New research by a scientist from the University of Bath’s Milner Center for Evolution suggests that “selfish chromosomes” explain why most human embryos die very early. The study, published in PLoS Biologyexplaining why fish embryos do well but unfortunately human embryos often do not survive has implications for the treatment of infertility.
About half of fertilized eggs die very early, before a mother even knows she is pregnant. Tragically, many of those who survive to become confirmed pregnancies will be spontaneously aborted after a few weeks. Such miscarriages are both remarkably common and very distressing.
Professor Laurence Hurst, director of the Milner Center for Evolution, has investigated why, despite hundreds of thousands of years of evolution, it’s still so difficult for humans to have babies.
The immediate cause of most of these early deaths is that the embryos have the wrong number of chromosomes. Fertilized eggs must have 46 chromosomes, 23 from mom in eggs, 23 from dad in sperm.
Professor Hurst said: “Very many embryos have the wrong number of chromosomes, often 45 or 47, and almost all of them die in the womb. Even in cases like Down syndrome with three copies of chromosome 21, unfortunately around 80% will not make it to term.”
Why then should the gain or loss of a chromosome be so common when it is also so deadly?
There are a number of clues that Hurst has collected. First, when the embryo has the wrong number of chromosomes, it is usually due to errors that occur when eggs are made in the mother, not when sperm are made in the father. In fact, more than 70% of eggs made have the wrong number of chromosomes.
Second, errors occur in the first of two stages of egg making. This first step, it had been noticed before, is vulnerable to mutations that interfere with the process, so 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 be somehow related to the problem of chromosome loss or gain.
What Hurst noticed is that, in mammals, a selfish mutation that tries to do it but fails, resulting in an egg with too many or too few chromosomes, may still be evolutionarily better off. In mammals, because the mother continually nurtures the developing fetus in the womb, it is evolutionarily beneficial for embryos developing from defective eggs to be lost earlier rather than carried. term. This means that surviving offspring are doing better than average.
Hurst explained: “This first step of egg making is strange. One chromosome of a pair will go to the egg, the other will be destroyed. But if one chromosome ‘knows’ that it is going to be destroyed, it doesn’t There’s nothing to lose, so for Remarkable recent molecular evidence has shown that when certain chromosomes detect that they are about to be destroyed during this first stage, they change what they are doing to avoid be destroyed, which could lead to loss or gain of chromosomes and 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 siblings who receive the extra food, the mutation is better off because it kills the embryos”.
“Fish and amphibians don’t have this problem,” Hurst commented. “In more than 2000 fish embryos, none were found with chromosomal errors from the mother”. Rates in birds are also very low, about 1/25th the rate in mammals. This, notes Hurst, is also predicted that there is some competition between the nestlings after they hatch, but not before.
In contrast, the loss or gain of chromosomes is a problem for all mammals studied. Hurst commented, “It’s a downside to nurturing our offspring in the womb. If they die early, the survivors benefit. It makes us vulnerable to this kind of mutation.”
Hurst suspects that humans may indeed be particularly vulnerable. In mice, the death of an embryo gives resources to the survivors of the same brood. This gives about a 10% increase in survivability of others. Humans, however, usually only have one baby at a time and the early death of an embryo allows a mother to quickly reproduce again – she probably never even knew her egg had been fertilized. .
Preliminary data show that mammals such as cows, with one embryo at a time, appear to have particularly high embryonic death rates due to chromosomal errors, while those with many embryos in a clutch, such as mice and pigs, seem to have somewhat lower rates.
Hurst’s research also suggests that low levels of a protein called Bub1 could lead to the loss or gain of a chromosome in humans as well as in mice.
Hurst said: “Levels of Bub1 decline as mothers age and the rate of embryonic chromosomal problems increases. Identifying these suppressor proteins and increasing their levels in older mothers could restore fertility.
“I also hope that these ideas will be a step to help women who are having difficulty getting pregnant or who suffer from repeated miscarriages.”
Chromosomal errors that develop early lead to embryonic loss in assisted reproductive technologies
Selfish centromeres and waste of human reproduction, PLoS Biology (2022). DOI: 10.1371/journal.pbio.3001671
Provided by the University of Bath
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