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Science interrupted ... by milkshakes

This time on Science interrupted I’m going to talk to you about how my adventures in science were interrupted by milkshakes. Besides being delicious, they also make a great analogy for explaining how genetic conflict during pregnancy can have some pretty far-reaching consequences.

David Haig1 was one of the first scientists to describe how genetic conflict manifests across pregnancy. The paper provides a very thorough overview of the biology behind genetic conflict (and by thorough, I mean this paper is as dense as they come -- I’ve read it at least five times and still don’t think I fully understand all parts), but the main point of the paper boils down to a few main points.

  1. Pregnancy is often viewed as cooperative since mom and fetus have (some of) the same genes that should be working towards the same outcome.

  2. But fetuses also have genes in common with their dads, so not all of their genetic interests are perfectly aligned with the mother’s.

  3. This conflict of genetic interests can set up situations where there are negative outcomes for both mother and fetus (think pregnancy complications).

  4. Two prime examples of genetic conflict leading to adverse outcomes come from the literature on gestational diabetes and preeclampsia.

A lot of the literature on genetic conflict during pregnancy centers on two central themes: there is conflict over mom’s blood pressure, and there is conflict over mom’s blood sugar. This makes sense when we remember that all of the nutrients that fetuses need are provided via the mom’s circulatory system. Sugars, proteins, vitamins, minerals, oxygen, and all other nutrients are passed to the placenta (and, eventually, the fetus) from the mom’s bloodstream and all of the fetus’s waste products are passed through the placenta for the mom’s body to get rid of. If the fetus can alter blood pressure (research suggests is the case2), then it can get and get rid of resources more quickly. This translates into the fetus growing a little quicker than it otherwise could. And since fetuses are in the business of growing before they are born, it will surprise no one that getting more access to sugars is something that fetuses would like. In addition to changing blood pressure, fetuses (through the placenta) can directly alter their mom’s blood sugar by causing her to be less reactive to her own insulin3–8.

When things are working as they should, the mom experiences slightly elevated blood pressure and blood sugar. The fetus sings We are the Champions.

But, when the mom’s body tries to correct for blood pressure and blood sugar that is too high (by releasing hormones like relaxin and progesterone to lower blood pressure2 or releasing more insulin to lower blood sugar4) this can start an arms race between mom and fetus for control over blood pressure and blood sugar.

When this arms race escalates to full-on war, this is when pregnancy complications occur. High blood pressure becomes pre-eclampsia (or worse, eclampsia) and high blood sugar becomes gestational diabetes1. Both of these complications can have negative outcomes on the mom and fetus, but the mom will always bear the brunt of the burden since these diseases are altering her physiology. At the end of the day, she faces all of the consequences of the arms race.

If you’re thinking “Why does this happen? You’re making it sound like the fetus is a greedy little jerk who is out to kill its mom! You got some ‘splaining to do Lucy.”, don’t worry. This is where the milkshakes come in. Again, we have David Haig9 to thank for this analogy.

Pretend that all of the resources moms have to give their children come in the form of a milkshake; once the milkshake runs out, mom has no more resources to give her children. Maternal genes know that they have to ‘share’ this milkshake with all current and future children that mom may have, so they want each child to ‘drink’ only as much of the milkshake as they need to grow and develop properly. Paternal genes, on the other hand, do not have the same constraint. There is no certainty that any future children born to mom will have the same paternal genes as the current child. The best strategy for paternal genes is to take as many resources as possible (or ‘drink’ as much of the milkshake as they can) because these genes don't have the limiting pressure of needing to save the milkshake for guaranteed siblings. This sets up the premise that, all else being equal, paternally-expressed genes want the fetus to grow larger and acquire more resources in the womb while maternally-expressed genes want the fetus to grow slightly less and acquire fewer resources10. Remember that none of this is conscious -- these differences in optimal growth are really due to genes trying to guide the fetus’s growth and development with slightly different roadmaps that go in slightly different directions (see my last post on ducklings for a refresher).

This can put the mom in a tricky situation since she will need to split her resources between all of her kids. If her first fetus is greedy and takes more than its fair share, all the remaining fetuses have less for their own development. It’s the start of sibling rivalry before anyone is even born. (As a fun aside, I made this figure as part of my comprehensive exam defense. I think it helps readers picture what is going on.)

So if a fetus is being greedy and getting more of mom’s milkshake, mom faces potentially deadly changes to her physiology and has to start being the negotiator between siblings. Wild. This might seem like a strange way to talk about pregnancy since pregnancy is normally described as a cooperative, beautiful, and wonderful venture, but it is the truth of what is actually happening. And the truth is so much crazier than fiction.

Stay curious my friends,

JDA

In case you are interested, here are some of the articles that I read and thought about while writing this.

1. Haig, D. Genetic conflicts in human pregnancy. Q. Rev. Biol. 68, 495–532 (1993).

2. Kristiansson, P. & Wang, J. X. Reproductive hormones and blood pressure during pregnancy. Hum. Reprod. 16, 13–17 (2001).

3. Fowden, A. L. & Forhead, A. J. Endocrine regulation of feto-placental growth. Horm. Res. 72, 257–265 (2009).

4. Fowden, A. L. & Forhead, A. J. Endocrine interactions in the control of fetal growth. Nestle Nutr. Inst. Workshop Ser. 74, 91–102 (2013).

5. Giannoukakis, N., Deal, C., Paquette, J., Goodyer, C. G. & Polychronakos, C. Parental genomic imprinting of the human IGF2 gene. Nat. Genet. 4, 98–101 (1993).

6. Zhu, Y. et al. Insulin-Like Growth Factor Axis and Gestational Diabetes Mellitus: A Longitudinal Study in a Multiracial Cohort. Diabetes 65, 3495–3504 (2016).

7. Sonagra, A. D., Biradar, S. M., K, D. & Murthy, J. Normal Pregnancy- A State of Insulin Resistance. Journal of Clinical and Diagnostic Medicine 8, CC01–CC03 (2014).

8. Wang, X., Miller, D. C., Harman, R., Antczak, D. F. & Clark, A. G. Paternally expressed genes predominate in the placenta. Proc. Natl. Acad. Sci. U. S. A. 110, 10705–10710 (2013).

9. Haig, D. Genomic imprinting and the theory of parent-off-spring conflict. Semin. Dev. Biol. 3, 153–160 (1992).

10. McKeown, T. & Record, R. G. The influence of placental size on foetal growth according to sex and order of birth. J. Endocrinol. 10, 73–81 (1953).

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