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Updated: Mar 11, 2026

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A programmable platform enabling targeted chromosome substitution and cross-species stability profiling.

Lei Shi1, Xiali Yang1, Mingdi Wu1

  • 1State Key Laboratory of Genome and Multi-omics Technologies, Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Key Laboratory of Gene Editing Technologies (Hainan), Ministry of Agriculture and Rural Affairs, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518120, China.

Protein & Cell
|March 10, 2026
PubMed
Summary

We developed a new method for creating chromosome substitution strains (CSS) using CRISPR/Cas9 and microcell-mediated chromosome transfer (MMCT). This platform (TEAM) enables precise chromosome replacement for studying complex traits and genome evolution in mammals.

Keywords:
CRISPR/Cas9MMCTchromosome eliminationchromosome substitution strains

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Area of Science:

  • Mammalian genetics
  • Chromosome engineering
  • Synthetic biology

Background:

  • Chromosome substitution strains (CSS) are valuable for dissecting complex traits.
  • Conventional CSS development is limited by iterative breeding and intraspecific compatibility.
  • Novel methods are needed for efficient and programmable chromosome replacement.

Purpose of the Study:

  • To develop a novel platform for creating chromosome substitution strains.
  • To enable programmable chromosome replacement using CRISPR/Cas9 and microcell-mediated chromosome transfer (MMCT).
  • To investigate the stability and functional consequences of substituting mouse Y chromosomes with homologous or heterologous Y chromosomes.

Main Methods:

  • Developed the Targeted chromosome Elimination And Microcell-mediated chromosome transfer (TEAM) platform.
  • Combined CRISPR/Cas9-mediated chromosome elimination with MMCT for chromosome replacement.
  • Generated intraspecies (mouse Y) and interspecies (human Y) chromosome substitutions in mice.

Main Results:

  • Intraspecies Y chromosome substitutions resulted in stable embryonic stem cells and viable adult males.
  • Interspecies human Y chromosome substitutions led to severe instability, DNA damage, and inflammation.
  • Human Y chromosome instability was linked to reduced CENP-A levels, leading to segregation errors and rearrangements.

Conclusions:

  • The TEAM platform facilitates programmable construction of mammalian chromosome substitution models.
  • Interspecies chromosome substitution poses significant stability challenges, impacting animal health and development.
  • This technology offers new avenues for investigating chromosomal function, genome evolution, and synthetic karyotype design.