John Postlethwait

Professor, Department of Biology
Member, ION

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.

RECENT PUBLICATIONS

Curr Biol. 2021 Sep 1:S0960-9822(21)01134-9. doi: 10.1016/j.cub.2021.08.030. Online ahead of print.

ABSTRACT

Sex chromosomes are generally derived from a pair of classical type-A chromosomes, and relatively few alternative models have been proposed up to now.1,2 B chromosomes (Bs) are supernumerary and dispensable chromosomes with non-Mendelian inheritance found in many plant and animal species3,4 that have often been considered as selfish genetic elements that behave as genome parasites.5,6 The observation that in some species Bs can be either restricted or predominant in one sex7-14 raised the interesting hypothesis that Bs could play a role in sex determination.15 The characterization of putative B master sex-determining (MSD) genes, however, has not yet been provided to support this hypothesis. Here, in Astyanax mexicanus cavefish originating from Pachón cave, we show that Bs are strongly male predominant. Based on a high-quality genome assembly of a B-carrying male, we characterized the Pachón cavefish B sequence and found that it contains two duplicated loci of the putative MSD gene growth differentiation factor 6b (gdf6b). Supporting its role as an MSD gene, we found that the Pachón cavefish gdf6b gene is expressed specifically in differentiating male gonads, and that its knockout induces male-to-female sex reversal in B-carrying males. This demonstrates that gdf6b is necessary for triggering male sex determination in Pachón cavefish. Altogether these results bring multiple and independent lines of evidence supporting the conclusion that the Pachón cavefish B is a "B-sex" chromosome that contains duplicated copies of the gdf6b gene, which can promote male sex determination in this species.

PMID:34496222 | DOI:10.1016/j.cub.2021.08.030

PLoS Genet. 2021 Aug 26;17(8):e1009705. doi: 10.1371/journal.pgen.1009705. eCollection 2021 Aug.

ABSTRACT

Whole-genome duplication and genome compaction are thought to have played important roles in teleost fish evolution. Ayu (or sweetfish), Plecoglossus altivelis, belongs to the superorder Stomiati, order Osmeriformes. Stomiati is phylogenetically classified as sister taxa of Neoteleostei. Thus, ayu holds an important position in the fish tree of life. Although ayu is economically important for the food industry and recreational fishing in Japan, few genomic resources are available for this species. To address this problem, we produced a draft genome sequence of ayu by whole-genome shotgun sequencing and constructed linkage maps using a genotyping-by-sequencing approach. Syntenic analyses of ayu and other teleost fish provided information about chromosomal rearrangements during the divergence of Stomiati, Protacanthopterygii and Neoteleostei. The size of the ayu genome indicates that genome compaction occurred after the divergence of the family Osmeridae. Ayu has an XX/XY sex-determination system for which we identified sex-associated loci by a genome-wide association study by genotyping-by-sequencing and whole-genome resequencing using wild populations. Genome-wide association mapping using wild ayu populations revealed three sex-linked scaffolds (total, 2.03 Mb). Comparison of whole-genome resequencing mapping coverage between males and females identified male-specific regions in sex-linked scaffolds. A duplicate copy of the anti-Müllerian hormone type-II receptor gene (amhr2bY) was found within these male-specific regions, distinct from the autosomal copy of amhr2. Expression of the Y-linked amhr2 gene was male-specific in sox9b-positive somatic cells surrounding germ cells in undifferentiated gonads, whereas autosomal amhr2 transcripts were detected in somatic cells in sexually undifferentiated gonads of both genetic males and females. Loss-of-function mutation for amhr2bY induced male to female sex reversal. Taken together with the known role of Amh and Amhr2 in sex differentiation, these results indicate that the paralog of amhr2 on the ayu Y chromosome determines genetic sex, and the male-specific amh-amhr2 pathway is critical for testicular differentiation in ayu.

PMID:34437539 | DOI:10.1371/journal.pgen.1009705

J Anat. 2021 Aug 22. doi: 10.1111/joa.13537. Online ahead of print.

ABSTRACT

Ancestors of the Antarctic icefishes (family Channichthyidae) were benthic and had no swim bladder, making it energetically expensive to rise from the ocean floor. To exploit the water column, benthopelagic icefishes were hypothesized to have evolved a skeleton with "reduced bone," which gross anatomical data supported. Here, we tested the hypothesis that changes to icefish bones also occurred below the level of gross anatomy. Histology and micro-CT imaging of representative craniofacial bones (i.e., ceratohyal, frontal, dentary, and articular) of extant Antarctic fish species specifically evaluated two features that might cause the appearance of "reduced bone": bone microstructure (e.g., bone volume fraction and structure linear density) and bone mineral density (BMD, or mass of mineral per volume of bone). Measures of bone microstructure were not consistently different in bones from the icefishes Chaenocephalus aceratus and Champsocephalus gunnari, compared to the related benthic notothenioids Notothenia coriiceps and Gobionotothen gibberifrons. Some quantitative measures, such as bone volume fraction and structure linear density, were significantly increased in some icefish bones compared to homologous bones of non-icefish. However, such differences were rare, and no microstructural measures were consistently different in icefishes across all bones and species analyzed. Furthermore, BMD was similar among homologous bones of icefish and non-icefish Antarctic notothenioids. In summary, "reduced bone" in icefishes was not due to systemic changes in bone microstructure or BMD, raising the prospect that "reduced bone" in icefish occurs only at the gross anatomic level (i.e., smaller or fewer bones). Given that icefishes exhibit delayed skeletal development compared to non-icefish Antarctic fishes, combining these phenotypic data with genomic data might clarify genetic changes driving skeletal heterochrony.

PMID:34423431 | DOI:10.1111/joa.13537

Trends Genet. 2021 Jul 29:S0168-9525(21)00191-8. doi: 10.1016/j.tig.2021.07.002. Online ahead of print.

ABSTRACT

Model organism research is essential to understand disease mechanisms. However, laboratory-induced genetic models can lack genetic variation and often fail to mimic the spectrum of disease severity. Evolutionary mutant models (EMMs) are species with evolved phenotypes that mimic human disease. EMMs complement traditional laboratory models by providing unique avenues to study gene-by-environment interactions, modular mutations in noncoding regions, and their evolved compensations. EMMs have improved our understanding of complex diseases, including cancer, diabetes, and aging, and illuminated mechanisms in many organs. Rapid advancements of sequencing and genome-editing technologies have catapulted the utility of EMMs, particularly in fish. Fish are the most diverse group of vertebrates, exhibiting a kaleidoscope of specialized phenotypes, many that would be pathogenic in humans but are adaptive in the species' specialized habitat. Importantly, evolved compensations can suggest avenues for novel disease therapies. This review summarizes current research using fish EMMs to advance our understanding of human disease.

PMID:34334238 | DOI:10.1016/j.tig.2021.07.002