Biology subjects

Baker, J. A.

Publications and source records attributed to Baker, J. A..

5 recordsLinked to original sources

bioRxiv2025

Rapid and repeated evolution of myosin copy number in threespine stickleback

Copy number variants at genomic loci evolve at a high rate, are linked to many different diseases, and play a role in adaptive evolution in humans and other organisms. Here we show that stickleback fish from freshwater environments have rapidly and repeatedly evolved an expanded number of copies of a gene family involved in muscle development, Myosin Heavy Chain 3 Cluster C (MYH3C), compared to marine populations. Differences in copy number between marine and freshwater fish are maintained even in the presence of gene flow, suggesting that MYH3C changes represent adaptive divergence between ecotypes. Copy number expansion occurs by tandem duplication of MYH3C coding and regulatory regions on the stickleback sex chromosome. We identify a muscle regulatory enhancer within the expanded MYH3C region and show that elevated copy number is associated with developmental and tissue-specific increases in corresponding mRNA expression levels in skeletal muscle. Common MYH3C clusters include 3-, 4-, 5-, and 6-copy variants that likely evolved through a combination of microhomology-mediated break repair and non-allelic homologous recombination. Our results provide a new example of copy number changes in a wild species and identify CNVs as potential "hotspots" of repeated adaptive evolution.

evolutionary biology↗

bioRxiv2025

Adolescent intermittent ethanol exposure induces sex-specific and time-dependent changes in affective behaviors and metabolomic profiles.

Given the adverse effects of adolescent binge alcohol consumption in humans, the present work explores the lasting behavioral and metabolomic impacts following adolescent binge ethanol exposure. Here we determine short- and long-term changes in affective behaviors and metabolomic profiles in male and female adolescent binge ethanol-exposed mice. Male and female C57BL/6J mice were exposed to adolescent intermittent ethanol (AIE) as a model of binge ethanol exposure using intermittent vapor inhalation from postnatal day (PND) 28-42. Mice were tested in a battery of behavioral tests and metabolomic analyses were conducted following short-term and long-term withdrawal from AIE exposure. Mice were tested for affective behaviors using the open field test (OFT), the light/dark test (LDT), and the tail suspension test (TST) one week following AIE exposure from PND 49-53 and again from PND 91-95. Serum samples were collected on PND 43, corresponding to 24 hours after the last exposure, fecal samples were collected during each OFT, and liver samples were collected approximately 80 days after AIE exposure for metabolomic analysis. We show modest incubation of behavioral differences in anxiety-like behavior in males after adolescent binge ethanol exposure; an effect that was absent in female mice. In contrast, metabolomic differences in male mice that were more pronounced shortly after adolescent binge ethanol exposure waned as time progressed since last exposure. Male mice appear to be more susceptible to the persistent changes in adolescent binge ethanol exposure that varies over time. It is possible that short-term metabolomic changes may predict long-term behavioral changes in affective behaviors. Contribution to the field statementAdolescent binge alcohol exposure causes long-lasting changes in behavior, however the underlying biology mediating these changes have not readily been assessed in a sex-specific manner. Metabolomic assays are a powerful tool that can be used as biomarkers to determine changes in biological pathways that are linked to specific behavioral phenotypes. Here we explored the relationship between adolescent binge alcohol exposure, changes in anxiety-like behavior, and metabolomic profiles in male and female C57BL/6J mice. We find robust changes in metabolomic profiles following short-term withdrawal in male mice exposed to binge alcohol during adolescence. We also see modest changes in anxiety-like behavior following long-term withdrawal. Although female mice did not show any robust changes in anxiety-like behavior nor global changes in metabolomic profiles, in both sexes we do observe persistent changes in some amino acids, which may serve as specific biomarkers associated with changes in alcohol-induced behavioral changes. These data add to the field by conducting a novel longitudinal study following male and female mice from adolescence to early adulthood and measuring physiological biomarkers (metabolomics) coupled with behavioral changes following binge ethanol exposure.

neuroscience↗

bioRxiv2022

Mapping the Constrained Coding Regions in the human genome to their corresponding proteins

Constrained Coding Regions (CCRs) in the human genome have been derived from DNA sequencing data of large cohorts of healthy control populations, available in the Genome Aggregation Database (gnomAD) [1]. They identify regions depleted of protein-changing variants and thus identify segments of the genome that have been constrained during human evolution. By mapping these DNA-defined regions from genomic coordinates onto the corresponding protein positions and combining this information with protein annotations, we have explored the distribution of CCRs and compared their co-occurrence with different protein functional features, previously annotated at the amino acid level in public databases. As expected, our results reveal that functional amino acids involved in interactions with DNA/RNA, protein-protein contacts and catalytic sites are the protein features most likely to be highly constrained for variation in the control population. More surprisingly, we also found that linear motifs, linear interacting peptides (LIPs), disorder-order transitions upon binding with other protein partners and liquid-liquid phase separating (LLPS) regions are also strongly associated with high constraint for variability. We also compared intra-species constraints in the human CCRs with inter-species conservation and functional residues to explore how such CCRs may contribute to the analysis of protein variants. As has been previously observed, CCRs are only weakly correlated with conservation, suggesting that intraspecies constraints complement interspecies conservation and can provide more information to interpret variant effects.

bioinformatics↗

bioRxiv2022

Variation in morphology among populations of threespine stickleback (Gasterosteus aculeatus) from western Newfoundland, Canada.

Freshwater populations of threespine stickleback (Gasterosteus aculeatus) have diverged from their marine ancestor and show extensive variation among populations throughout most of their range. However, phenotypes of freshwater populations from the east coast of North America does not appear to demonstrate extensive variability observed throughout the rest of the species range. The relative young age of east coast North American populations may explain the apparent lack of freshwater variability. On the other hand, populations in this part of the species range have not received the level of attention as have populations throughout the rest of its range and the low level of variability observed may simply reflect lack of data for this region. We examined morphological traits (including linear measurements of body armor and body shape) of stickleback from 52 locations representing marine and freshwater populations along the west coast of Newfoundland, Canada. We found that variability in morphological traits among freshwater populations was much more extensive than previously assumed and similar to patterns observed throughout the rest of the species range.

evolutionary biology↗

bioRxiv2019

Structural analysis of pathogenic missense mutations in GABRA2 and identification of a novel de novo variant in the desensitization gate

Cys-loop receptors are vital for controlling neuronal excitability in the brain and their dysfunction results in numerous neurological disorders. Recently, six de novo missense variants in GABRA2 gene, a member of this family, have been associated with early infantile epileptic encephalopathy (EIEE) and intellectual disability with seizures. Here, using whole-genome sequencing we identified a de novo missense variant in GABRA2 gene in a patient with EIEE and developmental delay. We perform protein structural analysis of the seven variants and show that all the mutations are in the transmembrane domain, either close to the desensitization gate, the activation gate or in inter-subunit interfaces. Further investigations demonstrated that the majority of pathogenic variants reported are at equivalent positions in other Cys-loop receptors, emphasizing the importance of these residues for the adequate function of the receptor. Also, a comparison of the distribution of the mutations in all the Cys-loop receptors showed that pathogenic variants are more common in the transmembrane helices, more specifically in the M2 helix, highlighting the importance of this segment. Our study expands the clinical spectrum of individuals with pathogenic missense mutations in GABRA2, defines the regions where pathogenic mutations are in the protein structure, and highlights the value of considering sequence, evolutionary, and structural information from other Cys-loop receptors as a strategy for variant interpretation of novel missense mutations in GABRA2.

genetics↗