genes that modulate SMN function defects across species, two approaches were used. First, a genome-wide RNAi screen for C. elegans SMN modifier genes was undertaken, yielding four genes. Second, we tested the conservation of modifier gene function across species; genes identified in one invertebrate model were tested for function in the other invertebrate model. Drosophila orthologs of two genes, which were identified originally in C. elegans, modified Drosophila SMN loss of function defects. C. elegans orthologs of twelve genes, which were originally identified in a previous Drosophila screen, modified C. elegans SMN loss of function defects. Bioinformatic analysis of the conserved, cross-species, modifier genes suggests that conserved cellular pathways, specifically endocytosis and mRNA regulation, act as critical genetic modifiers of SMN loss of function defects across species

Migration-selection balance at multiple loci and selection on dominance and recombination

A steady influx of a single deleterious multilocus genotype will impose genetic load on the resident population and leave multiple descendants carrying various numbers of the foreign alleles. Provided that the foreign types are rare at equilibrium, and that all immigrant genes will eventually be eliminated by selection, the population structure can be inferred explicitly from the deterministic branching process taking place within a single immigrant lineage. Unless the migration and recombination rates were high, this simple method was a very close approximation to the simulated migration-selection balance with all possible multilocus genotypes considered.Comment: includes 6 figures and a Supporting Information. Mathematica notebook where the numerical results were obtained is available upon reques

Identification of PTEN Modifier Genes Using the Collaborative Cross Mouse Panel

Inactivation or mutation of phosphatase and tensin homolog (PTEN), a tumor suppressor gene, is implicated in unregulated cell proliferation, leading to tumor growth and the development of cancer. Identification of modifier genes, genes that alter the phenotype of another gene, of PTEN and their role in altering PTEN activity could provide insights into relationship between PTEN and cancer. The purpose of this study was to identify PTEN modifier genes by quantitative trait loci (QTL) mapping. To do so, we crossed transgenic mice that overexpress PTEN (super-PTEN) to lines of the Collaborative Cross (CC), a mouse population modeling human genetic diversity. We evaluated body weight at weaning as a surrogate for PTEN activity because it has been previously reported that super-PTEN expression is associated with reduced weight at weaning. Difference in body weight at weaning of super-PTEN pups compared to wild-type littermates was used for QTL analysis to identify modifier genes of PTEN. This approach has identified candidate genomic intervals harboring PTEN modifier genes. Further studies will identify candidate genes and confirm these genes as modifiers. A pilot study has been initiated to verify that the effect of PTEN on body weight is indicative of the effect of PTEN on cancer susceptibility

Genetic background influences tumour development in heterozygous Men1 knockout mice

Multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder caused by MEN1 germline mutations, is characterised by parathyroid, pancreatic and pituitary tumours. MEN1 mutations also cause familial isolated primary hyperparathyroidism (FIHP), a milder condition causing hyperparathyroidism only. Identical mutations can cause either MEN1 or FIHP in different families, thereby implicating a role for genetic modifiers in altering phenotypic expression of tumours. We therefore investigated the effects of genetic background and potential for genetic modifiers on tumour development in adult Men1+/- mice, which develop tumours of the parathyroids, pancreatic islets, anterior pituitary, adrenal cortex and gonads, that had been backcrossed to generate C57BL/6 and 129S6/SvEv congenic strains. A total of 275 Men1+/- mice, aged 5–26 months were macroscopically studied, and this revealed that genetic background significantly influenced the development of pituitary, adrenal and ovarian tumours, which occurred in mice over 12 months of age and more frequently in C57BL/6 females, 129S6/SvEv males and 129S6/SvEv females, respectively. Moreover, pituitary and adrenal tumours developed earlier, in C57BL/6 males and 129S6/SvEv females, respectively, and pancreatic and testicular tumours developed earlier in 129S6/SvEv males. Furthermore, glucagon-positive staining pancreatic tumours occurred more frequently in 129S6/SvEv Men1+/- mice. Whole genome sequence analysis of 129S6/SvEv and C57BL/6 Men1+/- mice revealed >54,000 different variants in >300 genes. These included, Coq7, Dmpk, Ccne2, Kras, Wnt2b, Il3ra and Tnfrsf10a, and qRT-PCR analysis revealed that Kras was significantly higher in pituitaries of male 129S6/SvEv mice. Thus, our results demonstrate that Kras and other genes could represent possible genetic modifiers of Men1

An Evolutionary Reduction Principle for Mutation Rates at Multiple Loci

A model of mutation rate evolution for multiple loci under arbitrary selection is analyzed. Results are obtained using techniques from Karlin (1982) that overcome the weak selection constraints needed for tractability in prior studies of multilocus event models. A multivariate form of the reduction principle is found: reduction results at individual loci combine topologically to produce a surface of mutation rate alterations that are neutral for a new modifier allele. New mutation rates survive if and only if they fall below this surface - a generalization of the hyperplane found by Zhivotovsky et al. (1994) for a multilocus recombination modifier. Increases in mutation rates at some loci may evolve if compensated for by decreases at other loci. The strength of selection on the modifier scales in proportion to the number of germline cell divisions, and increases with the number of loci affected. Loci that do not make a difference to marginal fitnesses at equilibrium are not subject to the reduction principle, and under fine tuning of mutation rates would be expected to have higher mutation rates than loci in mutation-selection balance. Other results include the nonexistence of 'viability analogous, Hardy-Weinberg' modifier polymorphisms under multiplicative mutation, and the sufficiency of average transmission rates to encapsulate the effect of modifier polymorphisms on the transmission of loci under selection. A conjecture is offered regarding situations, like recombination in the presence of mutation, that exhibit departures from the reduction principle. Constraints for tractability are: tight linkage of all loci, initial fixation at the modifier locus, and mutation distributions comprising transition probabilities of reversible Markov chains.Comment: v3: Final corrections. v2: Revised title, reworked and expanded introductory and discussion sections, added corollaries, new results on modifier polymorphisms, minor corrections. 49 pages, 64 reference

A large scale prediction of bacteriocin gene blocks suggests a wide functional spectrum for bacteriocins

Bacteriocins are peptide-derived molecules produced by bacteria, whose recently-discovered functions include virulence factors and signalling molecules as well as their better known roles as antibiotics. To date, close to five hundred bacteriocins have been identified and classified. Recent discoveries have shown that bacteriocins are highly diverse and widely distributed among bacterial species. Given the heterogeneity of bacteriocin compounds, many tools struggle with identifying novel bacteriocins due to their vast sequence and structural diversity. Many bacteriocins undergo post-translational processing or modifications necessary for the biosynthesis of the final mature form. Enzymatic modification of bacteriocins as well as their export is achieved by proteins whose genes are often located in a discrete gene cluster proximal to the bacteriocin precursor gene, referred to as \textit{context genes} in this study. Although bacteriocins themselves are structurally diverse, context genes have been shown to be largely conserved across unrelated species. Using this knowledge, we set out to identify new candidates for context genes which may clarify how bacteriocins are synthesized, and identify new candidates for bacteriocins that bear no sequence similarity to known toxins. To achieve these goals, we have developed a software tool, Bacteriocin Operon and gene block Associator (BOA) that can identify homologous bacteriocin associated gene clusters and predict novel ones. We discover that several phyla have a strong preference for bactericon genes, suggesting distinct functions for this group of molecules. Availability: https://github.com/idoerg/BOAComment: Accepted for publication in BMC Bioinformatic

The Interaction of Genetic Background and Mutational Effects in Regulation of Mouse Craniofacial Shape.

Inbred genetic background significantly influences the expression of phenotypes associated with known genetic perturbations and can underlie variation in disease severity between individuals with the same mutation. However, the effect of epistatic interactions on the development of complex traits, such as craniofacial morphology, is poorly understood. Here, we investigated the effect of three inbred backgrounds (129X1/SvJ, C57BL/6J, and FVB/NJ) on the expression of craniofacial dysmorphology in mice (Mus musculus) with loss of function in three members of the Sprouty family of growth factor negative regulators (Spry1, Spry2, or Spry4) in order to explore the impact of epistatic interactions on skull morphology. We found that the interaction of inbred background and the Sprouty genotype explains as much craniofacial shape variation as the Sprouty genotype alone. The most severely affected genotypes display a relatively short and wide skull, a rounded cranial vault, and a more highly angled inferior profile. Our results suggest that the FVB background is more resilient to Sprouty loss of function than either C57 or 129, and that Spry4 loss is generally less severe than loss of Spry1 or Spry2 While the specific modifier genes responsible for these significant background effects remain unknown, our results highlight the value of intercrossing mice of multiple inbred backgrounds to identify the genes and developmental interactions that modulate the severity of craniofacial dysmorphology. Our quantitative results represent an important first step toward elucidating genetic interactions underlying variation in robustness to known genetic perturbations in mice

RNA Levels and Activity of \u3cem\u3eFLOWERING LOCUS C\u3c/em\u3e are Modified in Mixed Genetic Backgrounds of \u3cem\u3eArabidopsis Thaliana\u3c/em\u3e

Flowering time and FLOWERING LOCUS C (FLC) RNA levels were analyzed in different accessions of Arabidopsis thaliana and in mixed genetic backgrounds resulting from crosses between accessions. Dominant alleles of FRIGIDA (FRI) promote accumulation of FLC RNA, which in turn promotes late flowering. Although the coding regions of sequenced FLC alleles are identical, some accessions have genetically weak alleles that do not promote late flowering in the presence of FRI. In this study, a new weak allele of FLC with open reading frame identity to previously sequenced alleles was isolated from a Niederzenz (Nd) accession. The FLC‐Nd allele accumulated less RNA in the presence of FRI than did the strong Columbia (Col) allele. The weak FLC‐Nd allele was semidominant in the mixed Nd/Col genetic background containing FRI, and a linear correlation between the level of FLC RNA and lateness of flowering was observed. However, late‐flowering transgressions with elevated levels of FLC RNA in the absence of FRI were also obtained from crosses between early‐flowering accessions Col and Nd. Moreover, compared to Nd, the weak Landsberg erecta (Ler) allele of FLC was recessive and not semidominant in the mixed Ler/Col genetic background. However, very early‐flowering transgressions lacking detectable FLC RNA were also obtained from crosses between FRI containing Col and Ler. The results indicate that modifier genes other than FRI influence the level and genetic activity of FLC RNA in different genetic backgrounds resulting from crosses between naturally occurring accessions of A. thaliana