2011 marks ten years since the release of the first draft of the human genome, and as often happens with anniversaries, there has been much recent discussion, within both the scientific community and the general public, about what has often been called “the genetics revolution” and its impact on science and medicine. In this essay, we will outline the gains and the challenges of neurogenetic disease-oriented research. Considering the past two decades of advances in neurogenetics, there has been a wealth of exciting discoveries, but there are also opportunities to learn some lessons from failed experiments and a chance to reflect on challenges that might have prevented or delayed the development of successful interventions for some disorders.
There is no doubt that the sequencing of the human genome has been a critical scientific milestone that has revolutionized biology and medicine. Yet, it is noteworthy that in the decade before the completion of the human genome project, neurogenetics was already on the rise. Looking back, it is clear that many exciting discoveries would not have been possible without some key collaborations between astute clinicians and technically innovative basic scientists. It is also astounding how much these gene discoveries have taught us not only about particular diseases but also about basic neurobiology. The discovery of the gene for Duchenne muscular dystrophy (DMD) (Koenig et al., 1987
) in 1986–1987 highlights the critical role of clinical genetics, cytogenetics, and linkage in delineating the location of a gene (Francke et al., 1985
; Lindenbaum et al., 1979
; Murray et al., 1982
). DMD was one of the first gene discoveries for an inherited disorder, and over the last two decades, DMD has been a model disorder for the development of new diagnostics and therapeutics for a genetic disorder. In 1983, mapping the gene of Huntington disease (HD) to the short arm of chromosome 4 by using restriction fragment length polymorphisms and linkage in a large family marked a new era, wherein a disease gene can be mapped without any prior knowledge from cytogenetic abnormalities (Gusella et al., 1983
). Likewise, the discovery of dinucleotide polymorphic repeats (Gyapay et al., 1994
) and the ease of genotyping such repeats with poylmerase chain reaction (PCR) facilitated genetic mapping and was a key factor in uncovering duplications and deletions of the PMP22
locus as the cause for Charcot-Marie tooth disease (CMT1A) and hereditary neuropathy with liability to pressure palsy (HNPP), respectively (Chance et al., 1994
; Lupski et al., 1991
). These landmark discoveries opened up the field of genomic disorders in neurobiology and beyond (Lupski, 2009
Similar combinations of advanced cytogenetics, somatic hybrid techniques, and molecular genotyping played a critical role in refining the maps of several neurodevelopmental disorders including fragile X syndrome, Miller-Dieker lissencephaly, and Prader-Willi-syndrome (Ledbetter et al., 1981
; Reiner et al., 1993
; Verkerk et al., 1991
). The discovery of polymorphic tri- and tetranucleotide repeats (Edwards et al., 1991
) was a critical advance for defining dynamic mutations as a new mutational mechanism in several neurological disorders (see below). Thanks to this discovery, clinical enigmas such as the Sherman paradox in fragile X syndrome and the clinical phenomenon of anticipation, involving an earlier onset and more severe disease in successive generations, such as seen in disorders like myotonic dystrophy, HD, and the ataxias, were resolved. The development of large insert cloning and other physical mapping techniques (Burke et al., 1987
; Schwartz and Cantor, 1984
), as part of the framework for sequencing the human genome, played a crucial role in facilitating the discovery of many disease genes during the nineties. Certainly, cloning the gene for Rett syndrome would not have been possible in 1999 had it not been for the intense mapping and sequencing efforts on the X chromosome (Amir et al., 1999
With the release of the first drafts of the human genome sequence in 2001, the landscape of gene discovery changed tremendously, so that the once tedious physical mapping and cloning experiments slowly gave way to candidate gene analysis by sequencing. Computational analysis of mapping intervals and careful selection of candidate genes for sequencing replaced months and years of bench work. Having the sequence of genomes from several other species, like mouse, Drosophila, and, more recently, nonhuman primates, has certainly advanced neurobiological disease research, permitting in vivo functional studies in a whole range of model organisms.
Without doubt, during the last ten years, thanks to the integration of phenotypic mapping and sequencing data with tremendous analytical and computational resources, the neurobiology community has witnessed disease gene discoveries at an amazing pace, sometimes on a monthly or even weekly basis. Equally inspiring and impressive has been the fact that these gene discoveries have revealed new insights into basic biological mechanisms that extend far beyond the specific disease in question. Yet in the face of such tremendous progress, it has been surprising to see that there has been a fair amount of pessimism within the popular press about whether “the genetics revolution” has fulfilled its promise. In June of this year, the title of a prominent NY Times article stated, “A decade later, genetic map yields few new cures” (Nicholas Wade, NY Times, June 12, 2010). The first sentence read, “Ten years after President Bill Clinton announced the first draft of the human genome was complete, medicine has yet to see any large part of the promised benefits.” Questions have been raised about whether the investment in genetics and genomics has delivered.
Yet, when one considers some of the transformative changes in the realm of human neurogenetic disorders, there can be little doubt that, in fact, genetic discoveries over the past two decades have already changed not only the practice of clinical medicine in neurology and psychiatry, but also the outlook for many families afflicted by these devastating disorders. A mere 20 years ago, patients with hereditary ataxia had to undergo a number of expensive and sometimes invasive investigations including brain scans, spinal taps, numerous blood tests, possibly electromyograms, nerve conduction studies, and sometimes peripheral nerve biopsies. Similarly, children with neurodegenerative disorders or cognitive disabilities had to endure a large number of tests, scans, and sometimes skin or conjunctival biopsies; worst yet, a definitive diagnosis could not be reached and the family was typically left with an uncertain 50% or 25% chance of recurrence in subsequent offspring. Today, a large number of childhood and adult neurological disorders can be diagnosed by a simple DNA test on peripheral blood, saving patients the pain and cost of many additional tests and providing them with a definitive diagnosis. This advancement affords families a better understanding of the disorder afflicting their relatives while providing them with the option of genetic counseling and allowing for preimplantation or prenatal genetic testing, which could not have been done previously. There are several hundred neurological disorders that can now be diagnosed molecularly, including hundreds of cognitive and developmental disabilities such as autism spectrum disorders, dozens of inherited ataxias, inherited neuropathies, dystonias, muscular dystrophies, epilepsies, familial degenerative disorders, and a handful of psychiatric disorders (http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests
). While arguably the pace of development of potential therapies has been relatively slow compared to the speed of disease gene discovery, we should not underestimate the great benefits to families of disease prevention through prenatal diagnosis, and the gains in fundamental neurobiology from pathogenesis studies of neurological disorders.