If you look at cells from a human or another mammal under a microscope, you will see large fat molecular complexes called chromosomes that contain our DNA. If the cells are from a bird or a reptile, you will see a few of these thick chromosomes, but also a flotilla of small spots that look like decomposed chromosome pieces or even dust spots.
These spots turned out to be small chromosomes, but their significance has been a mystery for decades. I gathered a talented team of young genome researchers to show that these “microchromosomes” are almost identical, and they represent the ancient chromosomes of a spineless animal ancestor who lived 684 million years ago.
The human genome and human chromosomes
The human genome comprises about 3 billion base pairs of DNA, each as a step on a long twisted ladder. If you stretched the entire genome out, it would be about 1 meter long. It contains about 20,000 genes and a lot of repeated sequences of DNA with few known functions.
Our genome is divided into 23 bits. We can see these chunks when a cell splits in two, because during this process, the DNA condenses with proteins into chromosomes (literally “staining bodies”), which we can see under the microscope. We have two copies of the genome in each of our cells (one from our mother and one from our father), so we see 46 chromosomes in each cell.
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Other mammals have roughly the same set of genes on a similar length of DNA, but it is divided differently. Some animals have lots of small chromosomes (there is a South American rat with 51), and others have a few large ones (the swamp wallaby has only 5).
Surprisingly, other higher vertebrates (birds and reptiles), although having somewhat smaller genomes (1 or 2 billion base pairs), have pretty much the same set of genes – as frogs and even fish. The genomes of all vertebrates are astonishingly similar.
The history of microchromosomes
When we look at chromosomes of birds, turtles and squamates (snakes and lizards), however, we see great differences from those of mammals. They have between six and nine normal-looking chromosome pairs, but also lots of tiny elements that were first thought to be decomposed chromosome pieces or even dust on the slide.
However, it proved that these elements were present in a constant – and even – number. Most birds have 62, which represents 31 pairs of small “microchromosomes”.
Although microchromosomes are small, they have the same ends (telomeres) and attachment points (centromeres) as larger chromosomes. Oddly enough, they seem to hang out together in the middle of the cell.
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The real surprise came when it became possible to sequence snippets of chicken microchromosome DNA and check the genes they contained. It turned out that the microchromosomes of the chickens carry a large part of the genes and contain far fewer repeated sequences than the large “macrochromosomes”. In fact, about half of the chicken genes lie on microchromosomes. This meant that microchromosomes are important parts of the bird’s genome.
But the mystery remained. Why are there two different size classes of chromosomes in birds and other reptiles? And why do you always see microchromosomes squeezed in the middle of the cell?
Microchromosomes are highly conserved across birds and reptiles
Thanks to huge improvements in DNA sequencing technology, there are now well-assembled end-to-end or “telomer-to-telomer” sequences of many birds and reptiles.
In our new work, we have set up DNA sequences of macro and micro chromosomes between several birds, turtles and squamates. We see startling similarities in the sequences.
Emus and pigeons are only remotely related to chickens that birds walk, but they have pretty much the same chromosomes. Turtles and squamates have fewer microchromosomes than birds, but the ones they have are very similar within each group.
When we compared sequences between emus, turtles, and squamates, we saw a high degree of homology in microchromosomal DNA sequences spanning the nearly 300 million years since these species last shared a common ancestor. Turtles and squamates each carry different subsets of emu microchromosomes. We could see the lost microchromosomes; they had fused with each other or with macrochromosomes.
This suggested that 31 bird microchromosomes were present in the genome of a common ancestor of birds and reptiles about 300 million years ago, and turtles and squamates independently lost different subgroups of these.
We used new techniques to reveal which bits of DNA are physically closest to those in the DNA vortice of a non-dividing cell. This showed that microchromosomes are labeled with each other, and not with macrochromosomes.
This gives molecular reality to the old observations that microchromosomes lie close together in bird and reptile cells. It seems that microchromosomes form a space in the cell that can help the genes work together.
Microchromosomes are ancient genetic elements
As it turns out, the microchromosomes go far, far further back than ancestral reptiles: all the way to the tiny chromosomes of a very distantly related animal called the amphioxus or lancelet. Lancelets are small fish-like invertebrates that last shared a common ancestor with vertebrates 684 million years ago, long before the backbone evolved.
Lanceletters have a very small genome (520 million base pairs) cut into 19 tiny, gene-dense chromosomes. This genome was duplicated twice during the evolution of the fish, giving rise to animals with four limbs (tetrapods).
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We found that most emu microchromosomes were aligned with a single lancelet chromosome, or sometimes with two. So the small lanceolate chromosomes have survived almost unchanged as bird and reptile micromosomes. The rest of the vertebrate genome consists of copies of these chromosomes, diluted with enormous amounts of replicated DNA.
This means that the tiny lancet chromosomes, represented today by bird and reptile micromosomes, were the original building blocks of vertebrate genomes.
Mammalian genomes have gone insane
Some reptile and bird groups appear to have lost all or most of their microchromosomes. We show that in these exceptional genomes, microchromosomes are fused with each other (as in crocodiles) or with macrochromosomes (as in eagles and their relatives).
But mammals are the real exceptions. They have no microchromosomes. When we lined up the emu sequence against the human and koala genomes (representing the marsupial and placenta branches of the mammalian family tree), we could find only small patches of homology with microchromosomes, scattered throughout the genome.
However, in monotremes (laying mammals representing a third and the oldest branch of mammals), we saw that four platelet chromosomes consist exclusively of fused microchromosomes.
This implies that microchromosomes fused into large blocks in the ancestor of a reptile-like mammal more than 200 million years ago. The chromosomes remained so in monotremes. However, in our own lineage (terrestrial mammals diverging to marsupials and placental mammals), blocks of micro- and macro-chromosomes were rearranged, erasing their origin.
After this rearrangement, the marsupial of the marsupial remained fairly conserved, 19 large blocks of genes were moved around in simple ways. However, the chromosomes of placental mammals have become quite insane and rearranged several times in many genera. Such dizzying chromosome variations are unusual in vertebrates.
So the small microchromosomes of birds and reptiles are really the “normal” chromosomes rather than our large, fat mammalian chromosomes, which are distorted and inflated by repeated DNA sequences.