An Overview

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Epigenetic Inheritance
My interest in human evolution led me to investigate epigenetic inheritance as a potential contributor to the divergence of human and chimp. Epigenetic inheritance, the inheritance of epigenetic variants in the absence of sequence variation, is compatible with Darwinian evolution if epigenetic states that specify traits can remain stable in the germline through generations, i.e. epigenetic states in the parents must predict states in succeeding generations. This form of inheritance is mediated by complex and highly diverse components of the chromosome that associate with DNA, control its transcription, and are inherited alongside it in the chromosome. In a comparison of the methylomes of humans and their closest relatives, the chimpanzees, we found that methylation differences are not distributed randomly among the individuals we analyzed, but recapitulate the known phylogenetic relationships of the three species in a pattern consistent with their stable inheritance. More importantly, we found that somatic methylation differences (which we are able to study) recapitulate methylation differences in the germline (where transgenerational inheritance occurs). Even though this work suggests that methylation differences can be inherited through the germline, the use of outbred populations makes it impossible to rule out a role of genetic variation in the maintenance of the methylation variants. I am developing inbred model systems to study epigenetic inheritance with a clean experimental design. Epigenetic inheritance is a controversial and somewhat misunderstood topic; as an attempt to unravel some of the controversy, together with David Martin I contributed some opinion works to the field.

Martin, D.I., M. Singer, J. Dhahbi, G. Mao, L. Zhang, G.P. Schroth, L. Pachter, and D. Boffelli, Phyloepigenomic comparison of great apes reveals a correlation between somatic and germline methylation states. Genome Res, 2011. 21(12): p. 2049-57. PMCID: PMC3227095.
Suter, C.M., D. Boffelli, and D.I. Martin, A role for epigenetic inheritance in modern evolutionary theory? A comment in response to Dickins and Rahman. Proc Biol Sci, 2013. 280(1771): p. 20130903; discussion 20131820. PMCID: PMC3790474.
Boffelli, D. and D.I. Martin, Epigenetic inheritance: a contributor to species differentiation? DNA Cell Biol, 2012. 31 Suppl 1: p. S11-6. PMCID: PMC3460613.

Genomewide Methylation Analysis
Cytosine methylation is an important component of the epigenome; it has a strong association with gene silencing and a straightforward mechanism for replication at cell division. It is however relatively difficult to assay, and different approaches balance cost with resolution. I contributed to the development of two effective methods for genomewide methylation analysis. One method, called MetMap and developed together with Lior Pachter at UC Berkeley, combines digestion with a methylation-sensitive restriction enzyme and a statistically sound and cohesive Bayesian framework to infer the extent of methylation at individual CGs and across regions. It provides a superior approach for identifying functionally significant regions in the genome. A second method combines immunoprecipitation of methylated DNA with bisulfite sequencing to enable the detection of DNA methylation in genomes with very low levels of methylation: with this method we were able to construct the first map of cytosine methylation in Drosophila melanogaster, a species often assumed to lack genome methylation. This last finding opens a new area of epigenetic study in Drosophila.

Takayama, S., J. Dhahbi, A. Roberts, G. Mao, S.J. Heo, L. Pachter, D. Martin, and D. Boffelli, Genome methylation in D. melanogaster is found at specific short motifs and is independent of DNMT2 activity. Genome Res, 2014. 24: p. 821-830. PMCID: PMC4009611.
Bolotin, E., A. Armendariz, K. Kim, S.J. Heo, D. Boffelli, K. Tantisira, J.I. Rotter, R.M. Krauss, and M.W. Medina, Statin-induced changes in gene expression in EBV-transformed and native B-cells. Hum Mol Genet, 2014. 23(5): p. 1202-10. PMCID: PMC3919007.
Meacham, F., D. Boffelli, J. Dhahbi, D.I. Martin, M. Singer, and L. Pachter, Identification and correction of systematic error in high-throughput sequence data. BMC Bioinformatics, 2011. 12: p. 451. PMCID: PMC3295828.
Singer, M., D. Boffelli, J. Dhahbi, A. Schonhuth, G.P. Schroth, D.I. Martin, and L. Pachter, MetMap enables genome-scale Methyltyping for determining methylation states in populations. PLoS Comput Biol, 2010. 6(8): p. e1000888. PMCID: PMC2924245.

Properties and Activities of Small RNAs
Short RNAs have emerged as a major quantitative component of transcribed sequences. They exist in several classes; Piwi-interacting RNAs (piRNAs) are a class of small RNAs that are expressed in the mammalian testis at different stages of development and are thought to help to determine the sites at which the genome is methylated. The function of piRNAs expressed in the adult testis is not well established, and the presence of piRNAs outside the testis is enigmatic. In a series of studies we investigated piRNA and piRNA-like transcripts in adult testis and somatic tissues. We found piRNA and piRNA-like transcripts are expressed in a variety of somatic tissues, most prominently in hematopoietic cell lines. They are often associated with 3’ UTRs of expressed mRNAs but do not affect mRNA levels. The presence of piRNAs in somatic cells indicates that this mechanism is more broadly distributed than currently appreciated and broadens the spectrum of cells and tissues in which the pathway can be investigated. I conceived the studies together with David Martin, and contributed to the computational analysis and the interpretation of the results.

Yamtich, J., S.J. Heo, J. Dhahbi, D.I. Martin, and D. Boffelli, piRNA-like small RNAs mark extended 3'UTRs present in germ and somatic cells. BMC Genomics, 2015. 16(1): p. 462. PMCID: PMC4469462.
Jacobs, J.E., M. Wagner, J. Dhahbi, D. Boffelli, and D.I. Martin, Deficiency of MIWI2 (Piwil4) induces mouse erythroleukemia cell differentiation, but has no effect on hematopoiesis in vivo. PLoS One, 2013. 8(12): p. e82573. PMCID: PMC3871168.
Dhahbi, J.M., S.R. Spindler, H. Atamna, A. Yamakawa, D. Boffelli, P. Mote, and D.I. Martin, 5' tRNA halves are present as abundant complexes in serum, concentrated in blood cells, and modulated by aging and calorie restriction. BMC Genomics, 2013. 14: p. 298. PMCID: PMC3654920.
Dhahbi, J.M., S.R. Spindler, H. Atamna, D. Boffelli, P. Mote, and D.I. Martin, 5'-YRNA fragments derived by processing of transcripts from specific YRNA genes and pseudogenes are abundant in human serum and plasma. Physiol Genomics, 2013. 45(21): p. 990-8. PMCID: Non-NIH supported.

Comparative Genomics of Closely Related Species
Comparisons between genomes of human and non-human primates are the most relevant to primate and human evolution. I pioneered methods for the comparative analysis of closely related genomes. These comparisons are complicated by the limited sequence divergence of the species involved; the approach that I developed essentially relied on obtaining the sequence of multiple species in order to increase the overall length of the phylogenetic tree involved in the analysis, coupled with careful modeling of evolutionary rates in the tree. Cholesterol metabolism is a physiological pathway marked by numerous differences between primates and other mammals. I applied the comparative approach to genes in this pathway and identified several functional enhancers with primate-specific conservation, and particularly discovered a cholesterol-sensing sequence motif that arose within a pre-existing enhancer in the common ancestor of anthropoid primates. This work illustrates one molecular mechanism by which ancestral mammalian regulatory elements can evolve to perform new functions in the primate lineage leading to human.

Yang, S., N. Oksenberg, S. Takayama, S.J. Heo, A. Poliakov, N. Ahituv, I. Dubchak, and D. Boffelli, Functionally conserved enhancers with divergent sequences in distant vertebrates. BMC Genomics, 2015. 16(1): p. 882. PMCID: PMC4628251.
Boffelli, D., J. McAuliffe, D. Ovcharenko, K.D. Lewis, I. Ovcharenko, L. Pachter, and E.M. Rubin, Phylogenetic shadowing of primate sequences to find functional regions of the human genome. Science, 2003. 299(5611): p. 1391-4.
Wang, Q.F., S. Prabhakar, S. Chanan, J.F. Cheng, E.M. Rubin, and D. Boffelli, Detection of weakly conserved ancestral mammalian regulatory sequences by primate comparisons. Genome Biol, 2007. 8(1): p. R1. PMCID: PMC1839124.
Wang, Q.F., S. Prabhakar, Q. Wang, A.M. Moses, S. Chanan, M. Brown, M.B. Eisen, J.F. Cheng, E.M. Rubin, and D. Boffelli, Primate-specific evolution of an LDLR enhancer. Genome Biol, 2006. 7(8): p. R68. PMCID: PMC1779597.
Boffelli, D., M.A. Nobrega, and E.M. Rubin, Comparative genomics at the vertebrate extremes. Nat Rev Genet, 2004. 5(6): p. 456-65.


Revised: Monday, September 19, 2016 11:38 AM



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