A new study by a researcher at the Milner Center for Evolution at the University of Bath suggests that “selfish chromosomes” are to blame for the early demise of the majority of human embryos. The research, which was published in PLoS Biology, explains why human embryos often do not survive while fish embryos are fine. The finding also has implications for the treatment of infertility.
Before a woman even realizes she is pregnant, over half of fertilized eggs experience a very early death. Tragically, after a few weeks, many of those that do survive to become a recognized pregnancy abruptly abort themselves. Such miscarriages are shockingly frequent and incredibly distressing.
The Milner Centre for Evolution’s Director, Professor Laurence Hurst, looked into why, after thousands of years of evolution, it’s still very difficult for humans to have children.
The immediate cause of many of these early deaths is that the embryos have the wrong number of chromosomes. Fertilized eggs should have 46 chromosomes, 23 from mom in the eggs, 23 from dad in the sperm.
Professor Hurst said: “Very many embryos have the wrong number of chromosomes, often 45 or 47, and nearly all of these die in the womb. Even in cases like Down syndrome with three copies of chromosome 21, about 80% sadly will not make it to term.”
Why then should gain or loss of one chromosome be so very common when it is also so lethal?
There is a number of clues that Hurst put together. Firstly, when the embryo has the wrong number of chromosomes it is usually due to mistakes that occur when the eggs are made in the mother, not when the sperm is made in the father. In fact, over 70% of eggs made have the wrong number of chromosomes.
Secondly, the mistakes happen in the first of two steps in the manufacture of eggs. This first step, it had been noticed before, is vulnerable to mutations that interfere with the process, such that the mutation can “selfishly” sneak into more than 50% of the eggs, forcing the partner chromosome to be destroyed, a process known as centromeric drive. This is well studied in mice, long suspected in humans, and previously suggested to somehow relate to the problem of chromosome loss or gain.
What Hurst noticed was that, in mammals, a selfish mutation that tries to do this but fails, resulting in an egg with one too many or one too few chromosomes, can still be evolutionarily better off. In mammals, because the mother continuously feeds the developing fetus in the womb, it is evolutionarily beneficial for embryos developing from faulty eggs to be lost earlier rather than be carried to full term. This means that the surviving offspring do better than the average.
Hurst explained: “This first step of making eggs is odd. One chromosome of a pair will go to the egg the other will be destroyed. But if a chromosome ’knows’ it is going to be destroyed it has nothing to lose, so to speak. Remarkable recent molecular evidence has found that when some chromosomes detect that they are about to be destroyed during this first step, they change what they do to prevent being destroyed, potentially causing chromosome loss or gain, and the death of the embryo.
“What is remarkable, is that if the death of the embryo benefits the other offspring of that mother, as the selfish chromosome will often be in the brothers and sisters that get the extra food, the mutation is better off because it kills embryos.”
“Fish and amphibians don’t have this problem,” Hurst commented. “In over 2000 fish embryos not one was found with chromosomal errors from mom.” Rates in birds are also very low, about 1/25th the rate in mammals. This, Hurst notes, is as predicted as there is some competition between nestlings after they hatch, but not before.
By contrast, chromosome loss or gain is a problem for every mammal that has been looked at. Hurst commented, “It is a downside of feeding our offspring in the womb. If they die early on, the survivors benefit. It leaves us vulnerable to this sort of mutation.”
Hurst suspects that humans may indeed be especially vulnerable. In mice, the death of an embryo gives resources to the survivors in the same brood. This gives about a 10% increase in the survival chance of the others. Humans, however, usually just have one baby at a time and the death of an embryo early on enables a mother to rapidly reproduce again – she probably never even knew her egg had been fertilized.
Preliminary data shows mammals such as cows, with one embryo at a time seem to have especially high embryo death rates owing to chromosomal errors, while those with many embryos in a brood, like mice and pigs, seem to have somewhat lower rates.
Hurst’s research also suggests that low levels of a protein called Bub1 could cause the loss or gain of a chromosome in humans as well as mice.
Hurst said: “The levels of Bub1 go down as mothers get older and as the rate of embryonic chromosomal problems goes up. Identifying these suppressor proteins and increasing their level in older mothers could restore fertility.
“I would hope too that these insights will be one step to helping those women who experience difficulties getting pregnant, or suffer recurrent miscarriage.”
Reference: “Selfish centromeres and the wastefulness of human reproduction” by Laurence D. Hurst, 5 July 2022, PLoS Biology.
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