A 20-year experiment cloning mice has revealed that clones develop significantly more genetic mutations than naturally reproduced mice, accumulating to fatal levels after multiple generations. Researchers led by Teruhiko Wakayama at Yamanashi University in Japan found over 70 mutations per clone generation on average, three times higher than in controls. The findings, published in Nature Communications, raise concerns for applications in farming, conservation and de-extinction efforts.
Teruhiko Wakayama at Yamanashi University in Japan began testing repeated cloning in mice in 2005 to assess the fidelity of the process. In 2013, his team reported success with 25 successive generations, producing more than 500 healthy mice that lived normal lifespans with no physical abnormalities. However, as cloning continued to the 58th generation, no clones survived, prompting genome sequencing of 10 mice from various generations. The analysis uncovered an average of more than 70 mutations per clone generation—three times as many as in naturally reproducing mice. Large-scale mutations emerged after the 27th generation, including the loss of an entire X chromosome. Wakayama noted, “Unfortunately, however, while clones were once thought to be identical to the original, it has become clear that this is not the case, suggesting that there may be issues with their use.” He suggested the nuclear transfer process might damage DNA due to physical shock and called for a gentler method, though none is yet available. Wakayama added, “Going forward, we need to demonstrate that mutations arising from cloning do not pose problems.” Shoukhrat Mitalipov at Oregon Health & Science University expressed skepticism, attributing higher mutation rates to the genomic state of donor adult cells rather than the cloning process itself. He emphasized selecting donor cells carefully, screening for variants and using gene editing if needed. The study builds on milestones like Dolly the sheep in 1996 and Wakayama's Cumulina mouse in 1997. While mutation rates remain relatively low per generation and screening is possible, the results highlight additional risks for cloning in agriculture, endangered species preservation and potential human therapies.
