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<p>The Spontaneously Hypertensive Rat (SHR) is a widely used model for hypertension and, more recently, for neuropsychiatric disorders such as ADHD and Substance Use Disorder (SUD). Despite a common origin, SHR substrains from different vendors exhibit distinct behavioral phenotypes, particularly in models of SUD. This study characterizes the genomic landscape of two such substrains, SHR/NCrl and SHR/NHsd, using high-fidelity long-read sequencing to identify genetic variants associated with their phenotypic divergence. We identified over 5.8 million variants shared by both substrains compared to the reference genome. These include high-impact variants in genes involved in blood pressure regulation, such as <i>Ramp2</i> and <i>Npy1r</i>, providing a potential genetic basis for their hypertensive phenotype. We also discovered 17,618 high-confidence variants unique to each substrain. From these, we selected 500 high-quality SNP markers suitable for genetic mapping studies, such as Reduced Complexity Crosses (RCCs). Computational predictions indicated moderate-impact variants in genes involved in neuroplasticity and synaptic function. Notably, the SHR/NHsd substrain carries unique missense variants in <i>Ptpro</i> and <i>Tenm2</i>, genes linked to glutamatergic synapses and SUD-related pathways. In contrast, the SHR/NCrl substrain has unique variants in genes such as <i>Wwc1</i> and <i>Pcdh10</i>, which are involved in synaptic plasticity and neurotransmission. These findings provide a critical genomic resource for dissecting the heritable components of SUD-related behaviors.</p>

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Long-read whole-genome sequencing of SHR rat substrains with distinct substance use phenotypes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月22日

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  • Adil Abdurahaman,
  • Paige M. Lemen,
  • Kathleen M. Kantak,
  • Britahny M. Baskin,
  • Camron D. Bryant,
  • Hao Chen

摘要

The Spontaneously Hypertensive Rat (SHR) is a widely used model for hypertension and, more recently, for neuropsychiatric disorders such as ADHD and Substance Use Disorder (SUD). Despite a common origin, SHR substrains from different vendors exhibit distinct behavioral phenotypes, particularly in models of SUD. This study characterizes the genomic landscape of two such substrains, SHR/NCrl and SHR/NHsd, using high-fidelity long-read sequencing to identify genetic variants associated with their phenotypic divergence. We identified over 5.8 million variants shared by both substrains compared to the reference genome. These include high-impact variants in genes involved in blood pressure regulation, such as Ramp2 and Npy1r, providing a potential genetic basis for their hypertensive phenotype. We also discovered 17,618 high-confidence variants unique to each substrain. From these, we selected 500 high-quality SNP markers suitable for genetic mapping studies, such as Reduced Complexity Crosses (RCCs). Computational predictions indicated moderate-impact variants in genes involved in neuroplasticity and synaptic function. Notably, the SHR/NHsd substrain carries unique missense variants in Ptpro and Tenm2, genes linked to glutamatergic synapses and SUD-related pathways. In contrast, the SHR/NCrl substrain has unique variants in genes such as Wwc1 and Pcdh10, which are involved in synaptic plasticity and neurotransmission. These findings provide a critical genomic resource for dissecting the heritable components of SUD-related behaviors.