Sperm pass on more than just their DNA. Chemical switches attached to the genomes of sperm – known as epigenetic tags – have been shown to alter the next generation for the first time.
The discovery could explain how a father’s experiences may later affect gene activity in their offspring, a vital step towards improving health and fertility.
Throughout life, our environment changes the activity of our genes, switching them on or off without altering DNA. It does this by epigenetics – adding or removing regulatory chemical tags. Both smoking and diet can alter which genes are tagged in this way, and epigenetic changes have also been linked to cancer.
Over the past decade, a handful of studies have suggested that environmental stressors experienced by parents can also affect the health of their children and even grandchildren. One controversial mouse study suggested that even the fear of a particular smell can be passed down epigenetically (see “Sins of the grandfather“ below the article).
“The implication is that a father’s experiences might affect their offspring’s characteristics”
Sperm and egg genes can carry epigenetic tags, but it has been difficult to show that these affect offspring. Now Jerome Jullien at the Wellcome Trust CRUK Gurdon Institute in Cambridge and his colleagues have shown for the first time that sperm epigenetic tags do change gene expression in embryos – and that these tags are essential for healthy development.
They made their discovery by comparing frog embryos made from sperm with those made from spermatids, a type of sperm precursor cell. The embryos made from sperm developed much better, but the only difference between sperm and spermatids is their epigenetics.
As spermatids mature into sperm, they lose some of their epigenetic tags – specifically, those that turn genes on. But a second type of tag, which suppresses gene activity, remains. To see if these have any effect on the next generation, the team decided to get rid of them.
No one had managed to do this before, because the DNA in sperm is difficult to manipulate. But the team got around this by engineering eggs to do it for them. They made eggs that had enzymes that remove certain types of tags when the sperm or spermatid is injected into the egg to fertilise it.
By removing different combinations of tags, they discovered that those normally retained in the sperm are important for embryonic development. Removing them leads to abnormal gene expression in the embryo, followed by developmental problems (Genome Research, doi.org/bd66).
It used to be thought that sperm merely delivered the male genetic code to an embryo, says Jullien. “Now we’re showing that there is epigenetic information attached to the sperm that affects the expression of genes in an embryo – and that these genes are important for directing how that embryo develops.”
Your father's legacy
We know life can affect a man’s sperm – for example, obese men have several epigenetic tags on their sperm that are not present in the sperm of men who are of a healthy weight. But until now, we did not know if these tags could affect the next generation.
Now that Jullien’s team have shown that some tags in sperm are crucial for healthy embryos, it suggests that environmentally influenced tags acquired throughout a father’s life may also affect subsequent generations in a similar way.
“The obvious implication is that whatever experiences the father has in life that end up epigenetically modifying sperm cells might also be transmitted to the offspring and affect their genetic development and characteristics,” says Jullien.
This work teaches us about the importance of the epigenetic changes that occur in sperm genomes to subsequent embryonic development, says David Moore at Pitzer College in Claremont, California.
However, he says it is not clear whether the findings tell us anything about how traits acquired through a father’s life might be passed on, because the team did not look at frogs that had been exposed to different environments.
And there is another hurdle. Many researchers are not convinced that epigenetic changes can affect the next generation. After conception, all epigenetic marks are thought to be wiped clean, leaving the embryo with a blank slate. There is evidence that a few tags can escape such reprogramming, and the new findings suggest that it is important that they do, but Timothy Bestor at Columbia University Medical Center, New York, says he is still very sceptical. “Extraordinary claims require extraordinary proof,” he says.
Sins of the grandfather
Whether epigenetics can transmit environmentally acquired traits to subsequent generations is controversial, but there is some circumstantial evidence.
One survey of British parents showed that fathers who had started smoking before puberty – when the body is particularly sensitive to environmental stress – had sons who, aged 9, were significantly fatter than average, even after removing other influencing factors.
When the same team analysed diet in a remote area of Sweden, they found that people whose grandparents had been short of food between the ages of 9 and 12 seemed to live longer.
A 2013 study suggested that even memories can be epigenetically inherited. Researchers gave male mice electric shocks every time they were exposed to a sweet fragrance, until eventually the smell alone was enough to make them shudder. Subsequent pups feared the same smell, even though they hadn’t received any shock – and so did the next generation of pups.