https://www.pnas.org/content/118/51/e2117557118

Significance
Comparative studies of humans and chimpanzees have revealed many
anatomical, physiological, behavioral, and molecular differences. However,
it has been challenging to map these differences to particular chromosome regions. Here, we develop a genetic approach in fused stem cell lines that makes it possible to map human–chimpanzee molecular and cellular
differences to specific regions of the genome. We illustrate this approach
by mapping chromosome regions responsible for species-specific gene
expression differences in fused tetraploid cells. This approach is general,
and could be used in the future to map the genomic changes that control
many other human–chimpanzee differences in various cell types or
organoids in vitro.


Abstract
Complete genome sequencing has identified millions of DNA changes that
differ between humans and chimpanzees. Although a subset of these
changes likely underlies important phenotypic differences between humans
and chimpanzees, it is currently difficult to distinguish causal from incidental
changes and to map specific phenotypes to particular genome locations. To facilitate further genetic study of human–chimpanzee divergence, we have generated human and chimpanzee autotetraploids and allotetraploids by
fusing induced pluripotent stem cells (iPSCs) of each species. The resulting tetraploid iPSCs can be stably maintained and retain the ability to differentiate along ectoderm, mesoderm, and endoderm lineages. RNA
sequencing identifies thousands of genes whose expression differs between humans and chimpanzees when assessed in single-species diploid or autotetraploid iPSCs. Analysis of gene expression patterns in interspecific allotetraploid iPSCs shows that human–chimpanzee expression differences
arise from substantial contributions of both cis-acting changes linked to the genes themselves and trans-acting changes elsewhere in the genome. To
enable further genetic mapping of species differences, we tested chemical treatments for stimulating genome-wide mitotic recombination between
human and chimpanzee chromosomes, and CRISPR methods for inducing species-specific changes on particular chromosomes in allotetraploid cells.
We successfully generated derivative cells with nested deletions or interspecific recombination on the X chromosome. These studies confirm
an important role for the X chromosome in trans regulation of expression differences between species and illustrate the potential of this system for
more detailed cis and trans mapping of the molecular basis of human and chimpanzee evolution.

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