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Walker, L. C.

Publications and source records attributed to Walker, L. C..

4 recordsLinked to original sources

Hunger alters approach-avoidance behaviours differently in male and female mice

BackgroundThe decision about whether to approach or avoid a reward while under threat requires balancing competing demands. Sex-specific prioritisations (e.g. mating, maternal care), or generalised prioritisations (e.g. feeding, drinking, sleeping) may differently influence approach-avoidance behaviours based on the level of "risk" and homeostatic need state of the organism. However, given known sex differences in key aspects that may influence this behaviour, direct comparison of how male and female mice make decisions to approach or avoid a dangerous area while in a fasted state have yet to be conducted. MethodsWe conducted several approach-avoidance tasks with varied levels of risk and reward in male and female mice that were either fasted or sated (fed). Mice underwent a light-dark box, elevated plus maze, baited large open field and runway task to assess their approach and avoidance behaviour. ResultIn the light-dark box and elevated plus maze, when no reward was available, fasted female mice showed greater approach behaviours than male counterparts. In the baited large open field, when reward was available, both sexes showed increased approach behaviours when fasted. However, when sated, male mice conversely showed greater approach behaviours compared to sated female mice. In the runway task, while sated mice failed to learn, fasted male mice inhibited their reward consumption in response to increased shock intensity; however, fasted female mice were resistant to increased shock intensity. ConclusionsOur study identifies sex differences in decision making behaviour in mice based on satiety state across a number of approach-avoidance tasks. We highlight several nuances of these differences based on reward availability and punishment intensity. These results shine a lens on fundamental differences between the sexes in innate, survival driven behaviours that should be taken into account for future studies. Plain English summaryEveryday decision making is often accompanied by conflict - whether we make the most appropriate decision or not can be influenced by both internal and external factors. Environmental threats and physiological pressures, such as hunger, can influence decision-making processes skewing the risk/reward ratio, yet how this may differ between the sexes has not been explored in detail. Here we used several tasks that assess decision-making in mice while manipulating the levels of risk or reward. Our findings show fasted female mice are more willing to engage in "risky" behaviour compared to fed female mice when risk levels were low, and no food reward was available. However, when a food reward was available, but risk levels were low, both male and female fasted mice were more likely to engage in risky behaviour compared to fed mice. Finally, when risk levels were high and food reward was available, fasted female mice continued to engage in risky behaviour, while male fasted mice were not. Together our study identifies nuanced sex differences in how male and female mice make decisions influenced by both physiological (hunger) and environmental threats and highlight the importance of understanding fundamental differences between the sexes in behaviour. Highlights- Fasted female mice showed greater approach behaviours compared to fasted male counterparts in tasks without reward availability. - Fasted mice of both sexes displayed greater approach behaviours when a reward was available, compared to sated controls. - Fasted male mice inhibited reward consumption under increased shock intensity, whereas fasted female mice were resistant to mild foot shock.

neuroscience↗

Rare copy number variants (CNVs) and breast cancer risk

BackgroundCopy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. ResultsGene burden tests detected the strongest association for deletions in BRCA1 (P= 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P= 0.0008), ATM (P= 0.002) and BRCA2 (P= 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. ConclusionsThis is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

genetics↗

Variable expression quantitative trait loci analysis of breast cancer risk variants

Genome wide association studies (GWAS) have identified more than 180 variants associated with breast cancer risk, however the underlying functional mechanisms and biological pathways which confer disease susceptibility remain largely unknown. As gene expression traits are under genetic regulation we hypothesise that differences in gene expression variability may identify causal breast cancer susceptibility genes. We performed variable expression quantitative trait loci (veQTL) analysis using tissue-specific expression data from the Genotype-Tissue Expression (GTEx) Common Fund Project. veQTL analysis identified 70 associations (p < 5x10-8) consisting of 60 genes and 27 breast cancer risk variants, including 55 veQTL that were observed in breast tissue only. Pathway analysis of genes associated with breast-specific veQTL revealed an enrichment of four genes (CYP11B1, CYP17A1 HSD3B2 and STAR) involved in the C21-steroidal biosynthesis pathway that converts cholesterol to breast-related hormones (e.g. oestrogen). Each of these four genes were significantly more variable in individuals homozygous for rs11075995 (A/A) breast cancer risk allele located in the FTO gene, which encodes an RNA demethylase. The A/A allele was also found associated with reduced expression of FTO, suggesting an epi-transcriptomic mechanism may underlie the dysregulation of genes involved in hormonal biosynthesis leading to an increased risk of breast cancer. These findings provide evidence that genetic variants govern high levels of expression variance in breast tissue, thus building a more comprehensive insight into the underlying biology of breast cancer risk loci.

cancer biology↗

Nanopore sequencing of full-length BRCA1 mRNA transcripts reveals co-occurrence of known exon skipping events

Laboratory assays evaluating the effect of DNA sequence variants on BRCA1 mRNA splicing may contribute to classification by providing molecular evidence. However, our knowledge of normal and aberrant BRCA1 splicing events to date has been limited to data derived from assays targeting partial transcript sequences. For the first time, we resolve the exon structure of whole BRCA1 transcripts using MinION nanopore sequencing of long-range PCR amplicons. Our study identified 32 BRCA1 isoforms, including 18 novel isoforms which comprised skipping of multiple contiguous and/or non-contiguous exons. Furthermore, we show that known BRCA1 exon skipping events, such as {Delta}(9,10) and {Delta}21, can co-occur in a single transcript, with some isoforms containing four or more alternative splice junctions. Our results highlight complexity in BRCA1 transcript structure that has not previously been described. This finding has key implications for predicting translation frame of splicing transcripts, important for interpreting the clinical significance of spliceogenic variants. Future research is warranted to quantitatively assess full length BRCA1 transcript levels, and to assess the application of nanopore sequencing for routine evaluation of potential spliceogenic variants.

genomics↗