Bulletin No. 1, 2011

Breakthroughs in Fetal Genomic Mapping   35  Breakthroughs in Fetal Genomic Mapping P rof. Dennis Y.M. Lo, Li Ka Shing Professor of Medicine and Professor of Chemical Pathology at CUHK, made a splash in 1997 by discovering that the DNA of an unborn fetus could be found in the blood plasma of its pregnant mother. He went on to develop a new method for the prenatal diagnosis of Down syndrome which averted the risk of miscarriage inherent in traditional invasive methods. His pioneering work has made possible a new generation of non-invasive tests but so far these have been limited to screening one disease at a time. In 2010, he and his team made a breakthrough by showing that the entire fetal genome is represented in maternal plasma. The next step of devising a non-invasive fetal genome scan was challenging, as fetal DNA molecules, which account for only about 10% of the DNA in the maternal plasma, are highly fragmented. Constructing the fetus's genetic profile from these fragments would be tantamount to assembling a million-piece jigsaw puzzle. To overcome this, the CUHK research team led by Professor Lo sequenced nearly four billion DNA fragments from a maternal blood sample, which was equivalent to some 65-fold coverage of the human genome. They then constructed separate genetic maps that the fetus had inherited from the father and from the mother. By combining the paternally-inherited and maternally-inherited genetic maps, CUHK researchers were able to arrive at a genomic map of the fetus. They then used this map to confirm that, in the test case in point, the fetus was a carrier of beta-thalassaemia from the father’s side, which should not cause any serious postnatal problems. By carefully sequencing the maternal plasma DNA, Professor Lo’s team has been able to reveal the genome-wide genetic and mutational profile of the fetus. Their findings were published as the cover story in the 8 December 2010 issue of Science Translational Medicine , a prestigious interdisciplinary biomedical journal. The implication of this ground-breaking research is that by analysing a blood sample from the pregnant woman the entire genome of the fetus can be deduced and screened for many possible genetic disorders in one go.