New research from 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 Biologyexplaining why fish embryos do well but unfortunately human embryos often do not survive has implications for infertility treatment.
About half of the fertilized eggs die very early, before the mother even knows she is pregnant. Tragically, many of those who survive to a recognized pregnancy will miscarry after a few weeks. Such miscarriages are both remarkably common and very alarming.
Professor Lawrence Hirst, director of the Milner Center for Evolution, has investigated why, despite hundreds of thousands of years of evolution, it is still relatively difficult for humans to have a baby.
The immediate 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 the mother in the eggs, 23 from the father in the sperm.
Professor Hirst said: “A great 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, about 80% will unfortunately not make it to term.”
Why, then, should the gain or loss of a single chromosome be so common when it is just as deadly?
There are a number of clues that Hirst gathered. First, when an embryo has the wrong number of chromosomes, it is usually due to errors that occur when the eggs are made by the mother, not when the sperm are made by the father. In fact, over 70% of eggs produced have the wrong number of chromosomes.
Second, errors occur in the first of two steps in egg production. It was noticed that this first step is vulnerable mutations that interfere with the process so that the mutation can “selfishly” sneak into more than 50% of the eggs, forcing the partner chromosome to be destroyed, a process known as centromere drive. This has been well studied in mice, has long been suspected in humans, and was previously suggested to be somehow related to the problem of chromosome loss or gain.
What Hirst 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 superior. In mammals, because the mother feeds them continuously a developing fetus in utero, it is evolutionarily beneficial for embryos developing from defective eggs to be lost earlier rather than carried to term. This means that the surviving offspring will do better than average.
Hirst explained: “This first step of creation eggs that’s weird. One chromosome from a pair will go into the egg, the other will be destroyed. But if a chromosome “knows” it’s 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 destruction, potentially causing chromosome loss or gain and the death of the embryo.
“The remarkable thing is that if the death of the embryo benefits the other offspring of that mother, because the selfish chromosome will often be in the siblings that get the extra food, the mutation is better because it kills the embryos.”
“Fish and amphibians don’t have this problem,” Hirst commented. “In over 2,000 fish embryos, none with maternal chromosomal errors were found.” The percentages in birds are also very low, about 1/25 of the percentage in mammals. This, Hirst notes, is equally predictable, since there is some competition between the young after hatching, but not before.
Conversely, the loss or gain of chromosomes has been a problem for every mammal that has been studied. Hirst commented, “This is a disadvantage of feeding our offspring in the womb. If they die early, the survivors win. That makes us vulnerable to this kind of mutation.”
Hirst suspects that people may indeed be particularly vulnerable. In mice, the death of the embryo gives resources to the survivors in the same offspring. This gives about a 10% increase in the survival chance of the others. However, humans usually only have one baby at a time, and the early death of the embryo allows the mother to quickly reproduce again – 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 rates of embryonic mortality due to chromosomal errors, while those with many embryos in an offspring, 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 chromosome loss or gain in humans as well as in mice.
Hirst said: “Bub1 levels decline as mothers age and as the rate of embryonic chromosomal problems increases. Identifying these suppressor proteins and increasing their levels in older mothers may restore fertility.
“I also hope that these insights will be a step towards helping those women who have difficulty conceiving or suffer from recurrent miscarriages.”
Selfish centromeres and the wastefulness of human reproduction, PLoS Biology (2022). DOI: 10.1371/journal.pbio.3001671
University of Bath
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