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Making the most of a little DNA

June 16, 2006 By Jo Marchant This article courtesy of Nature News.

New tests could make it easier to detect IVF embryos at risk of genetic disease.

A way of vastly amplifying the genome of a single cell is allowing unprecedented insights into the potential of embryos created during fertility treatment. Embryos can already be checked for some genetic abnormalities, but tests are limited by the tiny amount of DNA in a single cell removed from the embryo.

The new approach will broaden the scope and reliability of such tests, according to British researchers. The team's first five pregnancies using embryos screened in this way have just been announced.

Pre-implantation genetic diagnosis (PGD) is generally used by couples at risk of passing a serious genetic condition to their children. Embryos are created by in vitro fertilization (IVF) and at the 8-cell stage, one cell is taken for testing. If given the all-clear, the embryo is implanted into the mother's womb.

Traditional PGD uses a method of DNA amplification called PCR, targeted to a specific DNA sequence, to test for a particular mutation. But the amount of DNA available in one cell of the embryo is miniscule — just 6 picograms, less than the mass of a single bacterium. Routine DNA tests aren't sensitive enough, so each PGD lab has to develop its own test for each mutation. For a couple with a rare mutation that hasn't been tested before, that can take 6-12 months, and many are turned away.

Pamela Renwick, Peter Braude and their colleagues from Guy's and St Thomas' Hospital in London believe they have found a better way. They have adapted a method called "whole genome amplification" to work on DNA from a single cell. This amplifies lots of DNA sequences at once, and can multiply a tiny scrap of DNA a million-fold in a few hours. It's rough and ready, but gives researchers a more manageable amount of DNA and vastly expands the range of tests they can do.

One the DNA is amplified, Braude and his colleagues have chosen a method called haplotyping to check whether the embryo carries a genetic abnormality. This doesn't detect the disease mutation — you don't even need to know what the mutation is. Instead it relies on detecting a panel of markers — parts of the DNA sequence that differ between chromosomes and can be used to track which of the mother's and father's chromosomes an embryo has inherited. If you know (from checking other family members) which chromosome carries the mutation, you can distinguish between unaffected, affected, and carrier embryos.

This means that couples can all undergo the same routine haplotype test, regardless of what mutation they have, and even if the precise mutation hasn't been identified. The technique will also make it possible to screen in cases where one parent is at risk of a late-onset disease and the couple wants to rule that condition out in the next generation without finding out whether the parent at risk actually carries the mutation. In this case the tests would look for haplotypes matching affected or unaffected siblings or parents of the possible carrier.

It is one more weapon in our arsenal, to try to get PGD sorted.
Karen Sermon
PGD researcher, Dutch-speaking Free University of Brussels
The method also improves the testing for sex-linked disorders such as Duchenne muscular dystrophy (DMD). Previously, couples at risk of DMD had embryos sexed — all males were discarded. The new test distinguishes between affected and unaffected males, so fewer embryos have to be rejected.

Braude and his colleagues announced at a meeting of the European Society for Human Reproduction and Embryology (ESHRE) in Prague on 19 June that they have used the technique on seven women. This work, discussed in a paper in Reproductive BioMedicine Online1, resulted in five pregnancies — two tested for cystic fibrosis, two for DMD, and one for a condition in which the embryo can become a tumour within the mother's placenta. All the women are due to give birth later this year.

Braude is clearly excited about the work. "It's revolutionary," he says. "This changes everything." He says the technique could work for thousands of disorders, and estimates that it will increase the number of treatments carried out in his lab two- to fourfold.

Stéphane Vivelle, of the Institute of Genetics and Molecular and Cellular Biology (IGBMC) in Strasbourg, France, is more cautious. He's not satisfied that whole-genome amplification is reliable enough yet, and in the meantime is developing ways to haplotype embryos directly from a single-cell's worth of DNA. Either way though, he doesn't think the approach will greatly increase demand for PGD except among very high-risk couples, as it will remain risky and expensive. "It's always more satisfactory to get your baby in your bed, not in our test tubes," he points out.

Karen Sermon at the Dutch-speaking Free University of Brussels is working on a similar technique to Braude, and told Nature that her team carried out its first clinical cycle just a few days ago (16-17 June), looking for a neuromuscular disorder called spino-cerebellar ataxia. "This isn't a paradigm shift," she says. "But it is one more weapon in our arsenal, to try to get PGD sorted."

More interesting, she believes, is the idea of using the amplified DNA to screen an embryo's entire genome. Some women going through IVF have embryos screened using a technique called fluorescent in situ hybridization (FISH). Coloured dyes confirm that particular chromosomes aren't duplicated or missing, but it's pretty crude and only nine chromosomes can be checked, partly because there are only so many different coloured dyes.

A larger sample would allow the use of a DNA chip to check in much greater detail whether all parts of the genome are present and correct. Sermon says she and her colleagues now hope to start a trial to see whether such a screen increases the success rate of IVF — if they can get funding to buy the appropriate chips.

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  1. Renwick P. J., et al. Reproductive BioMedicine Online, (2006).


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