Most DNA in organisms is inherited from its parent or parents. This form of genetic inheritance is referred to as vertical inheritance because genes are passed down from generation to generation.

In contrast, organisms can acquire DNA from organisms of the same species or other species outside of asexual or sexual reproduction through a process called horizontal gene transfer. For example, bacteria can take up free-floating DNA from dead bacteria in the environment. Bacteria can also form a tube between cells to exchange DNA. These mechanisms can spread antibiotic resistance genes among bacteria.

Eukaryotic organisms (whose cells contain nuclei) can also acquire genetic material through horizontal gene transfer by taking up DNA from the environment and through viral infection, but genome-scale transfers between distantly related eukaryotes are rarely documented.

More than 1.5 billion years ago, an ancestral eukaryotic cell engulfed a cyanobacterium, a type of photosynthetic bacterium, which eventually evolved into the chloroplasts (cell structures where photosynthesis occurs to produce energy from sunlight) found in present-day algae and plants. During this evolutionary process, many genes from the engulfed cyanobacterium were transferred to the host cell’s nuclear genome, allowing the two organisms to become an integrated biological system. This ancient event gave rise to the ancestors of modern red algae, green algae and land plants, demonstrating how the transfer of genetic material across species boundaries can lead to the evolution of entirely new cellular functions.

Despite our current understanding of how horizontal gene transfer occurs between prokaryotic organisms (which are single-celled and lack a nucleus), scientists have had little direct evidence of what happens when chromosome-scale foreign DNA enters a eukaryotic host cell. To address this knowledge gap, a research team led by scientists from the University of Tokyo recently designed a series of experiments to create “planimal” cells — mammalian cells containing algal DNA — to better characterize horizontal gene transfer in mammalian cells. The results are published in the journal Nature Communications.

“We wanted to understand whether entire chromosomes could cross the enormous evolutionary divide between algae and animals and whether animal cells could stably maintain and pass on such foreign genetic material to their daughter cells,” said Professor Sachihiro Matsunaga from the Laboratory of Integrated Biology at the University of Tokyo and senior author of the research study. “We also wanted to discover how animal cells accommodate DNA from such a different organism without losing their ability to survive and divide. These questions are fundamental to understanding how genetic material can move across species boundaries and contribute to evolution.”

Inspired by the ancient event more than an eon and half ago, the research team investigated genome transfer by fusing photosynthetic algal cells with hamster-derived mammalian cells or allowing the mammalian cells to engulf the algae. They found that cell fusion produced stable hybrid cells much more efficiently than engulfment. The team used live-cell imaging and genome sequencing to characterize how the host manipulated algal DNA over a number of generations. In one hamster-derived cell line, approximately 16.3 million base pairs of algal nuclear DNA — including intact chromosomes and sequences from all 20 algal chromosomes — were retained. Algal DNA remained detectable through 155 cell generations, with substantial portions persisting for 95 generations without antibiotic selection (a technique used to isolate genetically modified cells and generate stable cell lines).

“Plants and animals cannot reproduce with each other, so their chromosomes are never combined through mating. Yet, we have succeeded in creating hybrid chromosomes containing genetic material from both an alga and a mammal, and have shown that this genetic material can be stably passed on to daughter cells through repeated cell divisions,” said Matsunaga. “Remarkably, our planimal cells retained nearly an entire algal genome over many generations. This demonstrates that even the vast evolutionary divide between plants and animals can be crossed at the level of chromosomes, without reproduction.”

The researchers also found that most transferred algal genes were inactive, while the foreign DNA acquired DNA methylation and repressive histone marks, modifications associated with gene silencing. When the team repeated the experiment using hamster cells lacking DNMT3A, an enzyme involved in establishing DNA methylation, fewer stable hybrid colonies formed and the resulting cells retained less algal DNA. Together, the findings suggest that epigenetic “gatekeeping” (involving changes in gene function without altering the DNA sequence) helps mammalian cells accommodate large amounts of foreign DNA while keeping most imported genes inactive.

With about 96% of the transferred algal protein-coding genes showing no detectable expression, the team hopes to learn how selected algal genes might be switched back on.

“Our next challenge is to selectively switch on the genes we need and make them work inside animal cells,” said Matsunaga. “The red alga we use has a remarkably compact genome containing genes for metabolic functions that animal cells do not possess. Our ultimate goal is to activate these biological pathways and give animal cells some of the unique abilities of plants and algae. Imagine animal cells that could sustain photosynthesis for long periods, producing oxygen while using carbon dioxide to make useful organic compounds.”

The present study did not produce photosynthetic animal cells. Achieving this remains a long-term goal that will require functional chloroplasts and further engineering.

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Funding:
This research was supported by JST CREST (JPMJCR20S6), JST GteX (JPMJGX23B4), JST ASPIRE (JPMJAP2306), JST SPRING (JPMJSP2108), JST FOREST (JPMJFR2316), KAKENHI (24H02325 and 26H02362), KAKENHI (24H02323 and 26K23176), KAKENHI (25H01308), KAKENHI (26K02026), KAKENHI (25K22564), KAKENHI (23H04957, 23H04962, 25K02339 and 26H01791), KAKENHI (26K23769) and the Data Scientist Training/Education Program at The University of Tokyo.

Useful links:
Graduate School of Frontier Sciences
https://www.k.u-tokyo.ac.jp/en/index.html

Laboratory of Integrated Biology
https://park.itc.u-tokyo.ac.jp/matsunaga_lab/english/index.html

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