Funded Grants

Researcher: Leonid  Kruglyak, Ph.D.

Grantee: Fred Hutchinson Cancer Research Center, Seattle, WA, USA

Researcher: Leonid Kruglyak, Ph.D.HUMAN GENETICS

Grant Title: Human Genetics in the Twenty-First Century

Grant Type: Research Award

Year: 1999

Program Area: Centennial Fellowship

Amount: $1,000,000

Human Genetics in the Twenty-First Century

As human genetics approaches the turn of the century, many powerful molecular tools are either in place or about to arrive. They include a large capacity for DNA sequencing, an ability to examine many polymorphisms in many people, and techniques for monitoring expression levels of many genes under many conditions. These tools are already generating large amounts of data. Early in the next century, we can envision obtaining complete DNA sequences of many individuals, expression levels of all genes in a variety of cells, and a complete characterization of protein levels and interactions. The key task facing human genetics is interpreting this data.

My research centers on addressing different aspects of this task. These include understanding the genetic basis of diseases and other phenotypes, the evolutionary history of human populations, and the regulatory networks of gene expression.

Genetic basis of disease. Genetic factors are thought to play some role in susceptibility to almost all diseases. We can search for these factors using several approaches. The most well-known entails tracing inheritance patterns of disease in families in order to implicate particular chromosomal regions in disease transmission. Such studies have produced many important advances in our understanding of the genetic basis of diseases am other phenotypes, particularly those with simple Mendelian inheritance. For more common disease, such as diabetes, heart disease, cancer, multiple sclerosis, asthma, manic depression, and schizophrenia, success have harder to come by because of the problems posed by genetic complexity. The genetic basis of such diseases is likely to consist of a large number of subtle effects, whose detection may require a prohibitively large number of families. Population studies offer a potential way to overcome this hurdle. The most direct approach is to start with a mutation and examine its effect on frequency of disease in populations. Alternatively, we can recognize that an people share ancestry sufficiently far back in time, and that many mutations in today's population are likely to have a common origin. We can therefore search the DNA of population members for ancestral signatures of this origin.

Population history. The best repository of historical information is the DNA of population members. Patterns of spelling changes in the genetic code contain a record of population divergences, migrations, bottlenecks, replacements, and expansions. In addition to its inherent interest, this information provides important insights into the use of populations for studies of the genetic basis of disease, including the specific advantages offered by different populations. Molecular approaches have already contributed a great deal to our understanding of human evolution. These approaches need to be updated to take full advantage of modem molecular tools, provide a more detailed look at the entire genome, and resolve finer points of population diversity and relationships.

Regulatory networks. The genetic code is a static record of information. The dynamic response of a cell to changing conditions is governed in large part by which genes are expressed-transcribed into messenger RNA. Several emerging technologies now allow simultaneous measurements of transcription levels of many genes in a cell under a variety of conditions. A key task is to reconstruct the network of interactions among genes from these observations. Understanding such regulatory networks is an important part of studying any biological process. Going beyond gene expression, many important dynamic responses involve modifications and interactions of proteins. Once technology allows proteins to be monitored with ease, ideas developed to understand networks of interacting genes can be applied to this next level of complexity.

Genetic research must be applied responsibly. A key aspect of this goal is education. We must make our research and its implications clearly and broadly understood. Armed with appropriate information, society win be prepared to face the complex questions posed by progress in human genetics, reaping the benefits while avoiding the pitfalls. Genetic approaches extend beyond human genetics to studies of pathogens and organisms of agricultural importance, and even more broadly to a better understanding of genetics and biology of all organisms. The ultimate benefits of genetic research to society take many forms: better medicine, improved quality of life, increased knowledge, and a greater understanding of who we are and where we fit in among other forms of life.