Is the ability to withstand stress inherited from the “mother” considered a cheat?

Produced by: Science Popularization China

Produced by: Jiang Mengping (Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences)

Producer: Computer Network Information Center, Chinese Academy of Sciences

You may have heard something like this:

"You are so smart, your mother must be very smart too, right?"

"Your mother and grandmother lived such long lives, you will surely live a long life too."

These statements are all discussing the influence of mothers on their offspring, and indeed there are studies showing that the intelligence and lifespan of offspring are closely related to the mother.

Image source: Veer Gallery

However, today's article is not about these, but about another genetic phenomenon related to the mother - maternal inheritance of stress memory.

Can stress memory in nematodes be inherited across generations?

When subjected to environmental stress, organisms will produce adaptive stress responses to resist environmental stress. Can this stress response be passed on to offspring?

Earlier this month, the latest research results of Tian Ye's research group at the Institute of Genetics and Developmental Biology of the Chinese Academy of Sciences gave a positive answer to this question. They published an article titled "Neuronal mitochondrial stress induces transgenerational inheritance of stress memory by increasing the copy number of mitochondrial DNA in offspring" online in the journal Nature Cell Biology as a cover article, reporting the transgenerational inheritance phenomenon of nematode stress memory.

What is this nematode? Friends who are familiar with biology may know that nematodes are a classic model organism. They are transparent and the adult body is only 1mm long. However, their tiny bodies contain complete differentiated tissues and even a nervous system called a "brain".

Nematode (Image source: keys.lucidcentral.org)

Since the beginning of the 21st century, six scientists have won the Nobel Prize for their achievements using nematodes as experimental subjects, making nematodes a super star in the field of life science research.

Can you imagine that a millimeter-sized nematode can inherit stress memory across generations? Researchers have expressed the pathogenic gene of Huntingdon's disease in the neurons of nematodes, causing mitochondrial damage in the neurons and inducing the mitochondrial unfolded protein response (UPRmt) in the intestinal cells of nematodes across tissues and cells - a protective stress response of the nematode body. This cross-tissue communication of mitochondrial stress can help nematodes better cope with local mitochondrial damage.

When these nematodes mated with wild-type nematodes, 30% of the wild-type offspring that did not carry the disease-causing protein showed induction of UPRmt signals, that is, a stress response. Moreover, among the offspring that showed stress responses, 80% of them continued to pass the UPRmt signal to the second generation.

Incredibly, the researchers still observed this stress signal in the 50th generation of nematodes, indicating that the mother's stress memory can be inherited by offspring, even for more than 50 generations.

The stress memory of nematodes can be inherited for more than 50 generations (Image source: Reference 1)

The genetic code of stress memory

How does this stress memory achieve transgenerational inheritance? The answer lies in the number of copies of mitochondrial DNA (mtDNA).

Normally, there are multiple copies of mitochondrial DNA in a cell. The multi-copy nature of mitochondrial DNA is considered a self-protection mechanism, because most mitochondrial diseases require a certain proportion of gene mutations to occur.

For example, the more common mitochondrial diseases among maternal genetic diseases: Leber hereditary optic neuropathy (LHON), non-syndromic deafness, etc., require a gene mutation rate of more than 99.5%.

When the mitochondria in the nematode neurons are damaged, the neurons will communicate with the gonads, and through the Wnt pathway, the number of mitochondrial DNA copies in the offspring will increase. Excessive copies will cause an imbalance in the homeostasis of proteins in the mitochondria, which will then induce the body to activate UPRmt. This is the principle of transmitting stress memory through mitochondria.

In fact, the UPRmt induced by the increase in the number of mitochondrial DNA copies in the offspring has multiple effects on the body. Compared with their wild-type counterparts, these nematodes that inherited the maternal stress mechanism had a significantly increased lifespan and showed resistance to heat stress and paraquat.

However, you can't have your cake and eat it too. These individuals with greater resilience and longer lifespans have slowed development and reduced fertility.

Since mitochondrial DNA can only be obtained from the mother, this stress memory is inherited through the maternal line. Even if the offspring do not experience stress damage, they can still inherit the stress memory of the "mother", stand on the "mother's shoulders", and become stronger.

What is maternal inheritance? How does it differ from paternal inheritance?

So what exactly is maternal inheritance?

Before answering this question, let us first understand paternal inheritance. We know that genetic material mainly exists in chromosomes. Of the 46 chromosomes in an average person's body, half come from the mother and half from the father.

For men, what they get from their fathers are 22 autosomes and one sex chromosome Y. Some specific gene fragments only exist on the Y chromosome, and these fragments can only be inherited by boys.

This phenomenon of being passed from father to son and inherited along with the Y chromosome is called paternal inheritance. For example, human external auditory canal hypertrichosis and duck webbed disease are two common paternal inherited symptoms.

So, does maternal inheritance refer to some genes that can be passed on to daughters through the mother's X chromosome?

This is too simplistic, because maternal inheritance has nothing to do with the X chromosome.

Yes, it does matter! In genetics, maternal inheritance refers specifically to the mitochondrial DNA inheritance mentioned above.

In addition to chromosomal DNA, human genetic material also exists in mitochondrial DNA (accounting for about 1% to 2% of total DNA).

Mitochondria and mitochondrial DNA (Image source: Veer Gallery)

You may be confused. The father also has mitochondria, so why must mitochondrial inheritance be maternal?

This is because the mitochondria in the father's sperm are very few and are strictly monitored, and will be quickly degraded after fertilization.

Therefore, an individual that develops from a fertilized egg will only carry mitochondria from the mother, and these mitochondria will only be passed on to offspring through daughters. This is maternal inheritance. Isn’t it amazing!

The controversial "Mitochondrial Eve"

Mitochondrial DNA can only be inherited through the maternal line, so what is its origin?

In the 1980s, Wilson's genetics team at the University of California, Berkeley, found that modern human mitochondrial DNA can be divided into two categories: the first category is only found in some Africans, and the other category is distributed in all races including Africans, and its ultimate source is also Africans.

After further research, Wilson's research team believes that in ancient times, there was a common ancestor of mankind, and the mitochondrial DNA in all modern humans originated from this woman, who is the famous "Mitochondrial Eve". Once the "Eve" theory was proposed, it attracted the attention of many people and also caused great controversy.

Of course, we need to note that although the origin of mitochondria is related to the origin of humans, they can by no means be equated.

"Mitochondrial Eve" model: The mitochondrial DNA of modern humans can be traced back to a single woman

(Image source: Reference 4)

"Survival of the fittest", only with stronger adaptability can one survive in harsher environments.

The nematodes are lucky. They do not need to go through the "pain" of their mothers to acquire their adaptability. The maternal "ancestors" of the nematodes really worry about their "offspring and grandchildren". Mitochondrial DNA is very stable, and the mothers choose it as a carrier of stress memory, which is very smart.

Through the cross-generational inheritance of nematodes, we see the inheritance of life and the great wisdom of mothers.

References

1. Zhang, Q., Wang, Z., Zhang, W. et al. The memory of neuronal mitochondrial stress is inherited transgenerationally via elevated mitochondrial DNA levels. Nat Cell Biol (2021). https://doi.org/10.1038/s41556-021-00724-8

2. Cann RL, Stoneking M, Wilson AC (1987), "Mitochondrial DNA and human evolution", Nature, 325 (6099): 31-36

3. Lewin R (1987). "The unmasking of mitochondrial Eve". Science. 238 (4823): 24–26. Bibcode:1987Sci...238...24L. doi:10.1126/science.3116666. PMID 3116666.

4.https://commons.wikimedia.org/wiki/File:MtDNA-MRCA-generations-Evolution.svg