Biomedical subjects

Joshua M Schmidt

Publications and source records attributed to Joshua M Schmidt.

3 recordsLinked to original sources

PubMed2026

Seasonal fluctuations in fitness result in severe reductions in effective population size.

Genetic evidence for fluctuating selection has begun to accumulate for different species over the past few decades, especially for the Drosophila genus where studies have reported hundreds of loci undergoing putatively adaptive oscillations across successive seasons. However, most theoretical and simulation studies of fluctuating selection have relied on abstract or weakly parameterized models, making it difficult to assess their relevance for natural populations. In this study, we simulate multilocus seasonally fluctuating selection acting on standing genetic variation under a recently developed model and examine its effect on the variance effective population size (Ne) at a genome-wide scale. By recapitulating genomic, demographic, and evolutionary parameters from natural Drosophila populations in our simulations, we were able to reproduce allele frequency oscillations reported in recent studies and show that these lead to ∼50% genome-wide reductions in Ne. We also demonstrate that Ne reductions are well predicted by the maximum frequency amplitude among all adaptively fluctuating loci, and that the frequency amplitudes are largely determined by the number of adaptively fluctuating loci and the strength of their epistatic interactions. Our results demonstrate that fluctuating selection can substantially reduce effective population size and underscore the importance of temporally variable selection in shaping genome-wide patterns of variation beyond classical models.

Drosophila melanogaster↗

PubMed2026

Association of FOXC1 Duplications With Juvenile Open-Angle Glaucoma.

IMPORTANCE: While FOXC1 single-nucleotide variants and deletions are well-established causes of Axenfeld-Rieger syndrome, few FOXC1 duplications have been reported. This study investigated families with duplications encompassing the FOXC1 gene to refine the associated phenotypic spectrum and contribution to glaucoma. OBJECTIVE: To investigate the prevalence and phenotype of FOXC1 duplications in 2 large glaucoma registries. DESIGN, SETTING, AND PARTICIPANTS: This retrospective observational genetic cohort study included participants recruited from the Australian & New Zealand Registry of Advanced Glaucoma (ANZRAG) and the Massachusetts Eye and Ear (MEE) cohort from 2008 through 2025. Participants with glaucoma, and available relatives, underwent genomic testing to identify duplications encompassing FOXC1 using exome sequencing and genotyping arrays (ANZRAG) or whole-genome sequencing (MEE). Data analyses were conducted from 2022 through 2025. MAIN OUTCOMES AND MEASURES: Prevalence of FOXC1 duplications, age at glaucoma onset, and phenotype, including ocular and systemic features. RESULTS: Twenty individuals from 10 families (50% female and 50% male; 70% self-described as broadly European [Australian/British, British, English/German, English/Polish, European, or Scottish], 25% as Asian [Chinese or Filipino], and 5% as Latin American [Salvadoran]) were identified with FOXC1 duplications. All genetically tested individuals were diagnosed with glaucoma, demonstrating high penetrance. Seventeen individuals were referred with juvenile open-angle glaucoma (JOAG), 1 with primary open-angle glaucoma, 1 with primary congenital glaucoma, and 1 with anterior segment dysgenesis. The diagnosis of 4 individuals from 1 family with ectropion uveae was revised to anterior segment dysgenesis. Systemic features were reported for 2 participants (10.5%), including subtle dental findings and mild facial dysmorphism. Duplications encompassing FOXC1 were among the most common monogenic contributors to JOAG. In the ANZRAG group, they accounted for 13.5% (95% CI, 6.7%-25.3%) of JOAG probands with a genetic diagnosis, second to MYOC (53.8%; 95% CI, 40.5%-66.7%). In the MEE group, FOXC1 duplications accounted for 9.5% (95% CI, 2.7%-28.9%) of JOAG probands with a genetic diagnosis. CONCLUSIONS AND RELEVANCE: These findings suggest FOXC1 duplications are an underrecognized, highly penetrant, but variably expressive, genetic variation associated with JOAG. Findings for the relatively modest number of individuals in the retrospective study were associated with wide confidence intervals. This limitation is often inherent to studies of JOAG, a rare condition for which individual genetic variants account for only a subset of cases. Despite this, the findings highlight the genetic heterogeneity of JOAG and support the potential importance of considering routine genetic copy-number variant analysis for individuals with JOAG.

Humans↗

PubMed2026

Seasonal fluctuations in fitness result in severe reductions in effective population size.

Genetic evidence for fluctuating selection has begun to accumulate for different species over the past few decades, especially for the Drosophila genus where studies have reported hundreds of loci undergoing putatively adaptive oscillations across successive seasons. However, most theoretical and simulation studies of fluctuating selection have relied on abstract or weakly parameterized models, making it difficult to assess their relevance for natural populations. In this study, we simulate multilocus seasonally fluctuating selection under a recently developed model and examine its effect on the variance effective population size (Ne ) at a genome-wide scale. By recapitulating genomic, demographic, and evolutionary parameters from natural Drosophila populations in our simulations, we were able to reproduce allele frequency oscillations reported in recent studies and show that these lead to ~50% genome-wide reductions in Ne . We also demonstrate that Ne reductions are well predicted by the maximum frequency amplitude among all adaptively fluctuating loci, and that the frequency amplitudes are largely determined by the number of adaptively fluctuating loci and the strength of their epistatic interactions. Our results demonstrate that fluctuating selection can substantially reduce effective population size and underscore the importance of temporally variable selection in shaping genome-wide patterns of variation beyond classical models.

Drosophila melanogaster↗