University of Pennsylvania The Children's Hospital of Philadelphia Department of Pediatrics, Division of Neurology 3615 Civic Center Blvd. Abramson Pediatric Research Center, Room 716B
(215) 590-4950


Human Genetics, Genomics

Research Interests
Human Genetics, Genomics

Key words: Human Genetics, Genomics.

Description of Research
Our research interest is in human genome variation. We are using genome-wide approaches to study the genetic basis of human phenotypes and traits.

Genetics of Gene Expression in Humans
Traditionally, we think of phenotypes as characteristics such as height, eye-color and serum cholesterol level. Today, with tools such as gene expression microarrays, we can expand these quantitative phenotypes to include expression levels of genes.
We are assessing the degree of variation in the expression level of genes among normal individuals. The human genome project has provided a detailed description of the variation in DNA sequence, but little is known about natural variation in gene expression. We begin by using microarrays to profile the expression levels of 10,000 genes in several hundred individuals that are members of large 3-generational families. Our goal is to identify the genes whose mRNA transcript levels vary the most among individuals. These variable genes are most amenable to genetic dissection. Then, we are using genetic analysis and computational approaches to map and identify the cis- and trans-acting elements that regulate expression levels of the ?variable? genes.

Genetics of Radiosensitivity in Humans
Although it is known that individuals have different responses to ionizing radiation, little is known about the genetic basis of this variation. Humans are exposed to radiation through the environment and in medical procedures. By understanding the genetic basis of radiosensitivity, we hope to identify radiosensitive individuals and to better understand cellular response to radiation exposure.
In part of this project, we are examining the expression profiles of heterozygous carriers of ataxia telangiectasia (AT). AT is a rare disease but its carriers are relatively common, about 1 per 100 individuals in the US. Studies have shown that AT patients and AT carriers are radiosensitive. AT is a typical autosomal recessive disease where carriers cannot be identified by physical exams or biochemical tests. Yet, by expression analysis, we found a set of genes whose expression levels are significantly different between AT carriers and non-carriers. Our result shows that AT carriers have a distinctive expression phenotype. It provides an opportunity for carrier testing and a basis for a better understanding of the long debated risk of cancer among AT carriers. We are extending this study of AT carriers to carriers of other diseases such as Bloom Syndrome, Nijmegen Breakage Syndrome and Fanconi Anemia whose carriers may also be radiosensitive.
In another part of this project, we are studying transcriptional response of human cells to radiation and assessing the extent of variation in this response. We are using genomic approaches to identify the genes and pathways that are involved in radiation response.

Direct IBD Mapping
We have developed a gene mapping method that does not require locus-by-locus genotyping known as ?direct IBD mapping.? All gene mapping methods rely on identifying regions that are shared identical-by-descent between affected individuals. The most commonly used method is to genotype polymorphic markers in order to determine the regions that are shared between individuals. In a genome scan for disease genes, several hundreds of thousands of polymorphic markers have to be genotyped. Even with tools such as microarrays, genotyping remains an expensive and laborious task. In direct IBD mapping, regions that are identical in sequences between pairs of related individuals are isolated by a biochemical method known as genomic mismatch scanning (GMS). The GMS-enriched DNA fragments are mapped by hybridization onto a microarray containing BAC clones that span the human genome at 1-Mb intervals. GMS is an enrichment procedure where IBD DNA fragments are selected. We are developing ways to improve the enrichment of IBD DNA and to construct microarrays that will allow GMS products to be mapped at higher than 1-Mb resolution.

Rotation Projects
1. Genetics of Gene Expression: To assess variation in human gene expression and to identify the determinants of this variation by using a combination of techniques, including microarrays, reporter assays and chromatin IP.
2. Variation in Meiotic Recombination: To identify hotspots of recombination by localizing sites for meiotic recombination in the human genome and to validate them experimentally using haploid cells.
3. Cellular Response to Radiation Exposure: To identify genes that are involved in radiation response in normal individuals and in patients with defects in DNA repair.

Lab Personnel
William Bernal, MD
Alan Bruzel, PhD, Lab Manager
Josh Burdick
Reshmi Chowdhury
Susannah Elwyn
Kris Halasa
Colleen McGarry, Assistant
Michael Morley
Renuka Nayak
Denis Smirnov, PhD
Sonia Solomon
Xiaorong Wang, PhD
Chris Weber

Assistant Professor of Pediatrics at University of Pennsylvania School of Medicine (1998 – 2004)
Associate Professor of Genetics at University of Pennsylvania School of Medicine (2004 – 2009)
Professor of Pediatrics at University of Pennsylvania School of Medicine (2011 – 2013)
Professor of Pediatrics at University of Pennsylvania School of Medicine (2009 – 2011)
Associate Professor of Pediatrics at University of Pennsylvania School of Medicine (2004 – 2009)
Professor of Genetics at University of Pennsylvania School of Medicine (2011 – 2013)
Assistant Professor of Genetics at University of Pennsylvania School of Medicine (2002 – 2004)
Professor of Pediatrics in Genetics at University of Pennsylvania School of Medicine (2009 – 2011)
M.D., Tufts University, Boston, Massachusetts (1993)
B.S., University of California, Los Angeles (magna cum laude) (1989)
Selected Publications