OF MICE AND MEN: PROBING THE MOUSE GENOME                  
   
   Rick Woychik of the Biology Division can tell you almost anything you
   want to know about mouse genes. So, what does this have to do with
   sequencing the human genome? Well, as it turns out, there are a number
   of similarities (perhaps more than we'd like to admit) between mouse
   genes and human genes. And, as a practical matter, it's a lot easier to
   conduct a controlled study of a mouse in a lab than a man on the
   street.      
   
   Woychik looks at efforts to sequence the human genome as the first step
   in understanding how the genetic code actually works. "Once we've
   sequenced and analyzed all the DNA bases of the human genome," he says,
   "we will know where all the genes are, but we won't know what they do."
   Studying the mouse genome could provide some of the missing pieces of
   the genomic puzzle.       
   
   "If we determine the function of a particular mouse gene whose location
   we know," Woychik says, "we can often look at the corresponding area on
   a human chromosome and locate the functionally equivalent human
   gene."       
   
   One of the techniques Woychik uses to probe the mouse genome is known as
   insertional mutagenesis. In this technique, hundreds of identical pieces
   of DNA are injected into mouse zygotes (fertilized eggs) in the hope of
   creating mutations in the resulting offspring. The DNA fragments, or
   "transgenes," are then incorporated, seemingly at random, into the
   zygote's genetic code. More often than not, this process results in
   normal laboratory mice, but every so often an unusual variation in the
   appearance or physical structure of one of the offspring, such as
   malformed limbs or internal organs, suggests that a mutation has
   occurred. "When we see an abnormality in the appearance of the
   offspring," Woychik says, "we test to determine whether the gene that
   was interrupted by a transgene is responsible for the change in
   appearance."        
   
   Another technique used to investigate the function of various mouse
   genes is known as targeted mutagenesis. In contrast to the random
   mutations introduced by insertional mutagenesis, targeted mutagenesis
   allows researchers to determine the effect of introducing a mutation at
   a specific site on a selected gene.                 
   
   This degree of accuracy is achieved by introducing changes in the
   chromosomal DNA of cultured embryonic cells using a process called
   homologous recombination. In this approach, altered genetic material is
   inserted back into the context of a living mouse by microinjecting the
   manipulated cells into a host blastocyst (a 4-day-old mouse embryo).       
               
   
   Uncovering all the functional parallels between the genes of mice and
   humans could easily occupy several research lifetimes, but Woychik and
   his group have a more modest goal. Says Woychik: "We hope we can begin
   to establish molecular connections between individual genes on the
   genome and specific developmental processes in both mice and men.
   

   ------------------------------------------------------------------------
   
   Please send inquiries or comments about this gopher to the mail address:
        gopher@gopher.ornl.gov
   
   Date Posted:  1/10/94  (ktb)