Mammals Go Viral

So far on Gene of Interest, we’ve explored what can go wrong: how genes are lost; terrible diseases caused by small mutations; tiny errors that have massive consequences.  But that’s only half the picture. With all this chaos, how did humanity end up with a working genome in the first place? Where do genes come from? The likely answer: many many happy accidents, but I’d like to examine one – without it none of us would have been born – this week’s gene of interest: syncytin (ERVW-1).

Humans are mammals – we’re hairy, warm-blooded, and the ladies have boobs – and we’re part of the largest subset of mammals, placentals. All placentals have the unique ability to carry their developing young inside a womb until fully developed. A baby needs nutrients to develop, so an unborn placental has to collects nutrients from its mother’s bloodstream, but it has to do so carefully. Not only can mother and child have different blood types (so direct connection of blood vessels would be a huge no-no), to the mother’s immune system, the developing baby is a foreign invader. The mother’s white blood cells are adapted to slip themselves between other cells to reach any part of the body, so baby has to create a barrier to protect itself from mommy [1].

Studies of Embryos by Leonardo da Vinci

The solution is a placenta – a vast network of intertwined capillaries from both mother and child. To keep out the mother’s immune system, the cells lining the fetal side of the placenta merge into one giant cell, leaving no gaps for white blood cells to squeeze through. This single cell layer is called a syncytiotropoblast, created by the production of syncytin [2].

But syncytin is an odd gene. It’s produced nowhere else in the body, only a particular type of cell in the placenta and then never again after birth. And it’s related to a protein found in retroviruses – a protein that helps viruses invade our cells [3].

We’ve discussed retroviruses before. A retrovirus inserts its viral RNA into the host cell’s genome using an enzyme called reverse transcriptase [4].  The host cell then reads these genes like an instruction manual to build more viruses. A gene similar to syncytin allows the virus to incorporate it’s membrane with that of the cell – sort of like a smaller soap bubble merging with a larger one.

Millions of years ago, an early mammal was infected with a virus that had this syncytin gene. After the infection had subsided, the syncytin gene was left in the mammals genome and it somehow found a way to put it to work, merging one cell with another cell to create a better barrier for the placenta [5].

Retroviral infection with syncytin. 1) Virus invades the cell using syncytin to merge with the cell membrane. 2) Reverse transcriptase converts viral RNA into DNA. 3) The syncytin gene integrates into the cells genome. 4) The cell copies the syncytin gene. 5) The cell produces its own syncytin and uses it to merge with surrounding cells to form a syncytiotrophoblast.

According to DNA analysis, this adoption of viral DNA happened more than once. The human syncytin gene is similar to that of other primates, but completely unique from the syncytin genes found cats, mice, and rabbits. So far, scientists have found six different versions of the syncytin gene in related species of placentals, suggesting multiple ‘infection’ events and a huge selective advantage to retaining this gene [6]. So even though the placenta developed first without viral DNA, the addition of syncytin was so beneficial that everyone starting doing it.

An estimated 8 percent of our genome came from viruses – the spoils of war after an infection. Most of our viral DNA is in pieces and sits dormant, but a few are functional and even essential to our survival [7]. Odd to think that pregnancy functions thanks to an ancient viral infection. Definitely a happy accident.

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References
[1] “Placenta ‘Fools Body’s Defences’“. BBC. 10 November 2007.
[2] Musicki B, Pepe G, Albrecht E. (1997). “Functional differentiation of placental syncytiotrophoblasts during baboon pregnancy: developmental expression of chorionic somatomammotropin messenger ribonucleic acid and protein levels.” J Clin Endocrinol Metab 82 (12): 4105–10, PMID 9398722
[3] “Virus Gene Syncytin Insinuated Itself in Mammalian DNA Millions of Years Ago“. SciTechDaily.com. 18 February 2012.
[4] Kurth, Reinhard; Bannert, Norbert, eds. (2010). Retroviruses: Molecular Biology, Genomics and Pathogenesis. Horizon Scientific. ISBN 978-1-904455-55-4.
[5] “The Syncytin Gene: Viruses Responsible for Human Life“. IScienceMag. 10 June 2015
[6] “Mammals Made by Viruses“. Discover Magazine. 14 February 2012.
[7] “Our Inner Viruses: Forty Million Years in the Making“. National Geographic. 1 February 2015.

 

Cyanide and the Cell

In Ian Fleming’s novels, all 00 agents are issued cyanide capsules in case of enemy capture, but James Bond threw his away. What a dummy. Sure, Bond always escapes, but why risk it? The rest of his peers understood their orders and were ready to die to keep their country’s secrets. Cyanide pills aren’t mere tropes either, but a real spy tool – a gruesome last resort to keep information out of enemy hands [1]. A lethal dose of cyanide kills in minutes – so effective because it blocks the body’s ability to make energy, via this week’s gene of interest: ATP synthase gamma subunit (ATP5C1).

There are few molecules so important that they’re found in all cellular life. DNA for one (obviously), but also the common fuel source for all cells: adenosine triphosphate or ATP [2]. Related to DNA, ATP is an adenine nucleotide with three phosphate groups attached. Think of each ATP molecule like a tiny rechargeable battery. The bonds connecting each phosphate group store the energy that drives the majority of biochemical reactions in the body – from charging neurons to powering muscle movement [3,4].

The charging stations for these molecular batteries are the mitochondria. Metabolites like glucose are broken down inside the mitochondria, one chemical bond at a time, to release energy [5]. ATP synthase, an enzyme embedded in the mitochondria, uses this released energy to make ATP. The gamma subunit (ATP5C1) sits in the center of ATP synthase and rotates to change the shape of the enzyme.  For each rotation, ATP synthase adds a phosphate group to ADP (adenosine diphosphate) to make ATP [6].  The cell then distributes these newly minted ATP molecules to power nearly all of its biochemical reactions.

ATP synthase in action.  ADP and a phosphate group (pink) attach to one of three sections of ATP synthase.  As the gamma subunit (black) rotates, ATP synthase changes shape, combining ADP and the phosphate group into ATP.  ATP synthase then ejects the ATP molecule (red) and the cycle repeats [6].

ATP synthase works constantly to keep up with the cell’s energy demands. Each molecule of ATP is created and consumed at a rate of approximately 3 times per minute [7]. In all its cells, the human body contains only 250 grams of ATP, but each day it turns over an equivalent of its own body weight in ATP. At any moment, one cell can have up to one billion ATP molecules, but that’s only enough energy to keep the cell running for a few minutes [2].

Cyanide pills take advantage of the cell’s lack of energy storage. By binding to another enzyme found in mitochondria, it blocks the cell’s ability to transfer energy from glucose to ATP synthase.  No energy means no rotation of the gamma subunit inside ATP synthase, which means no new ATP. Unable to recycle spent molecules, the body burns through its ATP reserves in minutes.  It’s effectively like an off-switch for a spy – not a pretty way to go, but effective at keeping state secrets out of the hands of villains like Goldfinger.

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References
[1] “Last hero of Telemark: The man who helped stop Hitler’s A-bomb“. BBC. 25 April 2013.
[2] “Nature’s batteries’ may have helped power early lifeforms“. Science Daily. 25 May 2010.
[3] “ATP and Muscle Contraction“. Boundless.com. 7 January 2016.
[4] “Nerve Impulse Transmission within a Neuron: Resting Potential “. Boundless.com. 8 January 2016.
[5] “How Cells Obtain Energy from Food“. (2002) Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science.
[6] Nakamoto RK, Scanlon JAB, Al-Shawi MK. (2008).”The Rotary Mechanism of the ATP Synthase” Arch. Biochem. Biophys. 476 (1): 43–80.  PMID 18515057
[7] Kornberg, A. (1989) “For the love of enzymes.”Harvard University Press. Cambridge, MA.Humphery, N. ISBN-13: 978-0674307766.
[8] “How cyanide affects the electron transport chain“. The Biochem Synapse. 13 April 2013.

 

Do-It-Yourself Vitamin C

People can’t live without vitamin C, but everyone’s heard a story about that one college student who tried to live off of nothing but chips and ramen [1]. And were it not for a mutation a few millions of years ago, the story wouldn’t end in the clinic with a diagnosis of scurvy.  We could synthesize all the vitamin C we need with a few repairs to this week’s gene of interest: L-gulono-γ-lactone oxidase or GLO.

Vitamin C has a several important jobs. It’s an antioxidant – neutralizing nasty free-radicals [2].  It stimulates the immune system, possibly by acting as an oxidizer to destroy bacteria and viruses during infection [3].  And it’s required to make collagen, a protein found in nearly every tissue in the body [4].

Vitamin C deficiency leads to scurvy, a disease forever linked to pirates and sailors. On lengthy sea voyages, fresh fruits and vegetables didn’t last long. Without any vitamin C, sailors became sluggish, their gums would bleed, old wounds would ache, then jaundice, fever, convulsions, and finally death [5]. A horrible way to go and easily remedied by an orange or two. Multiple times in history citrus was identified and dismissed as a cure for scurvy.  Many were confused why sucking on a lime might cure scurvy, but the juice was less effective and preserved fruit even less so. Vitamin C degrades in light and heat, so processing and preservation would make the food useless. It wasn’t until the 1930’s that vitamin C was isolated and identified as the cure to scurvy.

Raw meat can even cure scurvy, because most animals (like plants) make their own vitamin C.  Humans are among a minority of animals – along with guinea pigs, bats, and other primates – that can’t synthesize their own vitamin C.  Most animals convert glucose into vitamin C using several specialized enzymes [6].  We lost the ability due to mutations in the gene for GLO, the enzyme responsible for the last step in vitamin C synthesis [7].

We still have the GLO gene, it just doesn’t work anymore.  Ever since that first mutation knocked out GLO gene function 61 million years ago, more mutations have eaten away at the gene.  Every gene is made up of several sections of coding DNA (called exons) separated by sections of non-coding DNA. Only the exons are used to build a protein. Of the 12 exons in the GLO gene, humans have lost 7 [7].

Human GLO pseudogene compared to the functional GLO gene from a rat [7].

GLO is an example of a pseudogene – a gene that’s lost its function.  It differs from other mutated genes we’ve discussed because it’s harmless, as long as we eat enough vitamin C to compensate. Early primates may have lost the GLO gene because their diet was rich in vitamin C. Gorging on fruits and veggies, there was no real disadvantage to loosing natural vitamin C production [6].

Our genome is likely full of psuedogenes. Each one sits dormant in our genome, a relic of our evolution. For example, scientists have identified 390 different olfactory genes, responsible for our sense of smell, but there are another 468 olfactory pseudogenes [8]. Compared to what we’ve lost, our nose is basically worthless. Think of all the smells we’re missing.

So that’s why you should eat your fruits and veggies – because evolution has failed you. But considering the American diet, it’s probably a good thing we can’t make our own vitamin C. If not for a horrifying death by scurvy, too many people would opt to avoid anything green for tasty, tasty junk food.

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References
[1] “Scurvy Is a Serious Public Health Problem”. Slate. 20 November 2015.
[2] Padayatty SJ, Katz A, Wang Y, Eck P, Kwon O, Lee JH, Chen S, Corpe C, Dutta A, Dutta SK, Levine M. (2003). “Vitamin C as an antioxidant: evaluation of its role in disease prevention”. J Am Coll Nutr 22 (1): 18–35. PMID 12569111
[3] Wintergerst ES, Maggini S, Hornig DH.(2006) “Immune-enhancing role of vitamin C and zinc and effect on clinical conditions”. Ann Nutr Metab 50(2):85-94. PMID 16373990
[4] Peterkofsky B (1991). “Ascorbate requirement for hydroxylation and secretion of procollagen: relationship to inhibition of collagen synthesis in scurvy”. Am. J. Clin. Nutr. 54 (6): 1135S–1140S. PMID 1720597
[5] “Scott and Scurvy”. Idlewords.com. 6 March 2010.
[6] “Plagiarized Errors and Molecular Genetics”. Talkorigins.org. 5 May 2003.
[7] Drouin G, Godin JR, Pagé B. (2011). “The Genetics of Vitamin C Loss in Vertebrates”. Curr Genomics. 12 (5): 371–378. PMCID PMC3145266
[8] “The Smell of Evolution”.  National Geographic. 11 December 2013.