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Human Genetics of Complex Phenotypes and Gene Regulation
Summary: Vivian Cheung investigates the genetic basis of complex human traits and develops tools that facilitate such studies.
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 meiotic recombination 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.
In collaboration with Richard Spielman (University of Pennsylvania School of Medicine), we carried out genome-wide linkage and association analyses in large families to identify the determinants of expression phenotypes. The results allowed us to identify the regulatory regions for more than 1,000 genes. These include cis- and trans-acting regulators, as well as regulators that influence the expression of many genes. We are analyzing these regulatory regions to identify the sequence variants that influence gene expression, and we are performing molecular studies to characterize these regulators. We are also extending the study from cells at baseline to those that have been exposed to medically and environmentally relevant agents.
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. Although AT is a rare disorder, with a frequency of ~1/40,000, 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 are determining the mechanisms that lead to expression of these dominant phenotypes. Preliminary results show that these phenotypes are due to disruption of an ATM-mediated transcriptional regulatory pathway. This aberrant pathway also influences development of breast cancer in AT carriers.
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 the Centre d'Etude du Polymorphisme Humain families, 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. These findings have important implications for understanding genetic disorders that result from improper chromosome segregation. We are analyzing additional samples to characterize variation in human recombination phenotypes.
This research was supported by grants from the National Institutes of Health and an endowed chair from the W.W. Smith Charitable Trust.
Last updated: January 3, 2008
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