UW Medicine

Alan Herr

Alan Herr

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Research Associate Professor, Department of Lab Medicine and Pathology

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alanherr(at)uw.edu

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Dr. Herr studies the influence of genetic instability on the aging process, as well as basic mechanisms of mutator phenotypes resulting from error prone replication.  He has NIA R01 funding to support the use of budding yeast to measure the error rates of mutator cells at each division of their replicative lifespan.  Despite decades of research, the key assumption that mutator phenotypes are constant for each cell division remains untested: historically, all mutation rate measurements have relied on averaging mutations generated by many cell divisions.  Using whole genome sequencing of sequential daughter cells isolated from the same mother, he recently found that some mutator yeast strains exhibit two distinct age-independent mutagenic states [1,2].  His lab is investigating whether “volatility” occurs with other mutator alleles in an age-dependent or -independent manner.  He recently discovered that dNTP pool levels modulate Pol e mutator phenotypes [3] and is determining whether regulation of dNTP pools during S-phase accounts for mutator volatility.  Finally, Dr. Herr is investigating how mutation burden influences aging.  Having recently defined the maximum mutation rate of diploid cells [4], Dr. Herr has recently published the relationship between random heterozygous mutation burden of diploid cells and effects on replicative lifespan [5].

1. Kennedy SR, Loeb LA, Herr AJ (2012) Somatic mutations in aging, cancer and neurodegeneration Mech Ageing Dev 133:118-126 doi:10.1016/j.mad.2011.10.009

2. Kennedy SR, Schultz EM, Chappell TM, Kohrn B, Knowels GM, Herr AJ (2015) Volatility of Mutator Phenotypes at Single Cell Resolution PLoS Genet 11:e1005151 doi:10.1371/journal.pgen.1005151

3. Williams LN, Marjavaara L, Knowels GM, Schultz EM, Fox EJ, Chabes A, Herr AJ (2015) dNTP pool levels modulate mutator phenotypes of error-prone DNA polymerase epsilon variants Proc Natl Acad Sci U S A 112:E2457-2466 doi:10.1073/pnas.1422948112

4. Herr AJ, Kennedy SR, Knowels GM, Schultz EM, Preston BD (2014) DNA replication error-induced extinction of diploid yeast Genetics 196:677-691 doi:10.1534/genetics.113.160960

5. Lee MB et al. (2019) Defining the impact of mutation accumulation on replicative lifespan in yeast using cancer-associated mutator phenotypes Proc Natl Acad Sci U S A 116:3062-3071 doi:10.1073/pnas.1815966116