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.


Related Articles

Intergeneric hybrids inform reproductive isolating barriers in the Antarctic icefish radiation.

Sci Rep. 2019 Apr 12;9(1):5989

Authors: Desvignes T, Le François NR, Goetz LC, Smith SS, Shusdock KA, Parker SK, Postlethwait JH, Detrich HW

Interspecific hybridization or barriers to hybridization may have contributed to the diversification of Antarctic icefishes (Channichthyidae), but data supporting these hypotheses is scarce. To understand the potential for hybridization and to investigate reproductive isolating mechanisms among icefish species, we performed in vitro fertilization experiments using eggs from a female blackfin icefish Chaenocephalus aceratus and sperm from a male of another genera, the ocellated icefish Chionodraco rastrospinosus. Sequencing of genomic and mitochondrial DNA confirmed the intergeneric hybrid nature of resulting embryos which successfully developed and hatched as active larvae at about four and a half months during the Antarctic winter. This result demonstrates the compatibility of gametes of these two species and the viability of resulting zygotes and larvae. Due to logistic constraints and the slow developmental rate of icefishes, we could not test for long-term hybrid viability, fertility, fitness, or hybrid breakdown. Analysis of our fishing records and available literature, however, suggests that the strongest barriers to hybridization among parapatric icefish species are likely to be behavioral and characterized by assortative mating and species-specific courtship and nesting behaviors. This conclusion suggests that, in long-lived fish species with late sexual maturity and high energetic investment in reproduction like icefishes, pre-mating barriers are energetically more efficient than post-mating barriers to prevent hybridization.

PMID: 30979924 [PubMed - in process]

Related Articles

Brain of the blind: transcriptomics of the golden-line cavefish brain.

Curr Zool. 2018 Dec;64(6):765-773

Authors: Meng F, Zhao Y, Titus T, Zhang C, Postlethwait JH

The genus Sinocyclocheilus (golden-line barbel) includes 25 species of cave-dwelling blind fish (cavefish) and more than 30 surface-dwelling species with normal vision. Cave environments are dark and generally nutrient-poor with few predators. Cavefish of several genera evolved convergent morphological adaptations in visual, pigmentation, brain, olfactory, and digestive systems. We compared brain morphology and gene expression patterns in a cavefish Sinocyclocheilus anophthalmus with those of a closely related surface-dwelling species S. angustiporus. Results showed that cavefish have a longer olfactory tract and a much smaller optic tectum than surface fish. Transcriptomics by RNA-seq revealed that many genes upregulated in cavefish are related to lysosomes and the degradation and metabolism of proteins, amino acids, and lipids. Genes downregulated in cavefish tended to involve "activation of gene expression in cholesterol biosynthesis" and cholesterol degradation in the brain. Genes encoding Srebfs (sterol regulatory element-binding transcription factors) and Srebf targets, including enzymes in cholesterol synthesis, were downregulated in cavefish brains compared with surface fish brains. The gene encoding Cyp46a1, which eliminates cholesterol from the brain, was also downregulated in cavefish brains, while the total level of cholesterol in the brain remained unchanged. Cavefish brains misexpressed several genes encoding proteins in the hypothalamus-pituitary axis, including Trh, Sst, Crh, Pomc, and Mc4r. These results suggest that the rate of lipid biosynthesis and breakdown may both be depressed in golden-line cavefish brains but that the lysosome recycling rate may be increased in cavefish; properties that might be related to differences in nutrient availability in caves.

PMID: 30538736 [PubMed]

Related Articles

Adaptation of Proteins to the Cold in Antarctic Fish: A Role for Methionine?

Genome Biol Evol. 2019 01 01;11(1):220-231

Authors: Berthelot C, Clarke J, Desvignes T, William Detrich H, Flicek P, Peck LS, Peters M, Postlethwait JH, Clark MS

The evolution of antifreeze glycoproteins has enabled notothenioid fish to flourish in the freezing waters of the Southern Ocean. Whereas successful at the biodiversity level to life in the cold, paradoxically at the cellular level these stenothermal animals have problems producing, folding, and degrading proteins at their ambient temperatures of -1.86 °C. In this first multi-species transcriptome comparison of the amino acid composition of notothenioid proteins with temperate teleost proteins, we show that, unlike psychrophilic bacteria, Antarctic fish provide little evidence for the mass alteration of protein amino acid composition to enhance protein folding and reduce protein denaturation in the cold. The exception was the significant overrepresentation of positions where leucine in temperate fish proteins was replaced by methionine in the notothenioid orthologues. We hypothesize that these extra methionines have been preferentially assimilated into the genome to act as redox sensors in the highly oxygenated waters of the Southern Ocean. This redox hypothesis is supported by analyses of notothenioids showing enrichment of genes associated with responses to environmental stress, particularly reactive oxygen species. So overall, although notothenioid fish show cold-associated problems with protein homeostasis, they may have modified only a selected number of biochemical pathways to work efficiently below 0 °C. Even a slight warming of the Southern Ocean might disrupt the critical functions of this handful of key pathways with considerable impacts for the functioning of this ecosystem in the future.

PMID: 30496401 [PubMed - in process]

Related Articles

Female Sex Development and Reproductive Duct Formation Depend on Wnt4a in Zebrafish.

Genetics. 2019 01;211(1):219-233

Authors: Kossack ME, High SK, Hopton RE, Yan YL, Postlethwait JH, Draper BW

In laboratory strains of zebrafish, sex determination occurs in the absence of a typical sex chromosome and it is not known what regulates the proportion of animals that develop as males or females. Many sex determination and gonad differentiation genes that act downstream of a sex chromosome are well conserved among vertebrates, but studies that test their contribution to this process have mostly been limited to mammalian models. In mammals, WNT4 is a signaling ligand that is essential for ovary and Müllerian duct development, where it antagonizes the male-promoting FGF9 signal. Wnt4 is well conserved across all vertebrates, but it is not known if Wnt4 plays a role in sex determination and/or the differentiation of sex organs in nonmammalian vertebrates. This question is especially interesting in teleosts, such as zebrafish, because they lack an Fgf9 ortholog. Here we show that wnt4a is the ortholog of mammalian Wnt4, and that wnt4b was present in the last common ancestor of humans and zebrafish, but was lost in mammals. We show that wnt4a loss-of-function mutants develop predominantly as males and conclude that wnt4a activity promotes female sex determination and/or differentiation in zebrafish. Additionally, both male and female wnt4a mutants are sterile due to defects in reproductive duct development. Together these results strongly argue that Wnt4a is a conserved regulator of female sex determination and reproductive duct development in mammalian and nonmammalian vertebrates.

PMID: 30446521 [PubMed - indexed for MEDLINE]

Related Articles

Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease.

N Engl J Med. 2018 11 29;379(22):2131-2139

Authors: Splinter K, Adams DR, Bacino CA, Bellen HJ, Bernstein JA, Cheatle-Jarvela AM, Eng CM, Esteves C, Gahl WA, Hamid R, Jacob HJ, Kikani B, Koeller DM, Kohane IS, Lee BH, Loscalzo J, Luo X, McCray AT, Metz TO, Mulvihill JJ, Nelson SF, Palmer CGS, Phillips JA, Pick L, Postlethwait JH, Reuter C, Shashi V, Sweetser DA, Tifft CJ, Walley NM, Wangler MF, Westerfield M, Wheeler MT, Wise AL, Worthey EA, Yamamoto S, Ashley EA, Undiagnosed Diseases Network

BACKGROUND: Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most challenging cases and to identify the biologic characteristics of newly discovered diseases. The UDN, which is funded by the National Institutes of Health, was formed in 2014 as a network of seven clinical sites, two sequencing cores, and a coordinating center. Later, a central biorepository, a metabolomics core, and a model organisms screening center were added.
METHODS: We evaluated patients who were referred to the UDN over a period of 20 months. The patients were required to have an undiagnosed condition despite thorough evaluation by a health care provider. We determined the rate of diagnosis among patients who subsequently had a complete evaluation, and we observed the effect of diagnosis on medical care.
RESULTS: A total of 1519 patients (53% female) were referred to the UDN, of whom 601 (40%) were accepted for evaluation. Of the accepted patients, 192 (32%) had previously undergone exome sequencing. Symptoms were neurologic in 40% of the applicants, musculoskeletal in 10%, immunologic in 7%, gastrointestinal in 7%, and rheumatologic in 6%. Of the 382 patients who had a complete evaluation, 132 received a diagnosis, yielding a rate of diagnosis of 35%. A total of 15 diagnoses (11%) were made by clinical review alone, and 98 (74%) were made by exome or genome sequencing. Of the diagnoses, 21% led to recommendations regarding changes in therapy, 37% led to changes in diagnostic testing, and 36% led to variant-specific genetic counseling. We defined 31 new syndromes.
CONCLUSIONS: The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%. (Funded by the National Institutes of Health Common Fund.).

PMID: 30304647 [PubMed - indexed for MEDLINE]

Related Articles

Reply to: 'Subfunctionalization versus neofunctionalization after whole-genome duplication'.

Nat Genet. 2018 Jul;50(7):910-911

Authors: Braasch I, Bobe J, Guiguen Y, Postlethwait JH

PMID: 29955179 [PubMed - in process]

Related Articles

Evolution of caudal fin ray development and caudal fin hypural diastema complex in spotted gar, teleosts, and other neopterygian fishes.

Dev Dyn. 2018 Jun;247(6):832-853

Authors: Desvignes T, Carey A, Postlethwait JH

BACKGROUND: The caudal fin of actinopterygians transitioned from a heterocercal dorsoventrally asymmetrical fin to a homocercal externally symmetrical fin in teleosts through poorly understood evolutionary developmental mechanisms. We studied the caudal skeleton of major living actinopterygian lineages, including polypteriformes, acipenseriformes, Holostei (gars and bowfin), and teleosts, compared with reports of extinct neopterygians and basal teleosteans. We focused on the hypural diastema complex, which includes (1) a gap between hypurals 2 and 3, that (2) separates two plates of connective tissue at (3) the branching of caudal vasculature; these features had been considered as a shared, derived trait of teleosts, a synapomorphy.
RESULTS: These studies revealed that gars and teleosts share all three features of the hypural diastema complex. Absence of a complex with these features from bowfin, fossil Holostei, and stem Teleostei argues in favor of repetitive, independent emergence in several neopterygian and basal Teleostei lineages, or less likely, many independent losses. We further observed that, in gars and teleosts, the earliest developing lepidotrichia align with the horizontal adult body axis, thus participating in external symmetry.
CONCLUSIONS: These results suggest that the hypural diastema complex in teleosts and gars represents a homoplasy among neopterygians and that it emerged repeatedly by parallel evolution due to shared inherited underlying genetic and developmental programs (latent homology). Because the hypural diastema complex exists in gars with heterocercal tails, this complex is independent of homocercality. Developmental Dynamics 247:832-853, 2018. © 2018 Wiley Periodicals, Inc.

PMID: 29569346 [PubMed - indexed for MEDLINE]

Related Articles

Skeletal development in the heterocercal caudal fin of spotted gar (lepisosteus oculatus) and other lepisosteiformes.

Dev Dyn. 2018 05;247(5):724-740

Authors: Desvignes T, Carey A, Braasch I, Enright T, Postlethwait JH

BACKGROUND: The caudal fin of actinopterygians experienced substantial morphological changes during evolution. In basal actinopterygians, the caudal fin skeleton supports an asymmetrical heterocercal caudal fin, while most teleosts have a symmetrical homocercal caudal fin. The transition from the ancestral heterocercal form to the derived homocercal caudal fin remains poorly understood. Few developmental studies provide an understanding of derived and ancestral characters among basal actinopterygians. To fill this gap, we examined the development of the caudal fin of spotted gar Lepisosteus oculatus, one of only eight living species of Holostei, the sister group to the teleosts.
RESULTS: Our observations of animals from fertilization to more than a year old provide the most detailed description of the development of caudal fin skeletal elements in any Holostean species. We observed two different types of distal caudal radials replacing two transient plates of connective tissue, identifying two hypaxial ensembles separated by a space between hypurals 2 and 3. These features have not been described in any gar species, but can be observed in other gar species, and thus represent anatomical structures common to lepisosteiformes.
CONCLUSIONS: The present work highlights the power and importance of ontogenic studies and provides bases for future evolutionary and morphological investigations on actinopterygians fins. Developmental Dynamics 247:724-740, 2018. © 2018 Wiley Periodicals, Inc.

PMID: 29330942 [PubMed - indexed for MEDLINE]