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Developmental Biology - Genes|
"Many of the distinctive features that make us unique, including our color, height and susceptibility to diseases, are determined by our genomes. But as everyone looks pretty similar when embryos, gene assembly instructions at conception were thought to be nearly identical between us."
Enter the Worm
The C. elegans nematode worm is a celebrated lab animal used for decades to investigate animal development, including humans. Rothman's team, which included researchers at the University of Auckland, Australia, targeted the switches that turn on gene development of C. elegans' intestine with a tool called RNAi — a technique that shuts down individual gene functions.
What they learned was that the widely accepted "standard one-size-fits-all" concept of genetic assembly instructions did not apply.
"This remarkable difference is well hidden in the genome, but was uncovered when one of the [intestinal] switches was removed. We were startled to find that while some members of the species absolutely require this critical switch to start making an intestine, others can almost get rid of it. Prior to these findings, we were unaware that the blueprints for an early embryo change so rapidly within a species."
This discovery would be equivalent to finding that the manufacturing of two iPhones, which look and function identically, started out with different assembly instructions, the researchers said.
While humans are a far cry from C. elegans, once the initial events in embryo development begin, the later genetic instructions that create the endoderm appear to be similar to those likely used in all animals with a digestive tract, including humans. This result is particularly striking given that the endoderm is both the first layer formed in embryos and was probably the first to evolve over half a billion years ago.
"It reveals an extreme version of the first part of the 'hourglass' view of embryo development, in which very similar instructions across widely different animals during the middle stages of development are preceded and followed by very different starting and ending points."
These findings also shine light on why patients can respond so differently to drug therapies. "We found that these animals with relatively subtle genetic differences respond wildly differently to a gene 'switch' we used to turn off a gene," Torres Cleuren added.
Thus, just as two people who might look very similar can respond very differently to a drug therapy, so these little worms of the same species respond dramatically differently to an administered substance as a result of their subtle but all-important genetic individuality, the researchers said.
The discovery of such hidden genetic mechanisms could help guide how pharmaceuticals are developed in this era of precision medicine, where drugs are ideally tailored to an individual's genome. This discovery also underscores the importance of natural variation in allowing evolution to occur.
"Genetic variation fuels the machine of evolution. Without it, life would be stuck in a dead end. There is much more of this variation than we had realized when evolution sculpts the remarkable entities known as embryos."
Innovations in metazoan development arise from evolutionary modification of gene regulatory networks (GRNs). We report widespread cryptic variation in the requirement for two key regulatory inputs, SKN-1/Nrf2 and MOM-2/Wnt, into the C. elegans endoderm GRN. While some natural isolates show a nearly absolute requirement for these two regulators, in others, most embryos differentiate endoderm in their absence. GWAS and analysis of recombinant inbred lines reveal multiple genetic regions underlying this broad phenotypic variation. We observe a reciprocal trend, in which genomic variants, or knockdown of endoderm regulatory genes, that result in a high SKN-1 requirement often show low MOM-2/Wnt requirement and vice-versa, suggesting that cryptic variation in the endoderm GRN may be tuned by opposing requirements for these two key regulatory inputs. These findings reveal that while the downstream components in the endoderm GRN are common across metazoan phylogeny, initiating regulatory inputs are remarkably plastic even within a single species.
Yamila N Torres Cleuren, Chee Kiang Ewe, Kyle C Chipman, Emily R Mears, Cricket G Wood, Coco Emma Alma Al-Alami, Melissa R Alcorn, Thomas L Turner, Pradeep M Joshi, Russell G Snell and Joel H Rothman.
National Institutes of Health (1R01HD082347) Joel H Rothman
National Institutes of Health (1R01HD081266) Joel H Rothman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Return to top of page.
Gene "switches" in the round worm C. elegans appear similar to those used by all animals with a digestive tract, even humans. The endoderm layer is the first layer formed in embryos and probably the first distinct tissue layer to evolve over half a billion years ago. Here we see the pharynx or 'throat' (RED) and intestine (GREEN/Cyan) of the worm C. elegans.
CREDIT University of California at Santa Barbara.