Three scientific papers about the Y chromosome, which determines maleness in humans and most other mammals, should lay to rest the myth that it may disappear after a few more million years of evolution. The idea of a dying Y chromosome was popular in the past but recent research shows that it is here to stay – and that it does more for men than merely determining their sex and enabling them to grow sperm.
The research, published in Nature and its sister journal Nature Genetics, shows that the Y chromosome has been stable in a shrunken state over the past 25 million years of primate and then human evolution. When it first appeared as a variant of the X chromosome 300 million years ago, the Y chromosome had about 600 genes but most of these were shed rapidly, early in the process.
The Y has only lost one gene in the past 25 million years, says David Page of Massachusetts Institute of Technology, whose lab carried out one of the studies. “This paper tells us that not only is the Y chromosome here to stay, but that we need to take it seriously – and not just in the reproductive tract,” says Page. “There are approximately a dozen genes conserved on the Y that are expressed in cells and tissue types throughout the body.”
His team and another group based at the University of Lausanne reached their conclusions by tracking the Y’s evolution across many different mammals. They found that what Page calls “an elite group of genes” has been conserved on the Y in distantly related species.
More research will be required to discover what the Y genes that are not involved in sex determination are doing elsewhere in the body. Winston Bellott, another member of the MIT team, argues that women (with two X chromosomes) and men (XY) are subtly different in every cell – a difference that biologists normally ignore.
“We have cell biologists and biochemists actively studying cells without any idea whether the cells are XX or XY,” he says. “This is so fundamental to biology and biomedicine, and yet no one’s really paid much attention to it.”
If scientists can draw up a biochemical catalogue of differences between XX and XY cells, there could be important benefits. “There is a clear need to move beyond a unisex model of biomedical research, which means we need to move beyond a unisex model of our understanding and treatment of disease,” Page says.
The third study, at Uppsala University in Sweden, adds further evidence. It found that the loss of the chromosome from blood cells in elderly men was associated with more cancer and shorter lifespan. “We believe that analyses of the Y chromosome could in the future become a useful general marker to predict the risk of men developing cancer,” says Jan Dumanski, project leader.
Scientific debate over the origin of life on Earth has recently focused on how self-replicating and self-organising molecules, precursors of the first micro-organisms, could have arisen. Another vital question – how metabolism, the series of biochemical reactions that provides cells with materials and energy, started – has been relatively neglected.
Now a study at Cambridge University has looked into metabolism. Research funded by the Wellcome Trust and published in the journal Molecular Systems Biology shows that reactions very similar to those underpinning modern biology could have taken place spontaneously in the early oceans.
The Cambridge scientists used geological evidence to reconstruct in their lab a miniature ocean with the chemical composition and temperature that it would have had four billion years ago, when the first life is believed to have started. There was no free oxygen then and the water would have been rich in iron.
“Our results show that reaction sequences that resemble two essential reaction cascades of metabolism, glycolysis and the pentose-phosphate pathways, could have occurred spontaneously in the Earth’s ancient oceans,” says Markus Ralser, the study leader.
In total, the researchers observed 29 reactions similar to those in biological metabolism, including ones that formed precursors to the building blocks of proteins and of RNA, which probably made up the first self-replicating chemical structures. They were most excited to detect an RNA component called ribose 5-phosphate.
If the results are confirmed by further research, they suggest that prebiotic metabolic networks could have arisen in early oceans and then been incorporated into self-replicating RNA proto-cells, which would have refined the biochemical reactions through the evolution of genetically encoded enzymes. The alternative scenario is that self-replicating RNA arose first and generated metabolic networks.
Promising treatments for specific subgroups of inherited disease are emerging as genetic technology makes it possible to pinpoint the DNA mutations causing trouble.
Duchenne muscular dystrophy is a good example. This distressingly common muscle-wasting disease, which mainly affects boys, results from defects in one of the largest human genes – located on the X chromosome – which makes an important structural protein called dystrophin.
The starting point for genetic treatment is to discover how and where the long dystrophin gene has undergone a harmful change. In about 15 per cent of patients a so-called nonsense mutation is involved: one of the chemical “letters” in the middle of the healthy gene has changed to produce a “stop” signal in the genetic code.
As a result no dystrophin is made. One solution, developed by PTC Therapeutics, a US biotechnology company, is to intervene in the transcription process in which the DNA is converted first to messenger RNA and then into protein. PTC’s experimental drug ataluren is designed to override the false stop signal by interacting with the ribosome – the tiny biological machine inside every cell that runs along messenger RNA and, following the genetic code, puts together protein. Ataluren effectively tells the ribosome to ignore the premature stop signal and keep going so that dystrophin is made after all.
Stuart Pelz, the company’s chief executive, says clinical trials of ataluren are going well, showing that the drug helps boys to walk better. Results of the Phase III trial should be available next year.
At the same time other biotechnology companies are developing drugs to help patients with different types of mutation in the dystrophin gene, which cannot be overridden by a relatively simple chemical like ataluren. Instead, Prosensa of the Netherlands and Sarepta of the US have designed special short stretches of RNA to splice on to harmful mutations, so that the ribosome ignores a small part of the gene.
This “exon-skipping” technology enables cells to make a slightly truncated version of dystrophin, which is not as good as the full protein but better than nothing. Although Prosensa and Sarepta have had trouble gathering clinical trial results good enough to convince the regulators, there is a chance that at least one of their products will reach the market by 2016.
Another option is gene therapy – giving patients a functioning dystrophin gene to do the work of the defective one. This is difficult because the gene is too large to be delivered by the sort of harmless virus normally used for this purpose. A possible solution is to give patients a cut-down gene on the grounds that, as with exon-skipping, a truncated protein can help to preserve muscle function.
Reviewing the whole field, Marita Pohlschmidt, research director of the Muscular Dystrophy Campaign, detects “cautious optimism in the scientific community that some treatments will come through in the coming years”. She notes that a combination of different approaches might be needed for treatment to be fully effective, “depending on the underlying mutations in the dystrophin gene”.
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