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.
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]
Adaptation of proteins to the cold in Antarctic fish: A role for Methionine?
Genome Biol Evol. 2018 Nov 29;:
Authors: Berthelot C, Clarke J, Desvignes T, Detrich HW, 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. Whilst 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 over-representation of positions where leucine in temperate fish proteins was replaced by methionine in the notothenioid orthologues. We hypothesise 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 - as supplied by publisher]
Female Sex Development and Reproductive Duct Formation Depend on Wnt4a in Zebrafish.
Genetics. 2018 Nov 16;:
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 non-mammalian 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 in teleosts 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 non-mammalian vertebrates.
PMID: 30446521 [PubMed - as supplied by publisher]
Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease.
N Engl J Med. 2018 Oct 10;:
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 - as supplied by publisher]