Biology subjects

Bredemeyer, K. R.

Publications and source records attributed to Bredemeyer, K. R..

3 recordsLinked to original sources

bioRxiv2026

Comparative Genomics Reveals the Ancestral Recombination Landscape of Placental Mammals

Meiotic recombination is a crucial biological process that ensures proper chromosomal pairing and promotes adaptation. In placental mammals, recombination rates vary widely across species, populations, sexes, individuals, and chromosomes. While the placental X chromosome shows remarkable conservation of both gene order and the recombination landscape across deep evolutionary history, it is unknown whether similar levels of autosomal conservation persist despite extensive chromosomal evolution. Here, we reconstructed an ancestral placental mammal karyotype from chromosome-level assemblies, using slow rates of karyotypic evolution, and inferred an ancestral autosomal recombination map. Analysis of phylogenetic branch lengths and PhyloP-based scores of evolutionary constraint reveals that conserved autosomal regions with low recombination rates have evolved under stronger purifying selection, whereas regions with conserved high recombination rates are less constrained and freer to evolve. Ancestral autosomal regions with low recombination rates were enriched for pathways and GO terms related to cellular function, whereas ancestral regions with high recombination rates were enriched for regulation and some immune-related systems. Tracking the fate of these conserved ancestral recombination hotspots and coldspots across 13 mammal lineages with variable rates of karyotype evolution revealed the retention of autosomal AHRs, but the absence of autosomal ALR conservation. Collectively, our findings reveal variable levels of evolutionary constraint at meiotic recombination in relation to karyotypic evolution, providing new insights into how natural selection influences the evolution of chromosomal organization.

genomics↗

bioRxiv2022

A genomic timescale for placental mammal evolution

The precise pattern and timing of speciation events that gave rise to all living placental mammals remain controversial. We provide a comprehensive phylogenetic analysis of genetic variation across an alignment of 241 placental mammal genome assemblies, addressing prior concerns regarding limited genomic sampling across species. We compared neutral genome-wide phylogenomic signal using concatenation and coalescent-based approaches, interrogated phylogenetic variation across chromosomes and analyzed extensive catalogs of structural variants. Interordinal relationships exhibit relatively low rates of phylogenomic conflict across diverse datasets and analytical methods. Conversely, X-chromosome versus autosome conflicts characterize multiple independent clades that radiated during the Cenozoic. Genomic timetrees reveal an accumulation of cladogenic events before and immediately following the KPg boundary implying important roles for Cretaceous continental vicariance and the KPg extinction in the placental radiation. One-Sentence SummaryA comprehensive whole genome phylogeny of extant placental mammals reveals timing and patterns of ordinal diversification.

evolutionary biology↗

bioRxiv2021

Development of an ASO therapy for Angelman syndrome by targeting an evolutionarily conserved region at the start of the UBE3A-AS transcript

Angelman syndrome is a devastating neurogenetic disorder for which there is currently no effective treatment. It is caused by mutations or epimutations affecting the expression or function of the maternally inherited allele of the ubiquitin-protein ligase E3A (UBE3A) gene. The paternal UBE3A allele is imprinted in neurons of the central nervous system (CNS) by the UBE3A antisense (UBE3A-AS) transcript, which represents the distal end of the SNHG14 transcription unit. Reactivating the expression of the paternal UBE3A allele in the CNS has long been pursued as a therapeutic option for Angelman syndrome. Here, we designed and optimized antisense oligonucleotides (ASO) targeting an evolutionarily conserved region demarcating the start of the human UBE3A-AS transcript and show that ASOs targeting this region can reverse imprinting of UBE3A in cultured Angelman syndrome neurons and throughout the CNS of a non-human primate model. Findings from this study advanced the first investigational molecular therapy for Angelman syndrome into clinical development (ClinicalTrials.gov, NCT04259281). SUMMARYHere, we describe the preclinical studies supporting the first investigational molecular therapy for Angelman syndrome to advance into clinical development (ClinicalTrials.gov, NCT04259281).

genetics↗