Professor, Department of Biology
Ph.D. Case Western Reserve
B.S. Stanford Univeristy
Research Interests: Genetic regulation of animal development including development of the nervous system, the mechanisms of sex determination, the origin of novel morphologies in evolution and the evolution of the vertebrate genome.
Overview: Our laboratory is interested in the genetic, genomic, and evolutionary principles that guide animal development. We investigate several aspects of this main problem:
Genome Duplication: The evolution of gene functions in development after genome duplication, focusing on skeletal development.
Fanconi anemia: A small molecule screen for compounds to rescue zebrafish Fanconi Anemia mutants as a way to identify potential therapeutics for human FA patients and to understand disease mechanisms.
MicroRNAs: The roles of microRNAs in embryonic (especially skeletal) development, including evolving miRNA functions after genome duplication.
Icefish: The genetic basis for the evolution of osteopenia or osteoporosis in Antarctic icefish.
Sex determinaion:The developmental genetic basis for sex determination in zebrafish.
Speciation: The roles of genome duplication in lineage divergence, focusing on the evolution of cis and trans acting regulation in the radiation of the danio lineage, including zebrafish, and on variation among populations of stickleback.
Oikopleura: Retaining a chordate body plan as an adult, the larvacean urochordate Oikopleura dioica represents the sister lineage to the vertebrates, diverging before the R1 and R2 rounds of genome duplication that led to the origin of vertebrate innovations.
Perchlorate toxicity and sex determination: Perchlorate is a pervasive environmental contaminant that can cause partial sex reversal in stickleback. We are investigating the hypotheses that perchlorate alters sex development through the thyroid or a non-thyroidal mechanism.
Drosophila developmental genetics: Work on Drosophila homeotic mutants, pattern formation, and ovary development.
Unification of miRNA and isomiR research: the mirGFF3 format and the mirtop API.
Bioinformatics. 2019 Aug 29;:
Authors: Desvignes T, Loher P, Eilbeck K, Ma J, Urgese G, Fromm B, Sydes J, Aparicio-Puerta E, Barrera V, Espín R, Thibord F, Ros XB, Londin E, Telonis AG, Ficarra E, Friedländer MR, Postlethwait JH, Rigoutsos I, Hackenberg M, Vlachos IS, Halushka MK, Pantano L
MOTIVATION: MicroRNAs (miRNAs) are small RNA molecules (∼22 nucleotide long) involved in post-transcriptional gene regulation. Advances in high-throughput sequencing technologies led to the discovery of isomiRs, which are miRNA sequence variants. While many miRNA-seq analysis tools exist, the diversity of output formats hinders accurate comparisons between tools and precludes data sharing and the development of common downstream analysis methods.
RESULTS: To overcome this situation, we present here a community-based project, miRTOP (miRNA Transcriptomic Open Project) working towards the optimization of miRNA analyses. The aim of miRTOP is to promote the development of downstream isomiR analysis tools that are compatible with existing detection and quantification tools. Based on the existing GFF3 format, we first created a new standard format, mirGFF3, for the output of miRNA/isomiR detection and quantification results from small RNA-seq data. Additionally, we developed a command line Python tool, mirtop, to create and manage the mirGFF3 format. Currently, mirtop can convert into mirGFF3 the outputs of commonly used pipelines, such as seqbuster, isomiR-SEA, sRNAbench, Prost! as well as BAM files. Some tools have also incorporated the mirGFF3 format directly into their code, such as, miRge2.0, IsoMIRmap, and OptimiR. Its open architecture enables any tool or pipeline to output or convert results into mirGFF3. Collectively, this isomiR categorization system, along with the accompanying mirGFF3 and mirtop API, provide a comprehensive solution for the standardization of miRNA and isomiR annotation, enabling data sharing, reporting, comparative analyses, and benchmarking, while promoting the development of common miRNA methods focusing on downstream steps of miRNA detection, annotation, and quantification.
AVAILABILITY: https://github.com/miRTop/mirGFF3/ and https://github.com/miRTop/mirtop.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
PMID: 31504201 [PubMed - as supplied by publisher]
The Molecular Evolution of Circadian Clock Genes in Spotted Gar (Lepisosteus oculatus).
Genes (Basel). 2019 Aug 17;10(8):
Authors: Sun Y, Liu C, Huang M, Huang J, Liu C, Zhang J, Postlethwait JH, Wang H
Circadian rhythms are biological rhythms with a period of approximately 24 h. While canonical circadian clock genes and their regulatory mechanisms appear highly conserved, the evolution of clock gene families is still unclear due to several rounds of whole genome duplication in vertebrates. The spotted gar (Lepisosteus oculatus), as a non-teleost ray-finned fish, represents a fish lineage that diverged before the teleost genome duplication (TGD), providing an outgroup for exploring the evolutionary mechanisms of circadian clocks after whole-genome duplication. In this study, we interrogated the spotted gar draft genome sequences and found that spotted gar contains 26 circadian clock genes from 11 families. Phylogenetic analysis showed that 9 of these 11 spotted gar circadian clock gene families have the same number of genes as humans, while the members of the nfil3 and cry families are different between spotted gar and humans. Using phylogenetic and syntenic analyses, we found that nfil3-1 is conserved in vertebrates, while nfil3-2 and nfil3-3 are maintained in spotted gar, teleost fish, amphibians, and reptiles, but not in mammals. Following the two-round vertebrate genome duplication (VGD), spotted gar retained cry1a, cry1b, and cry2, and cry3 is retained in spotted gar, teleost fish, turtles, and birds, but not in mammals. We hypothesize that duplication of core clock genes, such as (nfil3 and cry), likely facilitated diversification of circadian regulatory mechanisms in teleost fish. We also found that the transcription factor binding element (Ahr::Arnt) is retained only in one of the per1 or per2 duplicated paralogs derived from the TGD in the teleost fish, implicating possible subfuctionalization cases. Together, these findings help decipher the repertoires of the spotted gar's circadian system and shed light on how the vertebrate circadian clock systems have evolved.
PMID: 31426485 [PubMed - in process]
A Hormone That Lost Its Receptor: Anti-Müllerian Hormone (AMH) in Zebrafish Gonad Development and Sex Determination.
Genetics. 2019 Aug 09;:
Authors: Yan YL, Batzel P, Titus T, Sydes J, Desvignes T, Bremiller R, Draper B, Postlethwait JH
Fetal mammalian testes secrete Amh (Anti-Müllerian hormone), which inhibits female reproductive tract (Müllerian duct) development. Amh also derives from mature mammalian ovarian follicles, which marks oocyte reserve and characterizes PCOS (polycystic ovarian syndrome). Zebrafish (Danio rerio) lacks Müllerian ducts and the Amh receptor gene amhr2 but, curiously, retains amh To discover the roles of Amh in the absence of Müllerian ducts and the ancestral receptor gene, we made amh null alleles in zebrafish. Results showed that normal amh prevents female-biased sex ratios. Adult male amh mutants had enormous testes, half of which contained immature oocytes, demonstrating that Amh regulates male germ cell accumulation and inhibits oocyte development or survival. Mutant males formed sperm ducts and some produced a few offspring. Young female mutants laid a few fertile eggs, so they also had functional sex ducts. Older amh mutants accumulated non-vitellogenic follicles in exceedingly large but sterile ovaries, showing that Amh helps control ovarian follicle maturation and proliferation. RNA-seq data partitioned 21-day post-fertilization (dpf) juveniles into two groups that each contained mutant and wild type fish. Group21-1 up-regulated ovary genes compared to Group21-2, which were likely developing as males. By 35dpf, transcriptomes distinguished males from females and, within each sex, mutants from wild types. In adult mutants, ovaries greatly under-expressed granulosa and theca genes and testes under-expressed Leydig cell genes. These results show that ancestral Amh functions included development of the gonadal soma in ovaries and testes and regulation of gamete proliferation and maturation. A major gap in our understanding is the identity of the gene encoding a zebrafish Amh receptor; we show here that the loss of amhr2 is associated with the breakpoint of a chromosome rearrangement shared among cyprinid fishes.
PMID: 31399485 [PubMed - as supplied by publisher]
Epigenetic factors Dnmt1 and Uhrf1 coordinate intestinal development.
Dev Biol. 2019 Aug 05;:
Authors: Ganz J, Melancon E, Wilson C, Amores A, Batzel P, Strader M, Braasch I, Diba P, Kuhlman JA, Postlethwait JH, Eisen JS
Intestinal tract development is a coordinated process involving signaling among the progenitors and developing cells from all three germ layers. Development of endoderm-derived intestinal epithelium has been shown to depend on epigenetic modifications, but whether that is also the case for intestinal tract cell types from other germ layers remains unclear. We found that functional loss of a DNA methylation machinery component, ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1), leads to reduced numbers of ectoderm-derived enteric neurons and severe disruption of mesoderm-derived intestinal smooth muscle. Genetic chimeras revealed that Uhrf1 functions both cell-autonomously in enteric neuron precursors and cell-non-autonomously in surrounding intestinal cells, consistent with what is known about signaling interactions between these cell types that promote one another's development. Uhrf1 recruits the DNA methyltransferase Dnmt1 to unmethylated DNA during replication. Dnmt1 is also expressed in enteric neurons and smooth muscle progenitors. dnmt1 mutants have fewer enteric neurons and disrupted intestinal smooth muscle compared to wildtypes. Because dnmt1;uhrf1 double mutants have a similar phenotype to dnmt1 and uhrf1 single mutants, Dnmt1 and Uhrf1 must function together during enteric neuron and intestinal muscle development. This work shows that genes controlling epigenetic modifications are important to coordinate intestinal tract development, provides the first demonstration that these genes influence development of the ENS, and advances uhrf1 and dnmt1 as potential new Hirschsprung disease candidates.
PMID: 31394080 [PubMed - as supplied by publisher]
Eye Degeneration and Loss of otx5b Expression in the Cavefish Sinocyclocheilus tileihornes.
J Mol Evol. 2019 Jul 22;:
Authors: Huang Z, Titus T, Postlethwait JH, Meng F
Cave animals possess remarkable phenotypes associated with existence in their dark environments. The Chinese cavefish Sinocyclocheilus tileihornes shows substantial eye degeneration, a trait shared by most cave species. The extent to which independent evolution of troglomorphic traits uses convergent molecular genetic mechanisms is as yet unknown. We performed transcriptome-wide gene expression profiling in S. tileihornes eyes and compared results with those from the closely related surface species S. angustiporus and an independently derived congeneric cavefish, S. anophthalmus. In total, 52.85 million 100 bp long paired-end clean reads were generated for S. tileihornes, and we identified differentially expressed genes between the three possible pairs of species. Functional analysis of genes differentially expressed between S. tileihornes and S. angustiporus revealed that phototransduction (KEGG id: dre04744) was the most significantly enriched pathway, indicating the obvious differences in response to captured photons between the cavefish S. tileihornes and the surface species S. angustiporus. Analysis of key genes regulating eye development showed complete absence of otx5b (orthodenticle homolog 5) expression in S. tileihornes eyes, probably related to degradation of rods, but normal expression of crx (cone-rod homeobox). The enriched pathways and Otx5 are involved in phototransduction, photoreceptor formation, and regulation of photoreceptor-related gene expression. Unlike the S. tileihornes reported here, S. anophthalmus has reduced crx and otx5 expression. These results show that different species of cavefish within the same genus that independently evolved troglodyte characteristics can have different genetic mechanisms of eye degeneration.
PMID: 31332479 [PubMed - as supplied by publisher]
Evolutionary Origin and Nomenclature of Vertebrate Wnt11-Family Genes.
Zebrafish. 2019 Jul 11;:
Authors: Postlethwait JH, Navajas Acedo J, Piotrowski T
To adequately connect zebrafish medical models to human biology, it is essential that gene nomenclature reflects gene orthology. Analysis of gene phylogenies and conserved syntenies shows that the zebrafish gene currently called wnt11 (ENSDARG00000004256, ZFIN ID: ZDB-GENE-990603-12) is not the ortholog of the human gene called WNT11 (ENSG00000085741); instead, the gene currently called wnt11r (ENSDARG00000014796, ZFIN ID: ZDB-GENE-980526-249) is the zebrafish ortholog of human WNT11. Genomic analysis of Wnt11-family genes suggests a model for the birth of Wnt11-family gene ohnologs in genome duplication events, provides a mechanism for the death of a Wnt11-family ohnolog in mammals after they diverged from birds, and suggests revised nomenclature to better connect teleost disease models to human biology.
PMID: 31295059 [PubMed - as supplied by publisher]