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Functional screening and complex traits: human 21q22.2 sequences affecting learning in mice

D J Smith1, E M Rubin

  • 1Human Genome Center, Lawrence Berkeley National Laboratory, CA 94720, USA. des@ux5.lbl.gov

Human Molecular Genetics
|January 1, 1997
PubMed
Summary
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Researchers created an

Area of Science:

  • Genetics
  • Neuroscience
  • Developmental Biology

Background:

  • Mammalian genome libraries are typically propagated in single cells for in vitro gene discovery.
  • This study introduces an 'in vivo library' approach using YAC transgenic mice to propagate large genomic regions.

Purpose of the Study:

  • To establish and test an 'in vivo library' of a specific human chromosome region for gene discovery.
  • To identify genes influencing neural development and learning through functional screening of the mouse library.

Main Methods:

  • Construction of a 2 megabase (Mb) YAC transgenic mouse library for human chromosome 21q22.2.
  • Functional screening of the YAC transgenic mice to identify behavioral deficits, specifically learning impairments.
  • Localization of the causative gene through analysis of YAC fragmentation in founder lines.

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Main Results:

  • A 570 kilobase (kb) YAC identified in two founder lines was associated with significant learning deficits.
  • The responsible gene was identified as the human minibrain gene (MNB).
  • Homolog of minibrain in Drosophila also showed association with learning defects.

Conclusions:

  • Altered dosage of the minibrain gene is linked to abnormal neural development in both flies and mice.
  • The minibrain gene may play a role in the molecular pathology of Down syndrome.
  • The 'in vivo library' approach is effective for in vivo gene discovery and functional analysis.