Textbooks make reproduction sound pretty straightforward – although, for many, the reality can be heartbreakingly complex. Miscarriages and other fertility issues are very common, and a new paper in the journal PLoS Biology says that these seemingly random complications may be caused by rejected chromosomes deliberately sabotaging the health of developing embryos.
Penned by Professor Laurence Hurst, Director of the Milner Center for Evolution at the University of Bath, the essay examines the mechanisms underlying aneuploidy: the development of an unusual number of chromosomes within a sperm, egg, or embryo.
During typical human reproduction, fertilized eggs should receive 23 chromosomes from each parent, giving a total of 46 – yet a high proportion end up with too many or too few, rendering them inviable and typically resulting in pregnancy loss.
“Very many embryos have the wrong number of chromosomes, often 45 or 47, and nearly all of these die in the womb,” explained Hurst in a statement. Staggeringly, it’s estimated that over 70 percent of human oocytes may be aneuploids, and research suggests that this anomaly usually arises during the first stage of egg production, known as meiosis I.
During this phase, half of all chromosomes are selected for transmission into eggs while the other half are discarded. However, Hurst says that some of these jilted chromosomes are able to “selfishly” sneak their way into the nascent oocyte via a process called centromeric drive, thus creating an aneuploid.
"If a chromosome 'knows' it is going to be destroyed it has nothing to lose, so to speak,” he explains. “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.”
From an evolutionary perspective, this might sound somewhat counter-productive, but there may be a logic to this apparent chaos – by sabotaging some offspring, the selfish chromosome ensures that other eggs and embryos have a greater chance of survival. Since some of these will contain copies of that particular chromosome, the chances of its genetic code being passed on to offspring is increased.
“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," says Hurst.
This “reproductive compensation” is only possible in mammals, which carry their developing young in the womb and nourish them continuously until birth, so it makes perfect sense that aneuploidy would occur so frequently in mammals.
For instance, in species that usually produce litters of young, the death of any aneuploid embryos within the brood ensures that remaining siblings receive more of the mother’s resources and therefore have a higher chance of survival. Human pregnancies, meanwhile, usually involve a single baby, and high miscarriage rates ensure that we don’t have to wait a full nine months before trying again. This means the selfish chromosome immediately gets another chance to be transmitted into an embryo.
In contrast, aneuploidy is almost unheard of in fish, which reproduce by releasing their eggs to be fertilized externally. That being the case, the death of one or more embryos has no bearing on the fate of the other offspring, so it makes no sense for chromosomes to adopt such as tactic.
Ultimately, then, Hurst proposes that human infertility occurs simply because “mammalian compensation leaves us vulnerable to selfish centromeres that induce aneuploidy,” and that future research into the mechanisms behind aneuploidy may lead to new treatments.