Let’s play the most boring card game in the universe!
Here are the rules. We start with a fully sorted deck of 52 cards, and we deal out four hands. We don’t deal in the ordinary way, either: we give the top 13 cards to the first player, then the next 13 to the second, and so forth. (We could also do the usual deal, but it makes the illustration and logic a little more difficult to see. We’ll keep it simple for now.)
This is what the table will look like.
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Next, we play the game, whatever it is. It really doesn’t matter, since we know exactly what hand everyone has, right? So don’t worry about the rules for that. What’s important is that next the dealer carefully picks up each hand in reverse order and stacks them, restoring the original arrangement of the deck.
Then he deals them out again in the same way. NO SHUFFLING! You don’t even get to cut the cards. The next round will look like this:
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Then repeat. Millions of times.
What did I tell you? The most boring card game in the universe. Well, other than 52 card pick-up…this one at least has a few simple rules, and probably the source of the boredom is simply the inflexibility of those rules.
What is the point of this exercise? It’s an analogy. Think of the deck of cards as a genome, with each card representing a single gene. Each hand is a chromosome, so in this example, we’re looking at an organism with 52 genes in 4 chromosomes. This particular game is what mitosis is like — each cell division is a precise, boring set of mechanical operations that make sure the same genes get distributed to each daughter cell. The rules guarantee that the same arrangement will get passed on from generation to generation.
Now, though, this leads to an interesting logic game. It’s supposed to be boring and repetitive, but what if the dealer and the hands are imperfect, and occasionally make a mistake? Not often, mind you, but every once in a while the hands are dealt out, and the distribution is different. We can have some fun with this — it’s a kind of detective game. Say the hands are dealt out, and you see this (hint: look at hand 3):
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You don’t actually get to see the event that occurred, but only the result. How would you explain what happened in the prior round? Try to come up with the simplest, minimal explanation.
Answer: it looks like some of the cards in hand 3, the 5-8 of diamonds, were reversed in order. That’s all, a simple change that we can logically decipher from the outcome. Note also that from now on, every round dealt out from this deck will propagate this new arrangement — we will always have that inversion in the diamonds, unless an accident rearranges them again. And to keep with the analogy, we see this in chromosomes too, small blocks of genes that get flipped around.
So we deal a few hundred thousand more hands, all looking the same, and then we notice something new. Figure out the simplest explanation for what happened here:
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A-ha, you should be saying, it looks like hand 2 swapped her last 5 cards with the last 5 cards that were dealt to hand 3. We also have an analogous process in genetics — it’s called a reciprocal translocation.
If we wanted to make this an even harder game, I could have given you that last set of hands and told you to compare it to the first, without showing you the intermediate inversion error. You’d still be able to figure out, though, that the simplest explanation was that there was an inversion and then a translocation, in that order, and we’d be able to puzzle out the series of slow, small accidents that generated this arrangement. (This won’t always be true: some combinations of rearrangements will be ambiguous and you’ll only be able to approximate what happened.)
We can also make it harder. There are plenty of genetic operations that can be tossed in: we can fuse two hands. We could split one hand so that now 5 hands at a time get dealt out. We can toss in duplications — maybe one of the players has an ace of hearts up his sleeve, and he slips it into the deck. Maybe someone tosses out the 2 of spades. The important thing is that these little distortions of the arrangement happen relatively rarely, leading to a slow rearrangement of the cards in the deck. There is nothing like a series of shuffles that scramble everything all at once.
This particular game is one that is played in comparative genomics all the time, only the magnitude of the complexity of the puzzle is much, much greater. We’re now dealing with tens of thousands of cards in a deck, in a series of rounds that have been played over hundreds of millions of years. The only thing that makes it possible to play is that the changes have been relatively slow — not every generation and not even every speciation event is accompanied by an error — and that, whatever the card game is that real species are playing, some arrangements of cards are advantageous and are conserved. The problem can be so difficult that not everything can be figured out, and what we often settle for is mapping out synteny.
And what, please, is synteny? Synteny is the conservation of blocks of order within two sets of chromosomes that are being compared. Let’s look at our original set of hands, and compare it to the set that was produced by an inversion and a translocation as a simple example.
Here’s the original, and I’ve added a little color coding to mark out the clusters of cards. Let’s call each set of cards a species, as a simple label.
Species 1
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Now here’s the lightly scrambled round:
Species 2
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Real genes aren’t nicely picked out with suit markings to make it easy to see how they are related, but what we see here in the background colors are blocks of conserved order. Those blocks are regions of synteny. For instance, the region in Hand 2 of Species 2 that contains the 7-8-4-3-2 of diamonds corresponds coarsely to a region of Hand 3 in Species 1 — it’s not perfect, because it’s missing the 5 and 6 of diamonds, and the 7 and 8 are reversed, but we can at least say there’s a kind of macro-synteny at play here, a larger block of rough correspondence with a whole chromosome. Within that syntenic region, there is some local scrambling, so if we wanted to go into more detail, we could say that the 7-8 of diamonds in Hand 2 preserve the micro-syntenic order of a piece of Hand 3 in Species 1, and the 4-3-2 of diamonds in Hand 2 are another micro-syntenic region conserved from Hand 3 of Species 1.
I know. It’s complicated, it’s got some weird terminology, and the logic can get convoluted…and this is a very simple example. In the real world of comparative genomics, you get much more elaborately scrambled examples, and you don’t get to see the ancestral species — you get two independently evolved species, and you have to puzzle out the minimal set of separate operations that would generate the two products, and infer the ancestral chromosomal arrangement from that. Computers are essential for working out the permutations.
In papers that describe synteny between two species, they’ll often do exactly what I illustrated above: they’ll color code the chromosomes from one species, and then map those regions of color onto the chromosomes of the other. Here’s one example:
There’s a key at the bottom. In this case, the authors have color-coded the 21 chromosomes of the puffer fish, Tetraodon — all the genes on chromosome 1 are colored dark purple, for instance, and all the genes on chromosome 9 are light blue. Then they look in the human genome, and wherever a block of genes with similar sequence and order to a block of genes in chromosome 1 of Tetraodon are found, they are colored dark purple too. So, for instance, we find bits of Tetraodon chromosome 1 scattered throughout our chromosomes 1, 2, 3, 14, and so forth, and Tetraodon chromosome 9 has been broken apart and sprinkled through human chromosomes 1, 2, and largely in 6. By comparing these shattered scraps of chromosomes and assuming the minimal set of operations that must have occurred to create these rearrangements, we can deduce the organization of the ancestral chromosome set of the last common ancestor of Tetraodon and humans. It’s a combination of molecular archaeology and elaborate logic game, and it is impressive intellectual fun.
It’s an approach that has considerable power, too, to let us look back into the genetic state of long extinct organisms, which haven’t left us their actual, intact DNA, but only the somewhat scrambled strands of their descendant’s chromosomes.
Next up: I’ll summarize recent work on the amphioxus genome. Trust me, you need to understand the principle of synteny to see the significance.




