It was 1978 and I had no intention of working on muscular dystrophy. And then it happened. Dr. Christine Verellen, a young pediatrician from Belgium, contacted me to enquire about training in my lab while her husband was a neonatology fellow at SickKids. On her arrival she told me about Anne, a young European girl with Duchenne Muscular Dystrophy (DMD), an X-linked form of the disease normally affecting only boys. She also told me that Anne had a translocation in which part of the X chromosome had exchanged places with the top segment of chromosome 21. I knew that such a translocation generally results in non-random inactivation of the other (normal) X in most cells, and over the next year Christine proved that in Anne’s cells the normal X, and not the translocated X, was inactive. With her normal X inactive, a disrupted “DMD gene” at the translocation exchange point might explain the fact that she had the disease rather than being a carrier.
Two years passed until 1981 when Hunt Willard was a candidate for a position in Molecular Genetics. Walking with him along University Avenue from SickKids to MSB for his seminar I told him about Anne and mentioned that the short arm of the X appeared to be translocated to a block of genes encoding ribosomal RNA, and with probes for rRNA gene sequences we might be able to identify a piece of DNA from Anne in which ‘rDNA’ was attached to the putative DMD gene. Hunt told me that he had recently come from a job seminar in Philadelphia where a group had just isolated and sequenced the human rDNA gene complex. Bingo! I spent the entire hour of Hunt’s seminar sketching out experiments to isolate that translocation junction fragment and thereby identify the DMD gene. I did not hear a word of Hunt’s seminar.
So why do I tell this story? Serendipity plays a big role in science. What are the chances that the only known female in Europe with X-linked muscular dystrophy is diagnosed by a Belgian pediatrician who later comes with her husband to Toronto and into a lab previously unknown to her, that just happens to have the expertise to demonstrate non-random X-inactivation and experience in somatic cell genetics enabling us to use the power of chromosome segregation in human-rodent hybrid cells to isolate Anne’s translocated X – free of other rDNA-containing human chromosomes – necessary before tackling the next step, with Peter Ray, of isolating DNA from the translocation junction. Identification of the DMD gene was published in 1986 followed 2 years later by identification of dystrophin, its encoded protein.
I also tell the story because this was at a time when DNA technology was crude compared to what is available now, and the DMD gene was the first disease gene to be identified by “positional cloning” – using genetic mapping information to find the gene. (Another part of the gene was identified that same year by Lou Kunkel at Harvard, also by positional cloning.) Others have noted, and I would agree, that this was proof-of-principle for the human genome project that began three years later.
