New research by a scientist at the Milner Center for Evolution at the University of Bath suggests that “selfish chromosomes” explain why most human embryos die very early. The study, published in PLoS Biologywhich explains why fish embryos are fine, but unfortunately human embryos often do not survive, has implications for infertility treatment.
About half of fertilized eggs die very early, before a mother even knows she is pregnant. Tragically, many of those who survive to become a recognized pregnancy will spontaneously abort after a few weeks. Such miscarriages are both remarkably common and deeply distressing.
Professor Laurence Hurst, director of the Milner Center for Evolution, explored why, despite hundreds of thousands of years of evolution, it is still so relatively difficult for humans to have a baby.
The direct cause of many of these early deaths is that the embryos have the wrong number of chromosomes. Fertilized eggs must have 46 chromosomes, 23 from mother in the eggs, 23 from father in the sperm.
Professor Hurst said: “A lot of embryos have the wrong number of chromosomes, often 45 or 47, and these almost all die in utero. Even in cases such as Down syndrome with three copies of chromosome 21, unfortunately about 80% will not in time.”
Then why would gain or loss of one chromosome be so common when it is also so deadly?
There are a number of clues that Hurst has put together. First, when the embryo has the wrong number of chromosomes, it is usually due to errors that occur when the eggs are made in the mother, not when the sperm is made in the father. In fact, more than 70% of the eggs produced have the wrong number of chromosomes.
Second, the mistakes happen in the first of two steps in the manufacture of eggs. This first step, noted earlier, is vulnerable to mutations that disrupt the process, so the mutation can “selfishly” sneak into more than 50% of the eggs, destroying the partner chromosome, a process known as centromere drive. This has been well studied in mice, long suspected in humans, and previously suggested that it is somehow related to the problem of chromosome loss or gain.
What Hurst noted 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, may still be evolutionarily better off. In mammals, because the mother continuously feeds the developing fetus in the womb, it is evolutionarily favorable for embryos developing from defective eggs to be lost earlier rather than carried to full term. This means that the surviving offspring are doing better than the average.
Hurst explained: “This first step of making eggs is strange. One chromosome from a pair will go to the egg, the other will be destroyed. But if a chromosome ‘knows’ it will be destroyed, it has nothing Notable recent molecular evidence has shown that when some chromosomes detect during this first step that they are about to be destroyed, they change their behavior to avoid being destroyed, potentially causing chromosome loss or gain and can cause the death of the embryo.
“Notably, if the death of the embryo benefits the other offspring of that mother, because the egotistical chromosome is often in the siblings who get the extra food, the mutation is better off because it kills embryos.”
“Fish and amphibians don’t have this problem,” Hurst noted. “In over 2000 fish embryos, not one was found with maternal chromosomal errors”. Rates in birds are also very low, about 1/25th the rate in mammals. This, Hurst notes, is as predicted because there is some competition between nestlings after they hatch, but not before.
In contrast, chromosome loss or gain is a problem for any mammal that has been viewed. Hurst noted, “It’s a disadvantage of feeding our offspring in the womb. If they die early, the survivors benefit. It makes us vulnerable to these kinds of mutations.”
Hurst suspects that humans are indeed particularly vulnerable. In mice, the death of an embryo gives resources to the survivors in the same brood. This gives about 10% more chance of survival than the others. However, humans usually only have one baby at a time, and the early death of an embryo allows a mother to reproduce quickly — she probably didn’t even know her egg was fertilized.
Preliminary data show that mammals such as cows, with one embryo at a time, appear to have particularly high embryo death rates due to chromosomal errors, while those with many embryos in a brood, such as mice and pigs, appear to have slightly lower rates.
Hurst’s research also suggests that low levels of a protein called Bub1 can cause loss or gain of a chromosome in both humans and mice.
Hurst said: “Levels of Bub1 decline as mothers age and as the number of embryonic chromosomal problems increases. Identifying these suppressor proteins and increasing their levels in older mothers could restore fertility.
“I also hope that these insights will be a step to help those women who are experiencing difficulties conceiving or are having a recurrent miscarriage.”
Chromosomal errors that develop early lead to embryonic loss in assisted reproductive technology
Selfish centromeres and the waste of human reproduction, PLoS Biology (2022). DOI: 10.1371/journal.pbio.3001671
Provided by the University of Bath
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