Why Is It So Challenging for Humans To Have a Baby?

A research essay published in PLoS Biology suggests that “selfish chromosomes” identified in mammals could explain why so many human embryos are lost early in pregnancy.

Having a baby is not easy for humans

Getting pregnant and maintaining a pregnancy can be incredibly challenging for the human species. Approximately 40–60% of embryos are lost between fertilization and birth, in many cases without a mother knowing that she is pregnant. Unfortunately, one in eight recognized pregnancies will also end in miscarriage.

A common cause for embryo death in utero is aneuploidy – an excess or deficit of chromosomes. Gametes, or “sex cells” (the sperm and egg, in the case of human reproduction), possess half the number of chromosomes (23) as the other cells in the human body (46). When a sperm fertilizes an egg, the fertilized egg should possess a total of 46 chromosomes. However, this is often not the case, as Professor Laurence Hurst, director of the Milner Centre for Evolution, describes: “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.”

Considering that the human species has been evolving for thousands of years, the high prevalence of aneuploidy – which is so lethal to reproduction – has puzzled scientists. In a new essay, Hurst outlines several clues, collected through his study of reproduction across different organisms, which may help to explain why it can be so challenging for humans to have a baby.

The molecular mechanisms of aneuploidy

Aneuploidy is an issue that can often be traced back to the manufacturing of eggs, rather than sperm, with over 70% of eggs estimated to carry the incorrect number of chromosomes. The molecular processes that result in aneuploidy appear to occur in the first two stages of egg manufacturing. Research in mice suggests that the first step is susceptible to genetic mutations capable of “sneaking” into over 50% of eggs that, upon fertilization, “selfishly” force the partner chromosome to be destroyed. It has long been suspected that this mechanism, known as centromeric drive, also occurs in humans.

Selfish mutations that endeavor to force out the partner chromosome, but ultimately fail, result in fertilized eggs with the wrong number of chromosomes – aneuploidy. Interestingly, Hurst observed that, from an evolutionary standpoint, these mutations may possess an advantage. In mammals, he suggests that it is evolutionarily beneficial for embryos developing from eggs with the incorrect number of chromosomes to be lost, due to the energy expenditure required for a mother to continuously support the developing fetus in the womb.

Aneuploidy has been detected in every mammal that has been studied. However, when studying fish and amphibians – which do not carry their offspring – this problem has not been identified. “In over 2000 fish embryos, not one was found with chromosomal errors from mum,” Hurst describes. Chromosomal gain or loss is therefore a “downside” of feeding offspring in the womb, Hurst suggests.

Hurst believes that the human species – as mammals – could be vulnerable to the effect of “selfish” mutations. In mammals such as mice, which typically birth several pups in one litter, the death of an embryo offers resources to the survivors within the same litter. In humans, where a mother most commonly carries one baby at a time, the early death of an embryo with aneuploidy provides the opportunity for a mother to reproduce again, hopefully with a healthy pregnancy as the outcome.

“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,” – Hurst.

Hurst’s research also identified that a protein, known as Bub1, could be implicated in aneuploidy. “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,” he says.

“I would hope too that these insights will be one step to helping those women who experience difficulties getting pregnant, or suffer recurrent miscarriage,” Hurst concludes.

Reference: Hurst LD. Selfish centromeres and the wastefulness of human reproduction. PLOS Bio. 2022;20(7):e3001671. doi: 10.1371/journal.pbio.3001671.

This article is a rework of a press release issued by the University of Bath. Material has been edited for length and content.