Huntington F Willard, director of the Center
for Human Genetics talks with local doctors
about genetic advances in medicine. (photo BA)
Willard has written numerous papers on human molecular genetics. In 1997 he helped create the first human artificial chromosome, a major breakthrough in genetics given front page coverage by the national and international press. The human genome projected started with an ambitious agenda: identify the human genome, those 70,000 to 100,000 genes we all carry in our bodies, that is, all the inheritable traits of a human.
Today, this agenda is approaching reality. In the future, genomic medicine will increasingly affect the diagnosis and treatment of disease. Willard explored this theme in an Enloe Medical Conference talk, "When All Genes are Known: Genetic and Genomic Medicine in the 21st Century."
Within the next several years, the human genome, made up of about 3 billion base pairs of DNA, will be mapped. The average or "typical" gene has about 50,000 base pairs. Only one base pair may carry the mutation that relates to a particular disease. "It's the ultimate needle in a haystack," said Willard.
The Human Genome Project will provide a reference genomic sequence within the next two to five years, but it will not have defined all the functions of all genes and their variations. There are 3 to 5 million differences between any two human genomes. These variant sequences, or alleles, "occur in about every thousand base pairs in the population," Willard explained. "For each and every gene in our genome, there are dozens and dozens of relatively common variants."
Some of these variants lead to disease, although purely genetically determined diseases caused by a single gene are rare. "The mutations in these diseases, like cystic fibrosis and muscular dystrophy, are necessary and sufficient for the disease. If you have the mutation, you will get the disease; if you don't have the mutation, you can't get the disease," said Willard.
Far more common are the complex multi-factorial diseases, in which genetic susceptibility rather than genetic determinism, plays a role. Here, the "individual variants or mutations are neither necessary nor sufficient to lead to the disease," explained Willard. Multiple variants or a combination of variants and environmental insult leads to disease. This category includes not only diseases that run in families, such as diabetes, cancer, and cardiovascular disease, but also a wide range of other diseases, such as birth defects, mental illness, and infectious diseases.
Variants can increase susceptibility or can provide protection. For example, a protective variant in the chemokine receptor gene absolutely eliminates HIV infectivity. "So, despite the fact that an individual may be very highly exposed to the virus, if he carries a particular variant in this gene he will not become infected," said Willard.
Most genetically based diseases arise from a variety of mutations. Sometimes different mutations within the same gene can lead to different diseases; sometimes variants in multiple genes can lead to the same disease.
Cystic fibrosis, for example, a genetically determined disease, derives from one of many different variant alleles. There are about "700 different mutations in that gene that can result in cystic fibrosis," said Willard.
There are only two known diseases in which a specific mutation and only that specific mutation means having the disease: sickle cell anemia and achondroplasia, or short stature disease.
Understanding the genetic basis of disease will lead to improvements in pre-symptomatic diagnosis, at-risk screening, and disease management.Willard warned of the impending shortage of medical geneticists, emphasizing that all physicians will need some training to become more knowledgeable about genetics.