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Structural and Computational Biology and Molecular Biophysics

Houston, Texas

A BCM research lab.
Structural and Computational Biology & Molecular Biophysics
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Penelope E. Bonnen, Ph.D.

Penelope E. Bonnen, Ph.D. Assistant Professor, Department of Molecular and Human Genetics

Baylor College of Medicine

Education:

B.S., Texas A&M University, 1993
Ph.D., Baylor College of Medicine, 2002
Postdoc, Rockefeller University, 2008

Research Interests:

The intersection of genomics, population genetics, and disease

Our research objective is to understand how events in human history shape our genomic landscape and contribute to phenotypic diversity. Ever increasing amounts of sequence and SNP data have facilitated better characterization of the architecture of the human genome. Demographic and population genetic events, such as admixture, population bottleneck, and natural selection have left distinct signatures on our present day genomes. Characterization of these features of the genomic landscape is in its infancy. I seek to gain a better understanding of these features and exploit them to map loci that confer susceptibility to and protection from disease, particularly infectious and metabolic disease.

Utilizing population genetics to identify genes contributing to Metabolic Syndrome

The “Thrifty gene hypothesis” asserts that the ability to store energy may have been a selective advantage for human populations living through cycles of nutritional privation. It follows that this evolutionary adaptation could also confer susceptibility to obesity for these populations when no longer subjected to periods of privation. Pacific islanders are one such population who existed historically as hunter-gatherers, but who now have a Western diet and live a more sedentary life-style resulting in high rates of obesity, diabetes, heart disease, and hypertension (Metabolic Syndrome). I study a population of individuals from the Pacific Island of Kosrae who suffer from high rates of metabolic disease. Projects include mitochondrial genetic contribution to metabolic disease, testing the “thrifty gene hypothesis” by examining the autosomal genome for signs of selection, GWAS for iron-overload genes, and utilizing mitochondria and Y chromosome markers to decipher the peopling of Micronesia.

Genomics to indentify genes causing Mitochondrial Disease: The goal of this project is to combine high throughput genomics with studies of mitochondrial function to identify genes that cause mitochondrial disease and to translate these findings into diagnostic tests. Mitochondrial disease has an incidence of 1/5000 and can affect every organ system. Mitochondrial disease is known to have Mendelian inheritance, however most pateitns are not successfully molecularly diagnosed. We are using next-generation sequencing methods to generate genome-wide for potentially pathogenic mutations. We then perform functional analysis using rnal knockdown and complementation assays to identify disease genes and further elucidate their function. This project will significantly advance the diagnosis and treatment of mitochondrial disease, as well as provide new insights into the mechanisms underlying the pathology of mitochondrial respiratory chain disorders and commonly occurring conditions associated with mitochondrial dysfunction such as cancer, diabetes, and aging.

Understanding mutation dynamics and cancer: Lynch syndrom (LS), also commonly known as hereditary non-polyposis colorectal cancer, is an autosomal dominant disorder caused by an inherited pathogenic germline mutation in one of the DNA mismatch repair (MMR) genes. The deficient MMR predisposes mutation carriers to a variety of different cancers with colon and endometrial cancer being the most common. We hypothesize that LS patients experience increased levels of de novo mutations in germ cells due to decreased MMR capacity and that consequently these individuals transmit an increased mutational burden to their offspring. While most of these mutations are unlikely to affect cancer risk (i.e. passenger mutations), a small proportion may convey an increased risk for early onset cancer, thereby providing an explanation for genetic anticipation in LS. We are conducting whole genome sequencing of LS families to assess the extent of de novo mutations in the offspring and bioinformatically assess the potential for the genes harboring these mutations to influence cancer incidence.

Selected Publications:

  • Murdock D, Salit J, Stoffel M, Friedman JM, Pe'er I, Breslow JL and Bonnen PE. Longitudinal study shows increasing obesity and hyperglycemia in micronesia. Obesity (Silver Spring), [Epub ahead of print] (2012). PubMed
  • Bacino CA, Dhar SU, Brunetti-Pierri N, Lee B and Bonnen PE. WDR35 mutation in siblings with Sensenbrenner syndrome: a ciliopathy with variable phenotype. Am J Med Genet A, 158A(11):2917-24 (2012). PubMed
  • Bacino CA, Arriola LA, Wiszniewska J and Bonnen PE. WDR62 missense mutation in a consanguineous family with primary microcephaly. Am J Med Genet A, 158A(3):622-5 (2012). PubMed
  • Bonnen PE, Lowe JK, Altshuler DM, Breslow JL, Stoffel M, Friedman JM and Pe'er I. European admixture on the Micronesian island of Kosrae: lessons from complete genetic information. Eur J Hum Genet, 18(3):309-16 (2010). PubMed
  • Bonnen PE, Wang PJ, Kimmel M, Chakraborty R and Nelson DL. Haplotype and linkage disequilibrium architecture for human cancer-associated genes. Genome Res, 12(12):1846-53 (2002). PubMed
  • Aradhya S, Woffendin H, Bonnen P, Heiss NS, Yamagata T, Esposito T, Bardaro T, Poustka A, D'Urso M, Kenwrick S and Nelson DL. Physical and genetic characterization reveals a pseudogene, an evolutionary junction, and unstable loci in distal Xg28. Genomics, 79(1):31-40 (2002). PubMed

For more publications, see listing on PubMed.

Contact Information:

Department: Molecular and Human Genetics
Address: Baylor College of Medicine
One Baylor Plaza, N1419
Mail Stop: BCM226
Houston, TX, 77030, U.S.A.
Phone: 713-798-4256
Fax: 713-798-6977
E-mail: pbonnen@bcm.edu
Additional Links: Human Genome Sequencing Center

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