The genes of OMIM: A legacy of Victor McKusick

Victor McKusick is largely remembered as a clinician and cataloger of inherited disorders; however, those of us who worked with him know that he was perhaps most proud of this role in the effort to map the human genome. This is evident from his 2006 biographical article, A 60-year tale of spots, maps, and genes, in the Annual Review of Genomics and Human Genetics (McKusick, 2006). Originally dissuaded from leaving cardiology to enter the then nascent field of genetics, McKusick followed his passion and curiosity about genetics, perhaps in part because he was an identical twin who referred to his niece as his “half daughter. ” (Victor's brother Vincent would occasionally visit Baltimore and joyfully confuse OMIM staff some of whom did not know the two were twins.) His seminal work, Mendelian Inheritance in Man (MIM) and later the online version, OMIM, was begun at a time when the technology to physically isolate genes was impossible and was his way of trying to bring order to the growing, and often disorganized, body of literature about inherited disorders. MIM first published in 1966 as a catalog of 1487 Mendelian disorders, now, has over 25,700 entries describing both phenotypes (>9300) and genes (>16,400). The OMIM literature review process today focuses on identifying new gene-phenotype relationships or adding to knowledge about existing relationships. In addition, because approximately a third of surveyed users report that they use OMIM to learn about the biological function of genes, a substantial effort is made to identify and add genes with known biological function even in the absence of as yet Mendelian phenotypes associated with variants in those genes. The genetic code was fully deciphered in 1966 and by 1969 McKusick proposed at the International Conference on Birth Defects in The Hague that mapping all the genes would be a useful approach to understanding birth defects (Dronamraju, 2012). Because of his enthusiasm within the then relatively small community of geneticists interested in mapping, McKusick became a key figure in the formative years of what would become the Human Genome Project (HGP). Among several efforts that McKusick championed was the Human Gene Mapping (HGM) workshops that he organized with Frank Ruddle from Yale, a pioneer in the use of interspecies somatic cell hybrids for gene mapping. The first workshop took place in 1973 and by 1977, when McKusick and Ruddle (1977) published “The status of the human gene map,” 210 genes had been mapped with at least one to each chromosome. In 1980, McKusick (1980, 1981) proposed the aspirational goal that all human genes be mapped by the year 2000. The 11 international HGM workshops were held from 1974 to 1991 and led to the creation of the Genome Database (GDB), a repository of gene mapping information. The workshops dove-tailed with the ramp up of sequencing efforts with the initiation of Genome Mapping and Sequencing meetings at Cold Spring Harbor Laboratory (CSHL) in April 1988. At this first CSHL meeting, the idea of establishing an international coordinating scientific body to bring together nascent genome sequencing efforts around the world was suggested by Sydney Brenner. In September 1988, the Human Genome Organization (HUGO) held its founding meeting in Montreux, Switzerland. Thirty-one scientists, including five Nobel laureates from around the world, attended and McKusick was elected its president. Membership grew quickly and scientists from nearly two dozen countries joined. The goals of the organization as detailed in the journal Genomics (founded and co-edited initially by McKusick and Frank Ruddle) were to coordinate research among scientists, exchange data, encourage new technologies, and foster discussion of ethical, legal and commercial implications of the HGP (McKusick, 1989). McKusick had a deep appreciation of history and frequently talked about the development of genetics as well as the role played by Johns Hopkins University (JHU), an institution that he cared about deeply. When McKusick began creating his catalog of human inherited disorders in the late 1950s the molecular bases of very few diseases were known. The cloning of genes and the sequencing of the genome was in the realm of science fiction. As human geneticists identified families segregating phenotypes and markers such as RFLPs (Restriction Fragment Length Polymorphisms) and STRs (Short Tandem Repeats) were developed, the idea of using linkage analysis as Morgan had done decades earlier in Drosophila became a reality. McKusick tracked the pivotal role that technological advances made in science and often described those that made the genome project possible in his presentations (Figure 1). The discovery of restriction enzymes in 1970 (by Tom Kelly and Hamilton Smith at JHU; Kelly Jr. & Smith, 1970) and their subsequent use in DNA cloning and restriction mapping (Nathans & Smith, 1975) followed by the development of the polymerase chain reaction (Mullis et al., 1986) were pivotal advances and worthy of the Nobel prizes that they were awarded. With the ability to produce large amounts of specific DNA molecules, techniques quickly arrived to sequence DNA, first using a method by Maxam and Gilbert (1977) and in 1977 by Fred Sanger (Sanger et al., 1977). Sanger's method was easier and quickly became the standard. Because sequencing reads were only a few hundred base pairs, it was clear that assembling a genome would be a monumental task. In fact, Sanger is said to have joked that sequencing the human genome might have been best suited for prison labor in lieu of making license plates. At the beginning of the HGP, computational tools for analyzing sequences were still in early development and the amount of data generated from a 3 Gb (gigabases) human genome was too large to assemble in a reasonable time with the computational resources and software then available. In part, for that reason many of Received: 12 April 2021 Revised: 2 June 2021 Accepted: 5 June 2021