REVIEW PAPER Hunting human disease genes: lessons from the past, challenges for

Abstract The concept that a specific alteration in an individual’s DNA can result in disease is central to our notion of molecular medicine. The molecular basis of more than 3,500 Mendelian disorders has now been identified. In contrast, the identification of genes for common disease has been much more challenging. We discuss historical and contemporary approaches to disease gene identification, focusing on novel opportunities such as the use of popu-lation extremes and the identification of rare variants. While our ability to sequence DNA has advanced dra-matically, assigning function to a given sequence change remains a major challenge, highlighting the need for both bioinformatics and functional approaches to appropriately interpret these data. We review progress in mapping and identifying human disease genes and discuss future chal-lenges and opportunities for the field