Ira M. Hall
Assistant Professor of Biochemistry & Molecular Genetics
Ph.D., Watson School of Biological Sciences, Cold Spring Harbor
Genome variation; Bioinformatics

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Research in my laboratory is focused on understanding the mechanistic origins and functional consequences of genome variation in mammals. We are primarily interested in structural variation (SV), which includes duplications, deletions, inversions, insertions, translocations and other forms of genomic rearrangement. These large scale genetic differences comprise a significant fraction of inherited human genetic variation, are increasingly found to underlie sporadic disease, and are a driving force in the evolution of cancer genomes. Somatically-acquired structural variants may also contribute to phenotypes that emerge during development and aging.

Our understanding of structural variation has been, and remains to be, limited by technology. Due to the profound experimental and computational challenges associated with performing unbiased genome-wide experiments, many fundamental questions regarding the origin and impact of structural variation remain unanswered.

We are currently pursuing three general lines of investigation. First, we are developing methods to map and interpret genome variation from next-generation sequence data. These include algorithms to map structural variation by paired-end mapping, split-read mapping and depth of coverage analysis, as well as a suite of software tools for comparing raw sequence data, annotations and variant calls. We are also developing computational methods for optimal split-read alignment, haplotype-aware local assembly, and breakpoint visualization. Finally, we are working on experimental methods to map SV in small populations of cells, which will allow for a direct assessment of genetic diversity in somatic lineages.

Second, we are using these methods to tackle basic questions regarding structural variation in "normal" germline and somatic genomes. While our initial work on these topics has used the laboratory mouse as model, the recent explosion of human genome sequence data has allowed us to transition most of our work to human. Questions that we are interested in include: what are the mechanisms that generate new SV? To what extent are these mechanisms under cellular control, or affected by stress, and thus variable depending on genetic background or environmental conditions? What is the contribution of structurally unstable and/or hyper-variable loci to natural variation? How prevalent is de novo SV in different somatic lineages and single somatic cells, and to what extent can this phenomenon account for traits that emerge during the course of development or aging?

Finally, we are studying the process of tumor genome evolution by comparing the patterns and mechanisms of genomic rearrangement in cancer cells relative to those found in normal cells. We are mapping and assembling structural variant breakpoints from hundreds of human whole-genome sequence datasets, comparing the breakpoint properties of germline versus somatically-acquired structural variation, and attempting to understand the mutational forces that shape highly rearranged tumor genomes. It is our hope that these experiments will lead to new insights into tumor genome evolution and perhaps suggest novel genome-based diagnostic tests that correlate with malignancy.

Selected References

Malhotra A, Lindberg M, Faust GG, Leibowitz ML, Clark RA, Layer RM, Quinlan AR,Hall IM. (2013) "Breakpoint profiling of 64 cancer genomes reveals numerous complex rearrangements spawned by homology-independent mechanisms." Genome Res. Mar 20. [Epub ahead of print] [PubMed]

Faust GG, Hall IM. (2012) "GEM: crystal-clear DNA alignment." Nat Methods. 9(12):1159-61. doi: 10.1038/nmeth.2256. [PubMed]

Layer RM, Skadron K, Robins G, Hall IM, Quinlan AR. (2013) "Binary Interval Search: a scalable algorithm for counting interval intersections." Bioinformatics. Jan 29:1-7. doi: 10.1093/bioinformatics/bts652. Epub2012 Nov 4. [PubMed]

Faust GG, Hall IM. (2012) "YAHA: fast and flexible long-read alignment with optimal breakpoint detection." Bioinformatics. Oct 28(19):2417-24. Epub 2012 Jul 24. [PubMed]

Mell JC, Hall IM, Redfield RJ. (2012) "Defining the DNA uptake specificity of naturally competent Haemophilus influenzae cells." Nucleic Acids Res. Sep 40(17):8536-49. Epub 2012 Jun 29. [PubMed]

Chiang C, Jacobsen JC, Ernst C, Hanscom C, Heilbut A, Blumenthal I, Mills RE,Kirby A, Lindgren AM, Rudiger SR, McLaughlan CJ, Bawden CS, Reid SJ, Faull RL,Snell RG, Hall IM, Shen Y, Ohsumi TK, Borowsky ML, Daly MJ, Lee C, Morton CC,MacDonald ME, Gusella JF, Talkowski ME. (2012) "Complex reorganization and predominant non-homologous repair following chromosomal breakage in karyotypically balanced germline rearrangements and transgenic integration." Nat Genet. Mar 44:390-7, S1. doi: 10.1038/ng.2202. [PubMed]

Hall IM, Quinlan AR. (2012) "Detection and interpretation of genomic structural variation in mammals." Methods Mol Biol. 838:225-48. doi: 10.1007/978-1-61779-507-7_11. [PubMed]

Quinlan AR, Hall IM. (2012) "Characterizing complex structural variation in germline and somatic genomes." Trends Genet. 28:43-53. doi: 10.1016/j.tig.2011.10.002. Epub 2011 Nov15. [PubMed]

Quinlan AR, Boland MJ, Leibowitz ML, Shumilina S, Pehrson SM, Baldwin KK, HallIM. (2011) "Genome sequencing of mouse induced pluripotent stem cells reveals retroelement stability and infrequent DNA rearrangement during reprogramming." Cell Stem Cell. Oct 9:366-73. doi: 10.1016/j.stem.2011.07.018. [PubMed]

Keene KL, Quinlan AR, Hou X, Hall IM, Mychaleckyj JC, Onengut-Gumuscu S,Concannon P. (2012) "Evidence for two independent associations with type 1 diabetes at the 12q13 locus." Genes Immun. 13:66-70. doi: 10.1038/gene.2011.56. Epub 2011 Aug 18. [PubMed]

Mell JC, Shumilina S, Hall IM, Redfield RJ. (2011) "Transformation of natural genetic variation into Haemophilus influenzae genomes." PLoS Pathog. 7:e1002151. doi: 10.1371/journal.ppat.1002151. Epub 2011Jul 28. [PubMed]

Rich SS, Hall IM. (2011) "DNA structural variants as genetic risk factors for the long QT syndrome." J Am Coll Cardiol. Jan 57:48-50. doi: 10.1016/j.jacc.2010.07.040. [PubMed]

Quinlan AR, Clark RA, Sokolova S, Leibowitz ML, Zhang Y, Hurles ME, Mell JC, HallIM. (2010) "Genome-wide mapping and assembly of structural variant breakpoints in the mouse genome." Genome Res. 20:623-35. doi: 10.1101/gr.102970.109. Epub 2010 Mar 22. [PubMed]

Quinlan AR, Hall IM. (2010) "BEDTools: a flexible suite of utilities for comparing genomic features." Bioinformatics. Mar 26:841-2. doi: 10.1093/bioinformatics/btq033. Epub2010 Jan 28. [PubMed]

Egan CM, Sridhar S, Wigler M, Hall IM. (2007) "Recurrent DNA copy number variation in the laboratory mouse." Nat Genet. 39(11):1384-9. Epub 2007 Oct 28. [PubMed]

Lakshmi B, Hall IM, Egan C, Alexander J, Leotta A, Healy J, Zender L, Spector MS,Xue W, Lowe SW, Wigler M, Lucito R. (2006) "Mouse genomic representational oligonucleotide microarray analysis: detection of copy number variations in normal and tumor specimens." Proc Natl Acad Sci U S A. Jul 103(30):11234-9. Epub 2006 Jul 14. [PubMed]

Lakshmi B, Hall IM, Egan C, Alexander J, Leotta A, Healy J, Zender L, Spector MS,Xue W, Lowe SW, Wigler M, Lucito R. (2006) "Mouse genomic representational oligonucleotide microarray analysis: detection of copy number variations in normal and tumor specimens." Proc Natl Acad Sci U S A. Jul 103(30):11234-9. Epub 2006 Jul 14. [PubMed]