A quantitative trait locus on chromosome 1 modulates intermale aggression in mice.

Aggression between male conspecifics is a complex social behavior that is likely modulated by multiple gene variants. In this study, the BXD recombinant inbred mouse strains (RIS) were used to map quantitative trait loci (QTLs) underlying behaviors associated with intermale aggression. Four hundred and fifty-seven males from 55 strains (including the parentals) were observed at an age of 13 ± 1 week in a resident-intruder test following 10 days of isolation. Attack latency was measured directly within a 10-minute time period and the test was repeated 24 hours later. The variables we analyzed were the proportion of attacking males in a given strain as well as the attack latency (on days 1 and 2, and both days combined). On day 1, 29% of males attacked, and this increased to 37% on day 2. Large strain differences were obtained for all measures of aggression, indicating substantial heritability (intraclass correlations 0.10-0.18). We identified a significant QTL on chromosome (Chr) 1 and suggestive QTLs on mouse Chrs 1 and 12 for both attack and latency variables. The significant Chr 1 locus maps to a gene-sparse region between 82 and 88.5 Mb with the C57BL/6J allele increasing aggression and explaining about 18% of the variance. The most likely candidate gene modulating this trait is Htr2b which encodes the serotonin 2B receptor and has been implicated in aggressive and impulsive behavior in mice, humans and other species.

QTL and systems genetics analysis of mouse grooming and behavioral responses to novelty in an open field.

The open field is a classic test used to assess exploratory behavior, anxiety and locomotor activity in rodents. Here, we mapped quantitative trait loci (QTLs) underlying behaviors displayed in an open field, using a panel of 53 BXD recombinant inbred mouse strains with deep replication (10 per strain and sex). The use of these strains permits the integration and comparison of data obtained in different laboratories, and also offers the possibility to study trait covariance by exploiting powerful bioinformatics tools and resources. We quantified behavioral traits during 20-min test sessions including (1) percent time spent and distance traveled near the wall (thigmotaxis), (2) leaning against the wall, (3) rearing, (4) jumping, (5) grooming duration, (6) grooming frequency, (7) locomotion and (8) defecation. All traits exhibit moderate heritability making them amenable to genetic analysis. We identified a significant QTL on chromosome M.m. 4 at approximately 104 Mb that modulates grooming duration in both males and females (likelihood ratio statistic values of approximately 18, explaining 25% and 14% of the variance, respectively) and a suggestive QTL modulating locomotion that maps to the same locus. Bioinformatic analysis indicates Disabled 1 (Dab1, a key protein in the reelin signaling pathway) as a particularly strong candidate gene modulating these behaviors. We also found 2 highly suggestive QTLs for a sex by strain interaction for grooming duration on chromosomes 13 and 17. In addition, we identified a pairwise epistatic interaction between loci on chromosomes 12 at 36-37 Mb and 14 at 34-36 Mb that influences rearing frequency in males.

Systems genetic analysis of hippocampal neuroanatomy and spatial learning in mice.

Variation in hippocampal neuroanatomy correlates well with spatial learning ability in mice. Here, we have studied both hippocampal neuroanatomy and behavior in 53 isogenic BXD recombinant strains derived from C57BL/6J and DBA/2J parents. A combination of experimental, neuroinformatic and systems genetics methods was used to test the genetic bases of variation and covariation among traits. Data were collected on seven hippocampal subregions in CA3 and CA4 after testing spatial memory in an eight-arm radial maze task. Quantitative trait loci were identified for hippocampal structure, including the areas of the intra- and infrapyramidal mossy fibers (IIPMFs), stratum radiatum and stratum pyramidale, and for a spatial learning parameter, error rate. We identified multiple loci and gene variants linked to either structural differences or behavior. Gpc4 and Tenm2 are strong candidate genes that may modulate IIPMF areas. Analysis of gene expression networks and trait correlations highlight several processes influencing morphometrical variation and spatial learning.

Determinants of the broad recognition of exocytic Rab GTPases by Mss4.

Rab GTPases function as essential regulators of vesicle transport between subcellular compartments of eukaryotic cells. Mss4, an evolutionarily conserved Rab accessory factor, facilitates nucleotide release and binds tightly to the nucleotide-free form of exocytic but not endocytic Rab GTPases. A structure-based mutational analysis of residues that are conserved only in exocytic Rab GTPases reveals three residues that are critical determinants of the broad specificity recognition of exocytic Rab GTPases by Mss4. One of these residues is located at the N-terminus of the switch I region near the nucleotide binding site whereas the other two flank an exposed hydrophobic triad previously implicated in effector recognition. The spatial disposition of these residues with respect to the structure of Rab3A correlates with the dimensions of the elongated Rab interaction epitope in Mss4 and supports a mode of interaction similar to that of other exchange factor-GTPase complexes. The complementarity of the corresponding interaction surfaces suggests a hypothetical structural model for the complex between Mss4 and Rab GTPases.

Swarming ring patterns in bacterial colonies exposed to ultraviolet radiation.

We report a novel morphological transition in a Bacillus subtilis colony initially growing under ambient conditions, after ultraviolet radiation exposure. The bacteria in the central regions of the colonies are observed to migrate towards the colony edge forming a ring during uniform spatial exposure. When the radiation is switched off, the colonies were observed to grow both inward into the evacuated regions as well as outward indicating that the pattern is not formed due to depletion of nutrients at the center of the colony. We also propose a reaction-diffusion model in which waste-limited chemotaxis initiated by the UV radiation leads to the observed phenomenology.

An established light ear mutant (C57BL/6J-Pdeb(rd1) le) mouse cell line exhibits a block to secretion of lysosomal enzymes.

The hypopigment mutant mice, light ear, pallid, and beige, possess defects in melanosomes, lysosomes, and platelet dense granules, suggesting that these organelles share a common biogenesis and processing. Light ear and pallid mutants are animal models for Hermansky Pudlak syndrome, whereas the beige mouse is an animal model for Chediak Higashi syndrome. An established skin cell line from the light ear mouse was tested along with pallid and beige cell lines for mutant effects on secretion of lysosomal hydrolase activities of six different lysosomal glycosidases and the trafficking of N-[5-(5,7-dimethyl BODIPY)-1-pentanoyl]-D-erythrosphingosine (C(5)-DMB-ceramide). There were no consistently significant differences between the pallid and the beige mutant cell lines or between these two mutant lines and the control cell line in the percentage secretion of lysosomal hydrolase activities. The light ear mutant cell line, however, displayed a significantly lower percentage secretion of lysosomal hydrolase activities than all other cell lines tested. The light ear mutant cells processed C(5)-DMB-ceramide completely, as seen in the control cell line, whereas pallid and beige cell lines retained fluorescent material and exhibited a block in the complete processing of C(5)-DMB-ceramide 20 h after labeling. The block to secretion of lyososomal hydrolase activities in the light ear mutant cell line will be useful for further studies on this mutant's lysosomal defect.