© 2006 Nature Publishing Group Recent discussions about the state of the pharmaceuti- cal industry have decried annual decreases in new drug applications and new drugs coming to market 1,2 . Lack of novel drugs and drug candidates in the pipeline has become a concern for industry and medical profession- als alike. There are many reasons for this trend, among them the use of inadequately validated targets 3 . Target identification and validation is a crucial first step in developing a drug against a given disease 4,5 . Historically, many drugs were developed without a clear understand- ing of the molecular mechanisms or targets. Today this is seen as a highly inefficient (and expensive) way to screen chemical compounds for biological activities. The avail- ability of the complete human genome sequence has now uncovered all possible drug targets in this organism (or at least all protein and nucleic acid targets), although for many (perhaps most) of these the biological functions remain to be determined. The question has therefore shifted to choosing from among all potential targets those that are most amenable to chemical intervention and those that are most likely to yield desired physiological consequences in the disease state. A fundamental difficulty in drug design is that cru- cial steps of the process occur in a highly reductionist setting; for example, when large chemical libraries are screened for modulators of a biochemically purified enzymatic activity. But because the ultimate setting for the desired action of a drug is the living human milieu, a crucial challenge is to maximize the recovery of appropriate biological activities in the highly complex setting of the organism. There are currently three main approaches that address this problem: use of animal model systems, complex human genetic analysis and Mendelian human genetic analysis. The first involves large-scale mutagenesis in vertebrate model organisms (for example, mouse, fish or mammalian tissue culture cells), followed by the characterization of mutants and the orthologous human genes 6–11 . Such initiatives are complicated by high logistical costs, difficulties of phe- notyping and the continuing need to extrapolate the phenotypes to human disease. Targeted mutagenesis of specific genes reduces the logistical costs, and is widely used, but the challenge of interpreting the outcomes with respect to human biology still remains. The sec- ond approach, traditionally involving genetic analysis of candidate genes that are selected for biological plausibility, has been generalized by the International HapMap Project, which aims to identify all common genetic variants in human populations. Some of these variants help to identify factors that predispose to com- mon medically and commercially significant diseases, yielding insights into disease mechanisms of potential value in therapeutic development 12 . This model has the potential to provide human biological validation for any given gene of interest for a particular disease condition. Although haplotype mapping has yielded intriguing results, significant theoretical and technical obstacles remain before the fruits of this approach can be fully realized 13 . Less attention has been given to studying monogenic (that is, Mendelian) human disorders as a source of drug targets. Monogenic human genetics provides an ideal opportunity for target validation. When strong inferences can be made about the causal effects of a single genetic *British Columbia Cancer Research Centre, University of British Columbia, Vancouver, British Columbia V5Z 1C3, Canada. ‡ Montreal Heart Institute Research Centre, University of Montreal, Montreal, Quebec H1T 1C8, Canada. § Department of Medicine, University of Montreal. || Department of Ophthalmology & Visual Sciences, Dalhousie University, Halifax, Nova Scotia B3H 2Y9, Canada. ¶ Departments of Ophthalmology & Visual Sciences, Pediatrics and Psychiatry, Dalhousie University. Correspondence to M.E.S. e-mail: Mark.Samuels@iwk. nshealth.ca doi:10.1038/nrg1828 Published online 14 March 2006 Haplotype mapping A technique that involves the use of combinations of ‘common’ DNA polymorphisms to find blocks of association with phenotypic traits. Human monogenic disorders — a source of novel drug targets Ryan R. Brinkman*, Marie-Pierre Dubé ‡ , Guy A. Rouleau § , Andrew C. Orr || and Mark E. Samuels ¶ Abstract | The decrease in new drug applications and approvals over the past several years results from an underlying crisis in drug target identification and validation. Model organisms are being used to address this problem, in combination with novel approaches such as the International HapMap Project. What has been underappreciated is that discovery of new drug targets can also be revived by traditional Mendelian genetics. A large fraction of the human gene repertoire remains phenotypically uncharacterized, and is likely to encode many unanticipated and novel phenotypes that will be of interest to pharmaceutical and biotechnological drug developers. NATURE REVIEWS | GENETICS VOLUME 7 | APRIL 2006 | 249 REVIEWS FOCUS ON MONOGENIC DISORDERS