LDRD Report FY 03: Structure and Function of Regulatory DNA: A Next Major Challenge in Genomics

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With the human genome sequence now available and high quality draft sequences of mouse, rat and many other creatures recently or soon to be released, the field of Genomics has entered an especially exciting phase. The raw materials for locating the {approx}30-40,000 human genes and understanding their basic structure are now online; next, the research community must begin to unravel the mechanisms through which those genes create the complexity of life. Laboratories around the world are already beginning to focus on cataloguing the times, sites and conditions under which each gene is active; others are racing to predict, and then experimentally analyze, the structures of proteins that human genes encode. These activities are extremely important, but they will not reveal the mechanisms through which the correct proteins are activated precisely in the specific cells and at the particular time that is required for normal developmental, health, and in response to the environment. Although we understand well the three-letter code through which genes dictate the production of proteins, the codes through which genes are turned on and off in precise, cell-specific patterns remain a mystery. Unraveling these codes are essential to understanding the functions of genes and the role of humanmore » genetic diversity in disease and environmental susceptibility. This problem also represents one of the most exciting challenges in modern biology, drawing in scientists from every discipline to develop the needed biological datasets, measurement technologies and algorithms. The LDRD effort that is the subject of this report was focused on establishing the basic technical and scientific foundations of a well-rounded program in gene regulatory biology at LLNL. The motivation for building these foundations was based on several drivers. First, with the sea-change in genomics, we sought to develop a new, exciting and foreward-thinking research focus for the LLNL genomics team, which could leverage their long-standing investment and expertise in mapping, sequencing, and genetics of human chromosome 19 (ch19). The starting point of this effort was the LLNL and Joint Genome Institute (JGI) genomics teams' success in sequencing mouse DNA related to ch19. This effort was the first comparative sequencing project to be conducted on such a large scale; a manuscript describing this work was published in Science shortly after this LDRD began (Dehal et al., Science 293: 104-111, 2001). Like protein-coding genes themselves, DNA elements that control gene expression are protected from structural change over evolutionary time, since their function is dependent on sequence integrity. By contrast, DNA that serves no function (''junk DNA'') can accumulate mutations that change sequence content without biological consequence. As a result, the ''junk DNA'' of human and mouse are not at all alike in sequence; however, genes and regulatory elements (REs) of human, mouse, and other animals--as far removed from human and fish and birds--are very similar in sequence and structure.« less