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Screening for Functional Non-coding Genetic Variants Using Electrophoretic Mobility Shift Assay EMSA and DNA-affinity Precipitation Assay DAPA
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A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders.

Arthur S Lee1,2,3,4, Lauren J Ayers5, Michael Kosicki6

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Researchers developed a new single-cell multi-omic framework to identify non-coding variants in congenital cranial dysinnervation disorders (CCDDs). This approach aids in discovering genetic causes for rare diseases when coding variants are absent.

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Area of Science:

  • Genomics
  • Developmental Biology
  • Neuroscience

Background:

  • Unsolved Mendelian disorders often lack pathogenic coding variants, indicating non-coding regions may be implicated.
  • Congenital cranial dysinnervation disorders (CCDDs) are a group of Mendelian disorders affecting cranial motor neuron development.

Purpose of the Study:

  • To develop a single-cell multi-omic framework to identify cis-regulatory elements in cranial motor neurons (cMNs).
  • To nominate candidate non-coding variants in unsolved CCDD cases.
  • To establish a generalizable framework for discovering non-coding variants in other Mendelian disorders.

Main Methods:

  • Integrated single-cell chromatin accessibility, histone modification, and gene expression assays in embryonic mouse models.
  • Generated single-cell epigenomic profiles for approximately 86,000 cMNs and related cell types.
  • Validated enhancer activity using in vivo transgenic assays and applied the cMN atlas to whole genome sequences from unsolved CCDD pedigrees.

Main Results:

  • Identified approximately 250,000 accessible regulatory elements and 145,000 putative enhancers.
  • Validated 75% of tested elements, demonstrating single-cell accessibility predicts enhancer activity.
  • Nominated candidate non-coding variants regulating known CCDD genes (MAFB, PHOX2A, CHN1, EBF3) and identified variants in recurrently mutated enhancers.

Conclusions:

  • The study provides a powerful framework for discovering non-coding variants in CCDDs.
  • The findings highlight the importance of non-coding regulatory elements in Mendelian disorders.
  • The developed methodology is applicable to a broader range of genetic disorders.