Philip J. Hastings, Ph.D.
Professor of Molecular and Human Genetics
B.A., University of Cambridge, 1962
Ph.D., University of Cambridge, 1965
Postdoc, Harvard University, 1967
Part 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. We predict that amplification will be accompanied by a high rate of chromosomal instability throughout the genome, just as adaptive mutation is a genome wide phenomenon, not targeted to useful mutations. 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.
- Carvalho CM, Pehlivan D, Ramocki MB, Fang P, Alleva B, Franco LM, Belmont JW, Hastings PJ, Lupski JR (2013). Replicative mechanisms for CNV formation are error prone. Nat. Genet., in press. PubMed PMID: 24056715
- Wimberly H, Shee C, Thornton PC, Sivaramakrishnan P, Rosenberg SM, Hastings PJ (2013). R-loops and nicks initiate DNA breakage and genome instability in non-growing Escherichia coli. Nat. Commun. 4: 2115. PubMed PMID: 23828459
- 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 (2012). Identity and function of a large gene network underlying mutagenic repair of DNA breaks. Science 338(6112): 1344-8. PubMed PMID: 23224554
- Ira G, Hastings PJ (2012). DNA breakage drives nuclear search. Nat. Cell Biol. 14(5): 448-50. PubMed PMID: 22552144
- Hastings PJ, Rosenberg SM (2011). Genomic rearrangement in three dimensions. Nat. Biotechnol. 29(12): 1096-8. PubMed PMID: 22158363
- Lin D, Gibson IB, Moore JM, Thornton PC, Leal SM, Hastings PJ (2011). Global chromosomal structural instability in a subpopulation of starving Escherichia coli cells. PLoS Genet. 7(8): e1002223. PubMed PMID: 21901104
- Liu P, Lacaria M, Zhang F, Withers M, Hastings PJ, Lupski JR (2011). Frequency of nonallelic homologous recombination is correlated with length of homology: evidence that ectopic synapsis precedes ectopic crossing-over. Am. J. Hum. Genet. 89(4): 580-8. PubMed PMID: 21981782
- Liu P, Erez A, Nagamani SC, Dhar SU, Kołodziejska 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, Northrup H, Scaglia F, Strathearn L, Trapane P, Kang SH, Patel A, Cheung SW, Hastings PJ, Stankiewicz P, Lupski JR, Bi W (2011). Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell 146(6): 889-903. PubMed PMID: 21925314
- Carvalho CM, Ramocki MB, Pehlivan D, Franco LM, Gonzaga-Jauregui C, Fang P, McCall A, Pivnick EK, Hines-Dowell S, Seaver LH, Friehling L, Lee S, Smith R, Del Gaudio D, Withers M, Liu P, Cheung SW, Belmont JW, Zoghbi HY, Hastings PJ, Lupski JR (2011). Inverted genomic segments and complex triplication rearrangements aremediated by inverted repeats in the human genome. Nat. Genet. 43(11): 1074-81. PubMed PMID: 21964572
- Frisch RL, Su Y, Thornton PC, Gibson JL, Rosenberg SM, Hastings PJ (2010). Separate DNA Pol II- and Pol IV-dependent pathways of stress-induced mutation during double-strand-break repair in Escherichia coli are controlled by RpoS. J. Bacteriol. 192(18): 4694-700. PubMed PMID: 20639336
- Gibson JL, Lombardo MJ, Thornton PC, Hu KH, Galhardo RS, Beadle B, Habib A, Magner DB, Frost LS, Herman C, Hastings PJ, Rosenberg SM (2010). The sigma(E) stress response is required for stress-induced mutation and amplification in Escherichia coli. Mol. Microbiol. 77(2): 415-30. PubMed PMID: 20497332
- Hastings PJ, Lupski JR, Rosenberg SM, Ira G (2009). Mechanisms of change in gene copy number. Nat. Rev. Genet. 10(8): 551-64. PubMed PMID: 19597530
- Hastings PJ, Ira G, Lupski JR (2009). A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genet. 5(1): e1000327. PubMed PMID: 19180184
- Slack A, Thornton PC, Magner DB, Rosenberg SM, Hastings PJ (2006). On the mechanism of gene amplification induced under stress in Escherichia coli. PLoS Genet. 2(4): e48. PubMed PMID: 16604155
- Rosenberg SM, Hastings PJ (2004). Genomes: worming into genetic instability. Nature 430(7000): 625-6. PubMed PMID: 15295584
- Hastings PJ, Slack A, Petrosino JF, Rosenberg SM (2004). Adaptive amplification and point mutation are independent mechanisms: evidence for various stress-inducible mutation mechanisms. PLoS Biol. 2(12): e399. PubMed PMID: 15550983
- Rosenberg SM, Hastings PJ (2003). Microbiology and Evolution. Modulating mutation rates in the wild. Science 300(5624): 1382-3. PubMed PMID: 12775830
- McKenzie GJ, Lee PL, Lombardo MJ, Hastings PJ, Rosenberg SM (2001). SOS mutator DNA polymerase IV functions in adaptive mutation and not adaptive amplification. Mol. Cell 7(3): 571-9. PubMed PMID: 11463382
- Hastings PJ, Bull HJ, Klump J, Rosenberg SM (2000). Adaptive amplification: An inducible chromosomal instability mechanism. Cell 103(5): 723-31. PubMed PMID: 11114329
Philip J. Hastings, Ph.D.
Department of Molecular and Human Genetics
Baylor College of Medicine
One Baylor Plaza, MS BCM225
Houston, TX, 77030, U.S.A.