Biology subjects

Bell, T. A.

Publications and source records attributed to Bell, T. A..

22 records · Page 2Linked to original sources

bioRxiv2019

Collaborative Cross Mouse Populations as a Resource for the Study of Epilepsy

Epilepsy is a neurological disorder with complex etiologies and genetic architecture. Animal models have a critical role in understanding the pathophysiology of epilepsy. Here we studied epilepsy utilizing a genetic reference population of Collaborative Cross (CC) mice with publicly available whole genome sequences. We measured multiple epilepsy traits in 35 CC strains, and we identified novel animal models that exhibit extreme outcomes in seizure susceptibility, seizure propagation, epileptogenesis, and sudden unexpected death in epilepsy. We performed QTL mapping in an F2 population and identified seven novel and one previously identified loci associated with seizure sensitivity. We combined whole genome sequence and hippocampal gene expression to pinpoint biologically plausible candidate genes and candidate variants associated with seizure sensitivity. These resources provide a powerful toolbox for studying complex features of seizures and for identifying genes associated with particular seizure outcomes, and hence will facilitate the development of new therapeutic targets for epilepsy.

neuroscience↗

bioRxiv2019

Instability of the pseudoautosomal boundary in house mice

Faithful segregation of homologous chromosomes at meiosis requires pairing and recombination. In taxa with dimorphic sex chromosomes, pairing between them in the heterogametic sex is limited to a narrow interval of residual sequence homology known as the pseudoautosomal region (PAR). Failure to form the obligate crossover in the PAR is associated with male infertility in house mice (Mus musculus) and humans. Yet despite this apparent functional constraint, the boundary and organization of the PAR is highly variable in mammals, and even between subspecies of mice. Here we estimate the genetic map in a previously-documented expansion of the PAR in the Mus musculus castaneus subspecies and show that the local recombination rate is 100-fold higher than the autosomal background. We identify an independent shift in the PAR boundary in the Mus musculus musculus subspecies and show that it involves a complex rearrangement but still recombines in heterozygous males. Finally, we demonstrate pervasive copy-number variation at the PAR boundary in wild populations of M. m. domesticus, M. m. musculus and M. m. castaneus. Our results suggest that the intensity of recombination activity in the PAR, coupled with relatively weak constraints on its sequence, permit the generation and maintenance in the population of unusual levels of polymorphism of unknown functional significance.

genetics↗

bioRxiv2018

A diallel of the mouse Collaborative Cross founders reveals strong strain-specific maternal effects on litter size

Reproductive success in the eight founder strains of the Collaborative Cross (CC) was measured using a diallel-mating scheme. Over a 48-month period we generated 4,448 litters, and 24,782 weaned pups were used across 16 different published experiments. We identified factors that affect the average litter size in a cross by estimating the overall contribution of parent-of-origin, heterosis, inbred, and epistatic effects using a Bayesian zero-truncated overdispersed Poisson mixed model. The phenotypic variance of litter size has a substantial contribution (79%) from unexplained and environmental sources, but no detectable effect of seasonality. Most of the explained variance was due to additive effects (9.2%) and parental sex (maternal vs paternal strain; 5.8%), with epistasis accounting for 3.4%. Within the parental effects, the effect of the dams strain explained more than the sires strain (13.2% vs. 1.8%), and the dams strain effects account for 74.2% of total variation explained. Dams from strains C57BL/6J and NOD/ShiLtJ increased the expected litter size by a mean of 1.66 and 1.79 pups, whereas dams from strains WSB/EiJ, PWK/PhJ, and CAST/EiJ reduced expected litter size by a mean of 1.51, 0.81, and 0.90 pups. Finally, there was no strong evidence for strain-specific effects on sex ratio distortion. Overall, these results demonstrate that strains vary substantially in their reproductive ability depending on their genetic background and that litter size is largely determined by dam.strain rather than sire.strain effects, as expected. This analysis adds to our understanding of factors that influence litter size in mammals, and also helps to explain breeding successes and failures in the extinct lines and surviving CC strains.

genetics↗

bioRxiv2017

Parasympathetic and sympathetic activity are associated with individual differences in neural indices of selective attention in adults

Multiple theoretical frameworks posit that interactions between the autonomic nervous system and higher-order neural networks are crucial for cognitive regulation. However, few studies have directly examined the relationship between measures of autonomic physiology and brain activity during cognitive tasks, and fewer studies have examined both the parasympathetic and sympathetic autonomic branches when doing so. Here, 93 adults completed an event-related potential (ERP) auditory selective attention task concurrently with measures of parasympathetic activity (high-frequency heart rate variability; HF-HRV) and sympathetic activity (pre-ejection period; PEP). We replicate previous findings showing effects of selective attention on mean amplitude of the N1 ERP component (Hillyard et al., 1973; Coch et al., 2005), and extend this result to show that the effects of selective attention were associated with baseline values of HF-HRV and PEP. Individuals with higher resting HF-HRV and shorter resting PEP showed larger effects of selective attention on their ERPs. Follow-up regression models demonstrated that HF-HRV and PEP accounted for unique variance in selective attention effects on N1 mean amplitude. These results are consistent with the neurovisceral integration model, which posits that greater parasympathetic activity is a marker of increased cognitive capacity, as well as other theoretical models which emphasize the role of heightened sympathetic activity in more efficient attention-related processing. The present findings highlight the importance of autonomic physiology in the study of individual differences in neurocognitive function, and given the foundational role of selective attention across cognitive domains, suggest that both parasympathetic and sympathetic activity may be key to understanding variability in brain function across a variety of cognitive tasks.

neuroscience↗