Groundbreaking Discovery: Immune-Like Mechanism Safeguards Fertility

New insights into a sophisticated process that protects sperm cells has revealed a mechanism, similar to an immune system, thwarts genetic chaos during the earliest stages of their development. The study discovered a "nowhere-to-hide" mechanism that scans for threats and protects early-stage precursors to sperm, known as germ cells, from damage that could lead to a premature death. The study is published in the journal Nature. Sperm cells' biggest challenge starts long before the journey to reach the egg, as they are particularly vulnerable during the earliest stages of their development, as germ cells in developing embryos. Germ cells must protect their DNA from damage during the embryo's development so they can become the pool of self-renewing cells that produce healthy sperm throughout adult life. Much like an immune surveillance system, the mechanism scans the genome, neutralizing threats from rogue genes, known as jumping genes, while avoiding damaging a multitude of other essential genes. The results provide new insights into the elusive process that gives germ cells "genetic immortality"—escaping an early death to pass genetic information successfully from parents to their offspring. Disruptions in this pathway could provide new insights into certain unexplained forms of male infertility, which have long been suspected of having genetic causes, researchers say. How germ cells defend themselves During their development, germ cells undergo a reprogramming process that leaves them vulnerable to jumping genes, which can damage their DNA and lead to infertility. "Our immune system protects us from outside threats. But in germ cells the threat is coming from inside the house, from a subset of their own genes. Jumping genes can move around the genome, controlling how our genes are used, but their activity needs to be carefully regulated to avoid them causing damage. Left unchecked, jumping genes can lead to genetic chaos for germ cells and ultimately destroy them," explains lead author of the study, Professor Dónal O'Carroll at the University of Edinburgh. Previous studies by the researchers had revealed parts of the mechanism that protects germ cells, but it's unclear how it is able to precisely target and disable all jumping genes across the genome. University of Edinburgh researchers studied the development of germ cells in mouse embryos to better understand the biological pathway that protects them from jumping genes. The team's earlier research found that two genes, SPOCD1 and C19orf84, recruit protective chemical tags, known as DNA methylations, to disable jumping genes during the reprogramming process. Germ cells are extremely vulnerable to damage during reprogramming as it temporarily wipes their genetic slate clean of existing protective tags, making this mechanism an essential line of defense. Discovering the genomic blind spot But tests in male mice embryos revealed a potential 'genomic blind spot' for this mechanism as the methylation machinery is only found in easily accessible parts of the genome. This leaves structural parts of the genome, known as heterochromatin, which control how DNA is organized in cells, as potential 'safe harbors' for jumping genes as the machinery can't access these regions. The researchers found that SPOCD1 interacted with a protein, known as TPR, which prevents SPOCD1 and its target jumping genes from becoming incorporated into heterochromatin. In mouse embryos, mutations to the SPOCD1 gene led to infertility as it was not able to form a complex with TPR to prevent relocation of jumping genes into heterochromatin regions. "TPR forms a complex with SPOCD1, providing a surveillance checkpoint that ensures that jumping genes do not get the opportunity to hide, eliminating blind spots in the genome. Like an immune system, this sophisticated mechanism eliminates all jumping gene 'threats' while avoiding 'autoimmunity' by ensuring that other genes are not caught in the crossfire," says first author of the study, Tamoghna Chowdhury. Implications for male infertility Missing even one of the 100 active jumping genes among the approximately 20,000 genes in the human genome could severely damage germ cells and lead to infertility. Equally, accidently disabling other genes crucial for healthy embryo development or that have other essential functions could lead to death of the embryo or disease in adults. Earlier research by the group revealed that rare mutations of SPOCD1 and other known genes in this pathway could explain some rare cases of the most severe forms of male fertility. Cryptozoospermia and azoospermia, in which little or no sperm is produced, affects around 1% of men. The study also involved researchers from Zhejiang University.