Biology subjects

Hytönen, M. K.

Publications and source records attributed to Hytönen, M. K..

4 recordsLinked to original sources

bioRxiv2026

The DoGA Consortium Atlas of Canine Enhancers and Promoters Across Tissues and Development

The domestic dog is a powerful genetic model for complex traits, disease and behaviours relevant to human biology, yet the canine genome still lacks a systematic transcription-defined atlas of regulatory elements. Existing resources have improved annotation but largely infer regulatory activity from chromatin features rather than directly mapping transcription initiation at promoters and enhancers. Here, we address this gap using 114 CAGE-seq libraries spanning 56 tissues and developmental stages from 9 dogs. We identify 68,446 promoters and 46,661 active enhancers, and define their tissue-enriched activity across the canine body. Regulatory programmes are organized around shared transcription factor motif infrastructures, with prominent enrichment of KLF family motifs across tissues. The cerebellum emerges as a major regulatory hub, showing the highest density of enhancer-promoter interactions among brain regions. During embryogenesis, enhancer activity shifts from early neurodevelopmental patterning programmes, including OTX2 and ZIC1/4, towards regulators of functional maturation and synaptic organization, including AQP4 and NLGN3. Comparative analyses revealed 69 enhancers with highly similar regulatory structures linked to potential orthologous genes in dog and human. Together, these data establish a tissue-resolved transcription-based atlas of the canine regulatory genome that advances functional annotation and improves interpretation of non-coding variation in comparative and disease genomics.

genomics↗

bioRxiv2025

A nonsense mutation in the PRKG2 gene in Dalmatian dogs with chondrodysplasia

Skeletal dysplasias encompass a diverse group of genetic disorders characterized by short stature and dwarfism. In humans, 771 types of skeletal dysplasia have been documented. Similar forms of these disorders have also been observed in dogs. The first cases of documented skeletal dysplasia in Dalmatian dogs were reported in the early 1980s, with additional affected dogs observed in subsequent years. Careful radiological and histopathological examinations at the time revealed severe limb deformities, including shortened radii and ulnae, irregular growth plates and disrupted endochondral ossification. In this study, we applied whole-genome sequencing on samples collected in 1992 and identified a genetic variant in the PRKG2 gene, introducing a premature stop codon (XM_038582312: c.T1601G, p.L534X). Genetic variants in PRKG2 have previously been implicated in human acromesomelic dysplasia, a disorder affecting limb growth in young children. The PRKG2-encoded protein plays a crucial role in endochondral ossification, and if translated, the identified nonsense variant would result in a truncated protein lacking most of the catalytic domain. Extended screening of the genetic variant revealed its continued segregation in the current Dalmatian population. Furthermore, three recent cases of dwarfism in Dalmatians were found to be homozygous for the identified PRKG2 nonsense variant. These findings provide compelling evidence for the role of PRKG2 in Dalmatian dwarfism, resolving a decades-old genetic mystery in the breed.

genetics↗

bioRxiv2024

A genotype-first approach identifies variants for orofacial clefts and other phenotypes in dogs

Dog breeding promotes within-group homogeneity through conformation to strict breed standards, and also drives between-group heterogeneity in pursuit of characteristic breed traits. There are over 350 recognized dog breeds that provide the foundation for investigating the genetic basis of phenotypic diversity. Typically, breed standard phenotypes such as stature, fur length, and craniofacial structure are analyzed in genetic association studies. However, such analyses are limited to the assayed phenotypes, leaving difficult to measure phenotypic subtleties potentially overlooked. In this study, the genotype-first approach was adapted to the dog genome to investigate coding variation from over 2000 dogs, leading to discoveries of new mutations related to craniofacial morphology and stature. Breed-enriched variants were prioritized according to gene constraint, which was calculated using a mutation model derived from trinucleotide substitution probabilities in the dog. Among the discovered variants was a splice-acceptor mutation in PDGFRA associated with bifid nose, a characteristic trait of Catalburun dogs, implicating the genes role in midline closure, and a frameshift mutation in LCORL associated with large canine body size, thus highlighting the importance of allelic heterogeneity in selection for breed traits. Most priority variants were not associated with genomic signatures for breed differentiation, as these regions were enriched for constrained genes intolerant to nonsynonymous variation, suggesting a model of breed phenotype diversification based on regulatory changes to essential genes. Identification of trait-associated variants in dogs informs new biological roles for genes. Improved collection of breed disease risk data, along with increased breed representation, will drive further discoveries.

genomics↗

bioRxiv2024

IP3 receptor depletion in a spontaneous canine model of Charcot-Marie-Tooth disease 1J with amelogenesis imperfecta

Inositol 1,4,5-trisphosphate receptors (IP3R) mediate Ca2+ release from intracellular stores, contributing to complex regulation of numerous physiological responses. The involvement of the three IP3R genes (ITPR1, ITPR2 and ITPR3) in inherited human diseases has started to shed light on the essential roles of each receptor in different human tissues and cell types. Variants in the ITPR3 gene, which encodes IP3R3, have recently been found to cause demyelinating sensorimotor Charcot-Marie-Tooth neuropathy type 1J (CMT1J). In addition to peripheral neuropathy, immunodeficiency and tooth abnormalities are occasionally present. Here, we report the identification of a homozygous nonsense variant in the ITPR3 gene in Lancashire Heeler dogs, presenting with a severe developmental enamel defect and reduced nerve conduction velocity. We studied the primary skin fibroblasts of the affected dogs and observed that the nonsense variant in ITPR3 led to a complete absence of full-length IP3R3 protein. Unexpectedly, the protein levels of IP3R1 and IP3R2 were also markedly decreased, suggesting co-regulation. Functional Ca2+ measurements revealed reduced IP3R-mediated Ca2+ flux upon stimulation of G-protein-coupled-receptors in the affected dog fibroblasts. We were able to rescue the IP3R1 and IP3R2 depletion by proteasome inhibition but not the IP3R3 loss, which was facilitated by nonsense-mediated mRNA decay. These findings highlight the first spontaneous mammalian phenotype caused by a nonsense variant in ITPR3, leading to the loss of IP3R3. The human and canine IP3R3 proteins are highly similar, and our study suggests that the tissue involvement resulting from the receptors dysfunction is also conserved. In summary, IP3R3 is critical for enamel formation and peripheral nerve maintenance. Author summaryWe investigated pet dogs, Lancashire Heelers, with impairments in tooth development and in the nerves that regulate limb muscles. Through genetic studies of the dog pedigree, we found that the phenotypes were caused by a recessively inherited mutation in the ITPR3 gene, which encodes one of three IP3 receptors (IP3R) isoforms (IP3R3 isoform) that are needed for intracellular Ca2+ signaling. Mutated IP3R3 has been recently linked to a human inherited neuropathy called Charcot-Marie-Tooth disease type 1J, which impairs peripheral nerve function and is accompanied by immunodeficiency and abnormal teeth in some individuals. We showed that in the skin cells of the affected dogs, the full-length IP3R3 protein was completely absent, and also the protein levels of the other two IP3R isoforms (IP3R1 and IP3R2) were severely lowered. This led to impaired agonist-induced Ca2+ release and signaling. Our results demonstrate the high conservation between human and canine IP3 receptors and their significance for different tissue systems. The genetic studies now highlight that IP3R3 is vital for peripheral nerve function and enamel development.

genetics↗