A Benefit of Failed Pregnancy?

Scientists find a common genetic variant in mothers that decreases the chance of successful pregnancy.

By | April 9, 2015

Mis-segregating chromosomesSTEFANO SANTAGUIDA, ANGELIKA AMON, MITAneuploidy—the incorrect number of chromosomes in a cell—is extremely common in early embryos and is the primary reason for pregnancy loss. A report published today (April 9) in Science reveals that one cause of this aneuploidy—aberrant cell divisions in the embryo—is linked to a genetic mutation carried by the mother. Astonishingly, this mutation turns out to be very common and appears to have been under positive selection during human evolution.

“There’s this genetic variant that they’ve been able to identify with very nice evidence for positive selection, but that has a fitness consequence, a fecundity consequence . . . that decreases the viability of an embryo,” said evolutionary geneticist Ed Green of the University of California, Santa Cruz, who was not involved in the work. “It flies in the face of what we think of in terms of positive Darwinian selection and demands an explanation.”

Approximately 75 percent of human embryos exhibit some form of aneuploidy and most of those will result in a failed pregnancy. Indeed, fewer than 30 percent of all conceptions are thought to result in an actual pregnancy. The likelihood of aneuploidy in a woman’s eggs—so called meiotic-origin aneuploidy—increases with age, but “even when the egg doesn’t have any issues, errors can be introduced in the first few cell divisions [of the embryo] and are extremely common,” said Rajiv McCoy, lead author of the new study and researcher in the laboratory of Dmitri Petrov at Stanford University. In fact, such mitotic-origin aneuploidy is “even more common than meiotic-origin aneuploidy,” McCoy said.

The striking abundance of mitotic-origin aneuploidy has been discovered thanks to the advent of embryo screening during in vitro fertilization (IVF), explained McCoy. But the rates of mitotic aneuploidy vary considerably between couples undergoing IVF, he said. To understand what might be driving this variation, the team examined whether the existence of aneuploidy in three-day-old IVF-derived embryos was associated with the presence of certain nucleotide variants in the parents’ genomes.

This genome-wide association study (GWAS) revealed no link between parental genetic markers and the presence of meiotic aneuploidy events—defined by a set of particular chromosomal characteristics. The GWAS also found no genetic link between paternal genomes and mitotic aneuploidy events. It did, however, reveal a striking link between mitotic aneuploidy and a single nucleotide variant (SNP rs2305957) on chromosome 4 of maternal genomes.

The first few divisions of an embryo’s life require the use of protein machinery inherited with the egg. The team was thus excited to find that in the vicinity of rs2305957 was the gene encoding the enzyme PLK4. This kinase is critical for organizing the poles of the mitotic spindle—the framework that separates the chromosomes at each cell division.

“Based on the function of PLK4, it absolutely could cause what it is that [the authors] are observing,” said Andrew Holland of Johns Hopkins University who was not involved in the research. However, he warned, besides being in the linked region, “we really don’t have any evidence that there are alterations in PLK4 that are causing this phenotype.”

Whether PLK4 is in fact the gene influencing increased aneuploidy in embryos, the rs2305957 variant turns out to be very common. The team found it was present in diverse human populations at frequencies up to 45 percent. The variant is absent from Neanderthal genomes, however, which—together with its high frequency in modern populations—suggests it has been under positive selective pressure during human evolution, the researchers noted. Indeed, the region encompassing rs2305957 was previously identified, through sequence comparisons with Neanderthal genomes, to display features of positive selection.

Why should an apparently deleterious variant have been maintained in the population at all? It’s possible that the mutation is linked to another beneficial genetic trait and has simply evolutionarily hitchhiked to high frequency. It’s also possible however that the rs2305957 variant itself is beneficial. Petrov is putting his money on the latter.

The slightly reduced odds of successful pregnancy for those women carrying the rs2305957 variant, he suggested, could have helped establish something called paternity confusion—a hypothesis that suggests it was beneficial in early human communities for males to be uncertain whether children were their own. The theory is that this ensured all children were equally cared for, which benefited the group as a whole.

“There are many human characteristics and behaviors that can be explained in terms of paternity confusion,” said Green, such as the fact that unlike other primates and apes, human females do not physically advertise when they are ovulating. But “that the need to confuse paternity is so strong that . . . we have evolved the ability to reduce embryonic viability? That is crazy,” he said, “It would say a lot about the importance of paternity confusion, if in fact it is what’s driving this.”

Ultimately, because the findings seem “so paradoxical,” said Green, “I fear that any theory one can come up with is going to feel wrong in some way.”

R.C. McCoy, et al., “Common variants spanning PLK4 are associated with mitotic-origin aneuploidy in human embryos,” Science, 348:235-38, 2015.

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Avatar of: Mary P

Mary P

Posts: 1

April 10, 2015

Perhaps the benefit is to help women space their pregnancies so each viable pregnancy has a greater chance of success.  One pregnancy right after another is not good for either the mother or the fetus.  It is not all about the men.

Avatar of: James V. Kohl

James V. Kohl

Posts: 350

April 10, 2015

Re: "This genome-wide association study revealed "...a striking link between mitotic aneuploidy and a single nucleotide variant (SNP rs2305957) on chromosome 4 of maternal genomes."

Excerpt: "There’s this genetic variant that they’ve been able to identify with very nice evidence for positive selection, but that has a fitness consequence, a fecundity consequence . . . that decreases the viability of an embryo,” said evolutionary geneticist Ed Green of the University of California, Santa Cruz, who was not involved in the work. “It flies in the face of what we think of in terms of positive Darwinian selection and demands an explanation.”

My comment: It also attests to the fact that what most people think of in terms of positive Darwinian selection has no explanatory power. However, the thoughts of most theorists and sex researchers can be placed into the context of Dobzhansky's claim: "...the so-called alpha chains of hemoglobin have identical sequences of amino acids in man and the chimpanzee, but they differ in a single amino acid (out of 141) in the gorilla" (p. 127). Nothing in Biology Makes Any Sense Except in the Light of Evolution

To make sense of how a single amino acid substitution in the developing embryo determines an organism's fate, see also:

The smelling of Hedione results in sex-differentiated human brain activity

Section title: "3.1. mRNA of all intact VN1Rs is present in human olfactory mucosa"

See: 3.2. "Genetic variations of chemoreceptors caused by single nucleotide polymorphisms (SNPs) that result in an amino acid change..."

See also: A universal trend of amino acid gain and loss in protein evolution. 

Excerpt: "We cannot conceive of a global external factor that could cause, during this time, parallel evolution of amino acid compositions of proteins in 15 diverse taxa that represent all three domains of life and span a wide range of lifestyles and environments. Thus, currently, the most plausible hypothesis is that we are observing a universal, intrinsic trend that emerged before the last universal common ancestor of all extant organisms."

See also: "There is a Corrigendum (26 May 2005) associated with this document. We have since discovered that a similar scenario for protein evolution was proposed by Zuckerkandl and colleagues more than thirty years ago1."

It has now been nearly 45 years since publication of Mutational trends and random processes in the evolution of informational macromolecules.

It has been nearly 20 years since we linked RNA-mediated cell type differentiation in species from microbes to man via the conserved molecular epigenetics of their nutrient-dependent pheromone-controlled physiology of reproduction in From Fertilization to Adult Sexual Behavior.

It surprises me to see that the paradigm shift from the gene-centric view to an accurate representation of cell type differentiation has already taken more than two generations. Max Planck suggested it should take one. Perhaps he underestimated the "staying power" of wrong theories.

Avatar of: emefowler

emefowler

Posts: 1

April 11, 2015

I remember learning that maternal genes tend to favour the mother's survival in pregnancy and paternal the fetus (maintaining their genetic line). So maybe this is a coping strategy for womens' health - having babies is pretty stressful on our bodies!
Avatar of: Hugh-F-61

Hugh-F-61

Posts: 67

April 11, 2015

The claimed conceptus failure rate in humans is way above the 5 to 8 percent or so failure rate observed in sheep conceptuses and failed hatchings in (unpredated) eggs of wild birds. It could have been selected as a means of increasing the spacing of human births if close successive births were detrimental to the older sibling or all siblings. As Mary P says, the mother's health also needs to be protected so that she can successfully nurse the infants. There is a limit to how many toddlers a hunter-gatherer mother could carry and protect safely while foraging.

On the other hand the whole thing could be an artefact of IVF if some genotypes of  egg are particularly vunerable to the conditions used in vitro for egg fertilisation and culture. The growth medium itself, or temperature shocks when culture dishes are moved from incubators through the lab for observation or maintainance could disrupt mitotic spindles.

Avatar of: Paul R Walsh

Paul R Walsh

Posts: 8

April 14, 2015

I agree with “Mary P”.

This article asks, "Why should an apparently deleterious variant have been maintained in the population at all?”

I don’t think that this genetic variant is apparently deleterious. I think that it appears to be a regulatory mechanism to reduce the efficiency of the conception/gestation cycle. Bearing too many children in too rapid succession is dangerous for both the mother and fetus. 

If a woman were perfectly fecund, then each attempt at a conception would result in conception and would result in carrying the fetus for a full nine months. And, if perfectly fecund, then she would become pregnant within a week of bearing each child. Consider Stone Age humans: food was not abundant; it was difficult to find enough calories for a pregnant woman to keep her weight up during pregnancy.  Even today, many woman lose muscle mass during pregnancy due to fetal demands amino acids. And her bones become less dense as the fetus steals her calcium.  And her fat reserves will be depleted. After bearing a child, a stone age woman would have been metabolically and energetically depleted.  If she immediately became pregnant again, then that second pregnancy could result in her own death or could result in the birth of a small, weak baby.   

Perfect fecundity would probably result in the death of Stone Age woman before the age of 22, after bearing only 2 or 3 children in her lifetime.

Instead, if most attempts at pregnancy failed, then (statistically) there would be a long lag between pregnancies. If that reduced fecundity allowed her to bear only one child every two years, then her metabolic reserves would have repleted before each successive pregnancy.  And, if her childbearing years spanned age 18 to 40, then she could bear 10 children in her lifetime.  Such a woman would be evolutionarily selected as more fit than a perfectly fecund woman.  

So, it seems important and evolutionarily favorable for some genetic factor that limits fecundity. Theoretically, many methods could have arisen by natural selection to limit fecundity.  But it should not be surprising that the method happens to be PLK4’s activity of increased aneuploidy in embryos.

My questions are:

1.  Is the expression (or activity) of PLK4 influenced by the metabolic state of the mother?

2. Is the expression (or activity) of PLK4 altered if her fat reserves are low, or if her bone density is low, or if her muscle mass has been depleted, or if she has low levels of nutrients circulating in her blood stream?

Avatar of: James V. Kohl

James V. Kohl

Posts: 350

Replied to a comment from Paul R Walsh made on April 14, 2015

April 15, 2015

Sabatini’s group appears to have linked “Nutrient-sensing mechanisms and pathways” from the light-induced de novo creation of amino acids to the RNA-mediated stability of all organized vertebrate genomes via insertion of glycine in the GnRH decapetide. See “SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance

I requested a reprint 6 days ago in an attempt to confirm the difference between amino acid substitutions and mutations. He indicated the published work woud be added on his lab's site: http://sabatinilab.wi.mit.edu/publicationsDS.html

Avatar of: Mounthell

Mounthell

Posts: 42

Replied to a comment from Paul R Walsh made on April 14, 2015

April 15, 2015

Yes, Mary and Paul, nor should we forget that compromised maternal health jeopardizes not only survival of a current fetus but, perhaps more importantly, that of existing developing offspring who are crucially dependent upon her resources (including behaviorally) and, potentially therefore, that of the genetic contribution of the affected familial line.

Also, my money's on YES! to Paul's questions "is expression of PLK4 influenced by the metabolic state (and resource levels) of the mother"; this question is likely the basis for a very pregnant research program!

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