Faculty & Research
- Contact Information
- Contact Colin Meiklejohn by cmeiklej [at] indiana [dot] edu
- MY 216B
Research Scientist, University of Rochester, 2008-2012
Postdoctoral Fellow, Brown University, 2005-2008
Ph.D, Harvard University, 2003
B.A., University of Chicago, 1996
NSF DEB-0839348 (Evolutionary Genetics), 2008
NIH NRSA Postdoctoral Fellowship, 2005
My research program investigates how genome evolution and genetic conflict generate incompatibilities between species. I use classical, molecular and population genetics methods with functional and comparative genomics to study divergence between species and disrupted gene interactions in species hybrids of the genetic model organism Drosophila.
My previous research used microarrays to characterize the evolution of genome-wide transcript profiles and screen thousands of gene expression phenotypes for those that are rapidly evolving. We demonstrated that although the expression levels of most genes are predominantly subject to long-term stabilizing selection, there is ample variation in gene expression within species, and the expression levels of some genes, particularly those expressed in male reproductive tissues, diverge quite rapidly between species. I have also studied the molecular evolution and population genetics of three testes-expressed genes in order to understand the selective forces that shape their evolution. This work demonstrated a history of rapid evolution following gene duplication and associated with expression in the testes, and that positive selection acting in extant populations currently shapes patterns of nucleotide polymorphism at these loci.
Genetic dissection of regulatory evolution
The goal of these experiments is to characterize genetic divergence responsible for genome-wide differences in gene expression between closely related species. I performed a microarray screen for genetic interactions that cause aberrant gene expression in species hybrids by measuring expression in genotypes of Drosophila simulans that carry a small (~8 Mb) genomic region from its sister species, D. mauritiana. This screen identified more than 2000 genes that show significantly altered expression in these genotypes. Cis- and trans-acting regulators of expression were identified with fine-scale genetic mapping, and my collaborators and I confirmed ~90 cis-acting regulatory variants by assaying allele-specific expression with pyrosequencing. We observe that >90% of gene expression differences identified in this screen results from divergence at trans-regulatory factors. Divergent cis-regulatory effects differ from trans-regulatory effects in patterns of inheritance, degree of sexual dimorphism, and likelihood of causing regulatory incompatibilities, consistent with differential contribution of these two modes of gene regulation to functional divergence between species. Finally, genetic mapping indicates a single trans-regulatory factor of large effect affects expression levels at dozens of innate immunity genes.
X chromosome regulation during spermatogenesis and speciation
Intrinsic postzygotic reproductive isolation —e.g., hybrid inviability and sterility— is an important barrier to gene flow between populations and species. In many taxa, including Drosophila, hybrid male sterility evolves earlier than hybrid female sterility or hybrid inviability, and genetic analyses indicate that the density of genetic factors causing hybrid male sterility is enriched on the X relative to the autosomes. I have been testing the hypothesis that the X chromosome is enriched for hybrid sterility factors because X chromosome gene expression is misregulated in hybrid testes. There are two kinds of X chromosome-specific regulation that could be disrupted in hybrids. First, in the somatic cells of mammals, fruit flies, and nematodes, X chromosomes are dosage compensated to equalize expression in males and females. Second, during normal spermatogenesis in worms and mammals, the X chromosome is heterochromatinized early in meiosis and expression of X-linked genes is silenced. Both dosage compensation and meiotic X inactivation have been proposed to be disrupted in Drosophila hybrids, causing sterility. Because testing these hypotheses requires understanding X chromosome regulation in fertile non-hybrid males, I have been studying gene expression in wild-type D. melanogaster testes. Surprisingly, these experiments revealed that, unlike in male somatic cells, the X chromosome is not dosage compensated in the Drosophila male germline; and unlike mammals and nematodes, Drosophila shows no evidence of meiotic X chromosome inactivation. These conclusions indicate that neither of these processes are likely to contribute to hybrid male sterility in fruit flies, and as well, have important implications for our understanding of the genomic distribution of genes expressed in the testes.
Despite the absence of meiotic sex chromosome inactivation, evidence suggests independent genetic regulation of X-linked and autosomal genes during Drosophila male germline development. In light of these discoveries, I am currently pursuing experiments to identify loci responsible for X-specific gene regulation in the testes, and to understand the significance of disjunct X and autosomal regulation for patterns of genome evolution. Additionally, in order to determine why the X chromosome is a hotspot for the evolution of hybrid sterility factors, I have initiated genetic mapping experiments to directly identify X-linked loci responsible for hybrid male sterility in Drosophila.
Co-evolution of mitochondrial and nuclear genomes
In most eukaryotes, cellular metabolism is dependent on oxidative phosphorylation in the mitochondria. As the proteins required for this process are encoded in both the nuclear and the mitochondrial genomes, these two genomes must co-evolve in order to maintain proper metabolic function. To better understand the effects of mtDNA and nuclear sequence evolution in diverging lineages, my collaborators and I generated strains that carry mtDNA from multiple species of Drosophila in two inbred nuclear genotypes of D. melanogaster. We found that most foreign mitochondrial genomes show only slight effects on viability, development time, fecundity, and mitochondrial enzyme activities, indicating that the great majority of nonsynonymous mtDNA substitutions fixed between these lineages have little to no fitness effects.
However, we discovered that one mtDNA haplotype from D. simulans has profound phenotypic effects (e.g., a 2-day delay in development and 50% wild-type fecundity) in one D. melanogaster nuclear background. Using genetic mapping and transgenic rescue experiments, we have identified the causal nuclear factor in this interaction as a single nonsynonymous polymorphism in a nuclear encoded mitochondrial tyrosyl-tRNA synthetase, and the mitochondrial factor as a single SNP in the mitochondrially-encoded tRNATyr. These results indicate that tRNAs and their cognate synthetases may be an unappreciated source of mtDNA-nuclear interactions that drive co-evolution between these genomes, and suggest that these interactions may be responsible for the variable penetrance and complex genetic basis for many human mitochondrial diseases.
Meiklejohn, C. D., M. A. Holmbeck, M. A. Siddiq, D. N. Abt, D. M. Rand, and K. L. Montooth. An Incompatibility Between a Mitochondrial tRNA and its Nuclear-Encoded tRNA Synthetase Compromises Development and Fitness in Drosophila. PLoS Genetics, accepted.
Meiklejohn, C. D. and D. C. Presgraves (2012). Little evidence for demasculinization of the Drosophila X chromosome among genes expressed in the male germline. Genome Biology and Evolution, 4(10): 895-904.
Meiklejohn, C. D., E. L. Landeen, J. M. Cook, S. B. Kingan, and D. C. Presgraves (2011). Sex chromosome-specific regulation in the Drosophila male germline but little evidence for chromosomal dosage compensation or meiotic inactivation. PLoS Biology, 9(8): e1001126.
Montooth, K. L., Meiklejohn, C.D.*, D. Abt, and D. M. Rand (2010). Mitochondrial-nuclear epistasis affects fitness within species but does not contribute to incompatibilities between species in Drosophila. Evolution, 64: 3364-3379. *co-first author
Meiklejohn, C. D. and Y. Tao (2010). Genetic conflict and sex chromosome evolution. Trends in Ecology and Evolution, 25: 215-223.
Meiklejohn, C. D., K. L. Montooth, and D. M. Rand (2007). Positive and negative selection on the mitochondrial genome. Trends in Genetics 23(6): 259-263.
Lemos, B., B.R. Bettencourt, C. D. Meiklejohn, and D. L. Hartl (2005). Evolution of proteins and gene expression levels are coupled in Drosophila and are independently associated with mRNA abundance, protein length, and number of protein-protein interactions. Molecular Biology and Evolution 22: 1345-1354.
Lemos, B., C. D. Meiklejohn, M. Caceres, and D. L. Hartl (2005). Rates of divergence in gene expression profiles of primates, mice, and flies: Stabilizing selection and variability among functional categories. Evolution 59(1): 126-137. (Faculty of 1000 selection)
Meiklejohn, C. D., Y. Kim, D. L. Hartl, and J. Parsch (2004). Identification of a positively-selected locus in Drosophila simulans by haplotype mapping and composite likelihood estimation. Genetics 168: 265-279.
Lemos, B., C. D. Meiklejohn, and D. L. Hartl (2004). Regulatory evolution across the protein interaction network. Nature Genetics 36: 1059-1060.
Meiklejohn, C. D., J. Parsch, J. M. Ranz, and D. L. Hartl (2003). Rapid evolution of male-biased gene expression in Drosophila. Proceedings of the National Academy of Sciences, USA 100(17): 9894-9899. (Faculty of 1000 selection)
Ranz, J. M., C. I. Castillo-Davis, C. D. Meiklejohn, and D. L. Hartl (2003). Sex-dependent gene expression and the evolution of the Drosophila transcriptome. Science 300: 1742-1745.
Meiklejohn, C. D. and D. L. Hartl (2002). A single mode of canalization. Trends in Ecology and Evolution 17(10): 468-473.