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Evolution as a Framework for Genome Analysis

by Linda Strausbaugh, Univ. of Connecticut
Society for the Study of Evolutuion

NABT Convention, Reno, NV, Nov.4, 1998

Evolution as a Framework for Genome Analysis

by Linda Strausbaugh, Univ. of Connecticut
Society for the Study of Evolutuion

NABT Convention, Reno, NV, Nov.4, 1998

One of the basic tenets of evolution is the existence of conserved features between organisms as a result of their shared ancestry. This common biological history is inferred not only from the fossil record and contemporary morphological analyses, but also from the shared molecular biology and molecular genetics of living creatures. At the most fundamental levels, all living systems are composed of the same chemical components. In addition, they employ the same molecules for the storage and transmission of hereditary information between generations. The basic mechanisms of genetic information transfer, transcription and translation, are remarkably similar. The genetic code, the Rosetta stone for converting stored genetic information (the base sequence of nucleic acids) into the functional molecules of the cell (amino acid sequence of proteins), is universal. A multitude of biochemical pathways and structural proteins have high levels of identity in the living world.

The Human Genome Project (HGP) is arguably the most ambitious, as well as the most medically and socially relevant, scientific undertaking of all time. The immediate goal of the HGP is to obtain the DNA sequence of the genetic blueprint for the human being; the longer range goal is to decipher the genome and understand the functions of its genes. There are two large problems that accompany the latter goal. First, the enormous size of the human genome (3 billion base pairs) and the small fraction of the genome that is actually expressed (4%) combine to make it technically difficult to focus in molecular terms on a particular gene of interest. Second, once a potential coding region is discovered, it is a major challenge to identify its specific function. The scientific designers of the HGP realized that evolution provides an important framework in which to interpret the human genome, and made provisions for simultaneous study of a number of model organisms. The model organisms contribute advantages missing from humans: smaller genome sizes, the availability of extensive collections of mutations, and the potential for experimental manipulation. Utilization of those features that are conserved through the course of evolution between humans and the model organisms has greatly facilitated the advancement of the functional goals of the HGP.

An example that illustrates the use of an evolutionary framework in genome analysis is the identification of the gene that is responsible for cystic fibrosis. Starting with a broad scale chromosomal localization for the gene, scientists used a "zoo blot" (a DNA profile generated for many organisms) to concentrate their sequencing efforts to a smaller region of the chromosomal DNA. Once the sequence was determined, the scientists were still faced with the problem of determination of the molecular function of the sequence. Using the data bases for model organisms, and the similarity based on evolutionary relatedness, the investigators determined that the putative gene responsible for cystic fibrosis was highly similar to a membrane transport protein. The known functions of the encoded protein in model organisms was completely consistent with the phenotypes of people with cystic fibrosis! This strategy of using DNA and protein information from model organisms to interpret the human genome is at the heart of progress in deciphering the function of human coding sequences. A majority of coding sequences captured from human DNA have been previously studied counterparts in one or more of the model organisms, providing indispensable clues to the function of these genes in people.

 

RESOURCES

The Human Genome. Designed for both students and scientists, the Human Genome Project Information site contains a wealth of information, including very current news, FAQ, quick facts, and project reports. This site also contains information of the ethical, legal and social issues (ELSI) as well as a primer on molecular genetics and scientific terms <http://www.ornl.gov/TechResources/Human_Genome/home.html>

Cystic fibrosis. The Cystic Fibrosis Foundation maintains a site with basic information on the disease, as well as updates on research progress. <http://www.cff.org/>. PBS has also done an excellent documentary "A Question of Genes: Inherited Risks" that includes a case study on cystic fibrosis and the dilemma faced by parents following prenatal testing <www.pbs.org/gene/>.

General information on human genetics & the HGP. Excellent basic texts are available from WCB McGraw-Hill ( Human Genetics Concepts and Applications by Ricki Lewis) and West/Wadsworth (Human Heredity Principles and Issues by~Michael Cummings).

The Cloning and Genetics of Cystic Fibrosis. For the bold who wish to delve into the details of cystic fibrosis molecular genetics, the Sept. 1, 1989 issue of Science features the three basic research articles that elaborate the discovery of the gene responsible for Cystic Fibrosis.

Linda Strausbaugh, U-131, Dept. of Molecular & Cell Biology, The University of Connecticut, Storrs, CT.. 06269-2131 email: <strausba@uconnvm.uconn.edu>