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How small can a genome be and still remain functional?

Henry Gee investigates


Tuesday April 24, 2001 The Guardian


Once upon a time, many hundreds of millions of years ago, a few bacteria – a committee of microbes – got together to form the first eukaryote, the first cell with an organised nucleus.

After a while, almost all of the bacteria in this happy union submitted all their genes to this moloch of the nucleus, ceasing to exist as independent entities. The one holdout was the bacterium that became the mitochondrion – then, as now, the energy powerhouse of the cell.


Even today, the mitochondria of eukaryotic cells (yours and mine included) have small, bacterium-like genomes, entirely separate from the much larger genome of the cell nucleus. Some of these simple cells swallowed small, photosyn thetic bacteria, nature's own solar power cells: to invert Swift, capable of distilling sunshine into cucumbers. Like mitochondria, these bacteria retained a vestige of their own genomes even within the larger, symbiotic union.


They became the so-called chloroplasts, and with them, the first cells of green plants appeared. Even then, that was not the end of the story. Some of these simple plant cells – each loaded with a nucleus, a mitochondrion and a chloroplast – were swallowed by larger cells without chloroplasts. The results of this secondary symbiosis can be seen in many apparently simple green algae, whose chloroplasts seem enveloped in an unseemly complexity of membranes: the swallowed plant cell has lost most of its matter, its mitochondrion and even its nucleus, leaving just a chloroplast shrouded in the membranes, the husk of what was once a creature with its own destiny.


Well, almost. There are some single-celled algae, the romantic and mysteriously named cryptomonads, in which the secondary symbiont retains a tiny nucleus in addition to the chloroplast. The cryptomonad cell wears this shrivelled second nucleus, or "nucleomorph" the same way a headhunter would wear the shrunken heads of its enemies slung on its belt. But even after hundreds of millions of years of slavery, the nucleomorph is still not quite dead. Indeed, it may have much to teach us. In today's Nature, Thomas Cavalier-Smith, of the University of Oxford, and colleagues pre sent the complete sequence of the genome of the nucleomorph of a cryptomonad, called Guillardia theta.


Compacted into three, minute chromosomes, the nucleomorph contains 551,264 basepairs of DNA. It is the smallest eukaryote genome sequenced so far. For comparison, the human genome is 6,000 times the size. The genome of the leprosy bacterium Mycobacterium leprae – itself a relic of a much larger genome – is six times the size of the nucleomorph genome. But whereas the human genome is more than 90% junk, the nucleomorph genome is a model of succinct organisation. Its 551 genes are packed together with a density unknown in eukaryotes.


There is virtually no repetitive DNA or wasted gaps between genes – 44 of the genes even overlap, a feature virtually unknown outside the super-concise genomes of viruses. Not that the nucleomorph genome is a powerhouse of activity. The remorseless pressure of millions of years, in which virtually all the activities of the cryptomonad cell have devolved to the much larger principal nucleus, have left the nucleomorph with virtually no genes associated with any kind of metabolic activity. Of all its remaining genes, just 30 seem to be connected with the maintenance of the chloroplast. All the other genes – more than 400 – are concerned with genomic housekeeping, functions such as DNA replication.


These genes seem to be essential to keep the nucleomorph functioning as an independent genomic entity: teleologically, to support the 30 genes that seem necessary to attend to the chloroplast. This peculiar, desperate genome, hanging on to its own independence by its metaphorical fingernails, could have a lot to teach us about genome design. It could be the smallest possible genome that it is possible for a eukaryote to have.


This begs the question of why these nucleomorphs survive at all, when those of most of their relatives perished millions of years ago to leave lone and unattended chloroplasts. It could be that the nucleomorph is maintained because its particular service to the chloroplast in cryptomonads is vital.


Even allowing for what seems a somewhat ad-hoc explanation, one is entitled to ask why – if only for these nucleo morphs – there seems to be an irreducible genomic minimum? The answer, like so many things in biology, lies in comparisons with other creatures. Cryptomonads are not the only organisms whose chloroplasts retain a sliver of a remnant nucleus. Nucleomorphs, derived from an entirely independent symbiotic event from that which created cryptomonads, are also found in a group of single-celled organisms called chlorarachniophytes.


Although only distantly related to cryptomonads, these creatures also contain chloroplasts with attendant nucleomorphs of about the same size as that found in cryptomonads. Furthermore, the genomes of these nucleomorphs are divided into three minuscule chromosomes. Such a case of close, parallel evolution demands some explanation, and it comes from lateral thought.


Rather than asking the question of why the nucleomorph could not get any smaller, Cavalier-Smith and colleagues pose a deceptively simple question – why do the nucleomorphs of cryptomonads and chlorarachniophytes have just three chromosomes? Why not, say, two, or four, or six? The answer could be that to package the genome into one or two chromosomes would create a single stretch of DNA too long to divide reliably in the confined cell-within-cell space available.


On the other hand, dividing the DNA into more than three chromosomes would have led to chromosomes too small to be stable – chromosomes that would have fizzled away to nothing. Three seems to be the magic number that has allowed this weird, condensed, resilient genome to survive for long enough such that it can be wondered at by another eukaryote – this one a multicellular creature, put together by another committee of smaller beings – ourselves.


Henry Gee is a senior editor of Nature.

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