Our lab studies the genetic basis of human traits and diseases and develops tools that facilitate such studies. We are interested in basic genetic mechanisms and those that are related to human health and diseases. We use molecular and computational methods to study cellular processes such as regulation of gene expression and stress response in normal and diseased cells.
Genetics of Human Gene Expression
It is well known that individuals differ at the DNA sequence level; however, the effect of DNA sequence variants on phenotypes remains largely unknown. Since the expression level of genes has important effects on cellular phenotypes, we examined the extent of individual variation in gene expression. We found extensive variability and a heritable component to this variation. This allows us to treat expression levels of genes as quantitative traits and to screen the genome for variants that influence these gene expression phenotypes.
We are carrying out genome-wide linkage and association analyses in large families as well as molecular studies. The results have allowed us to identify the polymorphic regulators that influence expression levels of a few thousand human genes. These include cis- and trans-acting regulators, as well as regulators that influence the expression of many genes. More than 60 percent of the regulators were not known to play a role in gene expression regulation. We confirmed a number of these regulatory relationships by gene knockdown and metabolic perturbation studies. These results are allowing us to develop a deeper understanding of gene regulation.
We are continuing these genetic studies and extending our approach to include molecular methods and network analyses to characterize the regulatory landscape of gene expression in human cells at baseline and following cellular stress.
Phenotypes in Carriers of Ataxia Telangiectasia
Ataxia telangiectasia (AT) is an autosomal-recessive disorder characterized by progressive cerebellar ataxia, immune deficiency, and predisposition to cancer. Even though AT is a recessive disorder, population studies have shown that carriers of ATM mutations have increased risk of breast cancer and other diseases. AT is a rare disorder, with a frequency of ~1/40,000, but heterozygous carriers are not rare; their frequency is ~1/100.
To understand the molecular basis of phenotypes in AT carriers, we compared the gene expression phenotypes of noncarriers, AT carriers, and AT patients. As expected, we found expression phenotypes that showed a recessive pattern: where AT carriers are similar to noncarriers but differ from AT patients. There are also, however, gene expression phenotypes that showed a dominant pattern: where AT carriers are similar to AT patients but differ from noncarriers. We analyzed one of these dominant expression phenotypes, TNFSF4 level, and uncovered a regulatory pathway where ATM regulates TNFSF4 through miR125b. In AT patients and carriers, this pathway is disrupted. As a result, compared to noncarriers, AT patients and carriers have lower miR125b and higher TNFSF4 levels, which are associated with risk of breast cancer and atherosclerosis, respectively. We are continuing molecular and computational analyses to study the effects of ATM mutations on human cells.
Genetics of Radiosensitivity
Humans are exposed to radiation through the environment and in medical settings. In recent years, there has been a large increase in the use of radiation in diagnostic procedures and in treatment of diseases such as cancer. These radiation-based tools have significant medical benefits; however, cellular damage can result from exposure to radiation. Individuals differ in their sensitivity to radiation. In this project, we are studying how human cells deal with radiation-induced damages and identifying the DNA variants that influence sensitivity to radiation. We are measuring the gene expression and cellular responses of human cells to radiation, and carrying out genetic studies to map the determinants that influence individual variation in these responses. The results have allowed us to uncover polymorphic regulators of cellular and gene expression response to radiation and to identify genes that play a role in radiation response. Our ultimate goal is to develop ways to determine a person's sensitivity to radiation and make tumor cells more susceptible to radiation therapy.
Human Meiotic Recombination
Meiotic recombination, the process during meiosis I where homologous chromosomes break and rejoin, leads to a reciprocal exchange of chromosome segments. The product of this exchange is a recombinant that has a new combination of genetic alleles that differs from the parental arrangements. Recombination is the fundamental process that shapes genetic diversity. Using single-nucleotide polymorphism (SNP) genotypes of members of multigeneration families such as those in the Centre d'Etude du Polymorphisme Humain collections, we found extensive individual variation in the number of recombination events per meiosis. The locations and frequencies of these recombination events vary along the genome. Our analysis also shows that the preferred sites of meiotic recombination differ greatly among individuals. In collaboration with Eleanor Feingold (University of Pittsburgh) and Stephanie Sherman (Emory University), we are carrying out genetic studies to map the DNA variants that influence the number of crossovers per meiosis and the use of preferred sites for recombination. Early results have already identified several genes that were previously not known to participate in meiosis. These findings have important implications for understanding genetic disorders that result from improper chromosome segregation.
This research was supported by grants from the National Institutes of Health and an endowed chair from the W.W. Smith Charitable Trust.
As of May 30, 2012