Molecular and Human Genetics
Baylor College of Medicine
Houston, TX US
Dan L Duncan Comprehensive Cancer Center
Baylor College of Medicine
Houston, Texas United States
- BA from University Of Cambridge
- 01/1962 - Cambridge, United Kingdom
- PhD from University Of Cambridge
- 01/1965 - Cambridge, United Kingdom
- Post-Doctoral Fellowship at Harvard University
- 01/1965 - Cambridge, MA United States
- Mechanism of amplification and genome instability in Escherichia coli and human
Professional StatementPart of my current work is on the genetic responses to stress in Escherichia coli. We have shown that gene amplification occurs in response to stress, and is, therefore, an adaptive process comparable to the well-known adaptive mutation response. We are using genetic and molecular techniques to elucidate the mechanism by which adaptive amplification occurs. Because this genetic instability would be part of an adaptive response, we expect to be able to induce it, and thus to study the processes by which genetic instability occurs. This might provide a model system in which to study the induction of chromosomal instability in oncogenesis (about 80 percent of cancers show chromosomal instability), and in evolution.
We have discovered that amplification is initiated by a template-switch mechanism during replication. By comparing our data to those derived from yeast and human cancer and genomic disease, we have derived a model for the origin of chromosomal structural changes for all organisms. This then suggests a mechanism for the origin of copy number variation (the major genetic difference between individuals) and for genomic disease. The model involves modification of the mechanism of replication fork repair occurring in cells experiencing a programmed stress-response. We are testing predictions of this model both in E. coli and in human.
- Liu P, Erez A, Nagamani SC, Dhar SU, Kolodziejska KE, Dharmadhikari AV, Cooper ML, Wiszniewska J, Zhang F, Withers MA, Bacino CA, Campos-Acevedo LD, Delgado MR, Freedenberg D, Garnica A, Grebe TA, Hernández-Almaguer D, Immken L, Lalani SR, McLean SD, Nort "Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements.." Cell. 2011 Sep 16;146(6):889-903. Pubmed PMID: 21925314
- Al Mamun AA, Lombardo MJ, Shee C, Lisewski AM, Gonzalez C, Lin D, Nehring RB, Saint-Ruf C, Gibson JL, Frisch RL, Lichtarge O, Hastings PJ, Rosenberg SM "Identity and function of a large gene network underlying mutagenic repair of DNA breaks.." Science. 2012 Dec 7;338(6112):1344-8. Pubmed PMID: 23224554
- Beck CR, Carvalho CMB, Akdemir ZC, Sedlazeck FJ, Song X, (...), Hastings PJ, Lupski JR "Megabase Length Hypermutation Accompanies Human Structural Variation at 17p11.2.." Cell. 2019;176:1310-1324.e10.
- Xia J, Chiu LY, Nehring RB, Bravo Núñez MA, Mei Q, (...), Hastings PJ, Bates D, Queitsch C, Hilsenbeck SG, Coarfa C, Hu JC, Siegele DA, Scott KL, Liang H, Mancini MA, Herman C, Miller KM, Rosenberg SM "Bacteria-to-Human Protein Networks Reveal Origins of Endogenous DNA Damage.." Cell. 2019;176:127-143.e24..
- Pribis JP, García-Villada L, Zhai Y, Lewin-Epstein O, Wang AZ, (...), Hastings PJ, Rosenberg SM "Gamblers: An Antibiotic-Induced Evolvable Cell Subpopulation Differentiated by Reactive-Oxygen-Induced General Stress Response.." Mol Cell. 2019;74:785-800.e7.
- Nehring RB, Gu F, Lin HY, Gibson JL, Blythe MJ, Wilson R, Bravo Núñez MA, Hastings PJ, Louis EJ, Frisch RL, Hu JC, Rosenberg SM "An ultra-dense library resource for rapid deconvolution of mutations that cause phenotypes in Escherichia coli.." Nucleic Acids Res. 2016;44:e41.
- Carvalho CM, Pfundt R, King DA, Lindsay SJ, Zuccherato LW, (...), Hastings PJ, Brunner HG, Lupski JR "Absence of heterozygosity due to template switching during replicative rearrangements.." Am J Hum Genet. 2015;96:555-64.
- Moore JM, Magnan D, Mojica AK, Núñez MA, Bates D, Rosenberg SM, Hastings PJ "Roles of Nucleoid-Associated Proteins in Stress-Induced Mutagenic Break Repair in Starving Escherichia coli.." Genetics. 2015;201:1349-62..
- Carvalho CM, Pehlivan D, Ramocki MB, Fang P, Alleva B, Franco LM, Belmont JW, Hastings PJ, Lupski JR "Replicative mechanisms for CNV formation are error prone.." Nat Genet. 2013;45(11):1319-26. Pubmed PMID: 24056715
- Wimberly H, Shee C, Thornton PC, Sivaramakrishnan P, Rosenberg SM, Hastings PJ "R-loops and nicks initiate DNA breakage and genome instability in non-growing Escherichia coli.." Nat Commun. 2013;4:2115. Pubmed PMID: 23828459
- Liu P, Lacaria M, Zhang F, Withers M, Hastings PJ, Lupski JR "Frequency of Nonallelic Homologous Recombination Is Correlated with Length of Homology: Evidence that Ectopic Synapsis Precedes Ectopic Crossing-Over.." Am. J. Hum. Genet. 2011 Oct 7;89(4):580-8. Pubmed PMID: 21981782
- Lin D, Gibson IB, Moore JM, Thornton PC, Leal SM, Hastings PJ "Global Chromosomal Structural Instability in a Subpopulation of Starving Escherichia coli Cells.." PLoS Genet. 2011 Aug;7(8):e1002223. Pubmed PMID: 21901104
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