Nature’s genetic engineers
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Extrachromosomal DNA may be weird, but it’s just one of the many ways that cells break the rules when it comes to chromosomal behaviour.
If you know anything about mammalian development, you’ll know that we start life from a single cell, formed when egg and sperm meet, each bringing half a set of chromosomes that together make up the full genome. These chromosomes get copied and divided up time and time again as that single cell divides into two cells, four cells, eight cells, a tiny ball of cells, an embryo and then ultimately a new animal. So, to all intents and purposes, the chromosomes in one of the cells in your skin, liver, brain, bowel or pretty much anywhere else are broadly pretty much the same as the chromosomes in that very first cell when your mummy and daddy made you. But what seems obvious to us now, wasn’t always common knowledge.
Let’s travel back in time to the late 19th century. Back then, August Weismann was a big-shot German scientist who had major clout in the field of developmental biology - which is all about unravelling the mystery of how different tissues form in the developing embryo, known as differentiation. He had a theory that only germ cells - sperm and eggs - held the entire set of genetic instructions needed to make an animal. As cells divided and specialised as an embryo developed and grew, they lost some of that crucial info, keeping only the correct instructions for their specific cell type.
Given the evidence available at the time, Weismann's theory seemed legit, and was backed up by work done two years earlier in 1887 by a scientist called Theodor Boveri. At this time, Boveri was knee-deep in horse manure, studying parasitic roundworms called Ascaris. But one horse's poop is another man’s treasure - and Boveri found some intriguing clues in the muck. He noticed that as these worms developed, large portions of a darkly staining substance in each cell, which he termed chromatin, was getting eliminated. He named this process 'chromatin diminution', and suspected that it was something to do with the instructions that tell cells what to do, long before the discovery of genes.
As a side note connected to our first story - Boveri also has an important role in the history of cancer genetics as the first person to discover that cancer cells have abnormal chromosomes, sowing the seeds for the idea many decades later that cancer is driven by genetic mutations.
Based on Boveri’s equine poop parasite observations, it would have seemed obvious that cells chuck out the instructions they don’t need as they mature. But hold your horses folks, because not all organisms are cut from the same genetic cloth. As the 20th century rolled in, scientists started to understand more about heredity, chromosomes, and genes - and realised that Ascaris is an exception to the rule when it comes to genetic elimination and Weismann's theory faded into irrelevance.
Fast forward to today and we now know that most organisms keep their chromosomes stable across all cells at all stages of life, especially germ cells. Instead of tossing genes away, they have a sophisticated switchboard of proteins and modifications that controls when, where and which genes get activated. There are a few notable exceptions - such as the genetic cutting and pasting that goes on to generate diversity in our immune cells - but it’s a rule that broadly holds true.
However, there are some more weirdos like Ascaris out there, which intentionally chuck out parts of their genome along the way. This process, called programmed genetic elimination, allows cells to quickly manipulate their genes - allowing certain species to adapt fast and cope with tough and unique challenges. These are nature’s genetic engineers, and what they get up to with their genomes will blow your mind.
Taking out the genetic trash
Lampreys are ancient eel-like creatures which could be described as ocean-dwelling vampires. They use their jawless mouths, filled with rows of rasping teeth, to burrow into their prey's flesh, consuming their bodily fluids for sustenance. As you can already probably imagine, they aren’t easy on the eye - imagine a smaller but no less horrifying version of the sand-worms from Dune.
But nightmarish appearances and gruesome eating habits aren’t the only interesting things a little bit spooky about lampreys. They are one of the few vertebrates that can edit their genome. During development certain DNA sequences seem to disappear. One of them is called Germ1, which is in germline cells - these are the cells that become eggs and sperm - but is much less common in somatic cells (that’s the rest of the cells that make up the body). But this vanishing act isn’t random - it's a tightly regulated process that only occurs during the early stages of life as the embryo is developing.
This discovery turned some established ideas on their heads, and brought some even older ideas back to the fore. After the rejection of Weismann’s ideas, scientists broadly believed that vertebrate genomes were immutable blueprints in all cells of the body, with only minor tweaks allowed. But the lampreys proved us wrong - and they’re not the only creepy sea creature that can alter their genome - so can copepods.
Copepods are small oar-footed crustaceans - often described as the “insects of the sea”. They are only 1-2mm in size, with a semi-transparent body and large antennae, and are found in nearly every freshwater and saltwater habitat - in sea water, on the ocean floor, in swamps, bogs, springs, puddles, patches of damp moss. Where there's water, there's probably some copepods. The most famous of the family are the Cyclops, who get their distinctive name due to their single black or red eye.
Copepods, like Ascaris, undergo chromatin diminution during early embryonic development. This leads to over 90% of the total DNA content being chucked out of their genomes along the way. However, this extrachromosomal DNA doesn’t just float around the cell or get immediately broken down, it gets trapped in special granules.
Over time, these granules evolve, initially starting with pores in their membranes, then fusing together, after which the pores disappear. Once this happens, the DNA within the granules undergoes a range of cutting and pasting processes, chopping and changing it around until it forms some by now familiar-sounding structures - extrachromosomal DNA rings.
But why bother going to all this fuss in the first place? For the copepod Mesocyclops edax, the answer may lie in the fact that its genome has become over-run by unwanted junk DNA in the form of repetitive sequences such as transposable elements, picked up and amplified during the course of its evolution, bumping up the size of its germline genome to an incredible 15 billion letters or basepairs.
After taking out all this genetic trash, Mesocyclops’ somatic genome is a much more manageable 3 billion basepairs. It’s not necessarily very efficient, but given that it’s very difficult to purge junk out of the genome through evolution, it’s the way that works for this species. Plus, there may be some evolutionary benefits to being able to effectively sift through all your DNA in every cell, generating variations in different tissue types that may be biologically useful.
The surprising tale of the zebra finch genome
So far, some form of chromosome elimination or genome editing has been found in a diverse range of species. In addition to Ascaris, copepods and lampreys, it’s also been spotted in ciliates, nematodes, and the lamprey’s closest relatives, hagfish. You might be forgiven for thinking that these genetic antics are reserved for single celled organisms or weird aquatic creatures. But you’d be wrong.
The zebra finch is a cute little songbird, with rosy red cheeks and black and white stripes on its rump and upper tail. Its captivating song has fascinated researchers for years, and its become the model of choice for studying how birds learn to sing. But what’s equally fascinating is the curious way it reprograms its genome.
As you might expect for such an interesting organism, researchers were quick to sequence the songbird’s genome, and it was published in 2010. At that time, there was nothing to indicate anything unusual about the way that the zebra finch regulated its genome, and certainly no hint of the kinds of genetic shenanigans we’ve previously described for other, simpler species. But that’s because the zebra finch reference genome was compiled from a sample of muscle tissue collected from a male bird.
In 2018, scientists carried out a detailed comparison of patterns of gene activity between somatic and germline cells in male and female birds, and noticed something very weird going on. They discovered that Zebra finches have a peculiar chromosome called the Germline-Restricted Chromosome (GRC), which is removed from all non-reproductive somatic cells in the early embryo, and preserved in the germ cells that are the precursors of eggs and sperm. But even then, that’s not enough. The GRC is removed from mature sperm in male birds, so it’s only present in the egg, and is only passed down the female line. So it wouldn’t have been detected in any studies using only male samples or even female somatic tissue.
Rather than being a small genetic curiosity, the GRC is actually the largest chromosome in the finch genome at 120 million basepairs. Up until recently, it was thought to consist of junk DNA - but it turns out that the GRC actually contains many useful genes that are involved in female sex development. And zebra finches aren’t the only birds that have a GRC and carry out programmed genetic elimination of it - all songbirds studied to date also have something similar going on.
The world of natural genetic engineering is full of surprises and unsolved mysteries. It’s likely that programmed DNA or chromosome elimination is much more widespread and present in more complex organisms than we ever imagined. And although we haven’t yet found evidence of it happening in mammals, marsupial bandicoots prefer to kick out unnecessary sex chromosomes rather than just silence the irrelevant genes.
This phenomenon challenges our preconceived notions on inheritance, evolution, and the very nature of genomes themselves, not just in simpler organisms like horse poop parasites but all the way up the evolutionary tree. And who knows what we might find in the future once we start looking more closely? Seems like Weismann wasn’t completely wrong after all.
