Molecular Biology Faculty
Daniel A. Notterman
Lewis Thomas Lab, 205
Genetic, epigenetic, and environmental interactions with child development and health.
Dan is a pediatrician by clinical training and a biologist whose research examines interactions between genetic variants and environmental signals in the developing behavioral, cognitive and emotional phenotype of the child. He wishes to understand the interactions between specific genetic variants, environmental signals, and resulting behavioral and health outcomes. For example, his group recently showed that women with a short, hypomorphic form of the promotor region of HTT (serotonin transporter) are more likely to experience post-partum depression in stressful socioeconomic circumstances then they are in more stable environments. However, women with the major allele of this gene (long promotor) do not display this environment-based difference in rate of postpartum depression. This is consistent with the idea that some gene variants express proteins that enhance an organism's sensitivity to the environment—so called "reactive alleles."
It is also known that variations in environmental input induce longstanding behavioral changes by affecting the methylation state of DNA. There is great excitement around these sorts of findings because it points the way to a biological understanding—invoking epigenetic mechanisms—of the relationship between adverse or favorable early environments and lifelong behavioral traits.
Notterman's lab is engaging these issues through several collaborations with social scientists and pediatricians. The lab serves as the genomics/epigenomics resource for the Fragile Family and Child Wellbeing Study (FFS), based at the Woodrow Wilson School at Princeton. The FFS is following a cohort of nearly 5,000 children born in large U.S. cities between 1998 and 2000 (roughly three-quarters of whom were born to unmarried parents). The study is in its 15th year, and we have collected DNA from participants at year and 9 and again at year 15. This enables us to make detailed correlations between genetic and epigenetic states and social, behavioral, health, and demographic data.
Using this information, his group recently showed that adverse early environments are associated with accelerated loss of telomeres by age 9 years, and that the extent of loss is moderated by genetic variants in serotonergic pathways. This is again consistent with the hypothesis that the products of these genes modulate the organism's environmental sensitivity and was featured in a commentary in Nature. Since early life telomere length is associated with both adult health and with lifespan, this research suggests a mechanism for the known effect of social disparity on well being throughout the lifespan.
Major projects include the comprehensive genotyping of more than 7500 DNA samples from the FFS cohort (mothers and children). Accompanying this project is a complementary effort to measure the methylation of DNA CpG sites. At a more mechanistic level, his group is trying to understand the biological mechanism that seems to link telomere erosion to stress.
A second area of focus is the genetics of autism. His group has developed a cohort of families in which more than one sibling has an autism spectrum disorder. Currently, we are analyzing whole genome sequence data, as well as exam and methylation data on monozygotic and dizygotic twins (and their parents and siblings), some of whom have discordant phenotypes. This will enable us to make detailed correlations between the autistic phenotype and various genetic and epigenetic abnormalities.
Mitchell C, Hobcraft J, McLanahan SS, Siegel SR, Berg A, Brooks-Gunn J, Garfinkel I, Notterman D. (2014) Social disadvantage, genetic sensitivity, and children's telomere length. Proc Natl Acad Sci. 111:5944-9. Pubmed
Mitchell C, McLanahan S, Brooks-Gunn J, Garfinkel I, Hobcraft J, Notterman D. (2013) Genetic differential sensitivity to social environments: implications for research. Am J Public Health. 103 Suppl 1:S102-10. Pubmed
Lee D, Brooks-Gunn J, McLanahan SS, Notterman D, Garfinkel I. (2013) The Great Recession, genetic sensitivity, and maternal harsh parenting. Proc Natl Acad Sci. 110:13780-4. Pubmed
Giacobbe A, Bongiorno-Borbone L, Bernassola F, Terrinoni A, Markert EK, Levine AJ, Feng Z, Agostini M, Zolla L, Agrò AF, Notterman DA, Melino G, Peschiaroli A. (2013) p63 regulates glutaminase 2 expression. Cell Cycle. 12:1395-405. Pubmed
Mitchell C, Notterman D, Brooks-Gunn J, Hobcraft J, Garfinkel I, Jaeger K, Kotenko I, McLanahan S. (2011) Role of mother's genes and environment in postpartum depression. Proc Natl Acad Sci. 108:8189-93. Pubmed
Postel EH, Zou X, Notterman DA, La Perle KM. (2009) Double knockout Nme1/Nme2 mouse model suggests a critical role for NDP kinases in erythroid development. Mol Cell Biochem. 329:45-50. Pubmed
Sheffer M, Bacolod MD, Zuk O, Giardina SF, Pincas H, Barany F, Paty PB, Gerald WL, Notterman DA, Domany E. (2009) Association of survival and disease progression with chromosomal instability: a genomic exploration of colorectal cancer. Proc Natl Acad Sci. 106:7131-6. Pubmed
Postel EH, Wohlman I, Zou X, Juan T, Sun N, D'Agostin D, Cuellar M, Choi T, Notterman DA, La Perle KM. (2009) Targeted deletion of Nm23/nucleoside diphosphate kinase A and B reveals their requirement for definitive erythropoiesis in the mouse embryo. Dev Dyn. 238:775-87. Pubmed
Bacolod MD, Schemmann GS, Giardina SF, Paty P, Notterman DA, Barany F. (2009) Emerging paradigms in cancer genetics: some important findings from high-density single nucleotide polymorphism array studies. Cancer Res. 69:723-7. Pubmed
Cheng YW, Pincas H, Bacolod MD, Schemmann G, Giardina SF, Huang J, Barral S, Idrees K, Khan SA, Zeng Z, Rosenberg S, Notterman DA, Ott J, Paty P, Barany F. (2008) CpG island methylator phenotype associates with low-degree chromosomal abnormalities in colorectal cancer. Clin Cancer Res. 14:6005-13. Pubmed