Modular control of time and space during vertebrate axis segmentation
Posted on: 24 June 2024
Preprint posted on 31 August 2023
Article now published in The EMBO Journal at http://dx.doi.org/10.1038/s44318-024-00186-2
Natural genetic variation quantitatively regulates heart rate and dimension
Posted on:
Preprint posted on 2 November 2023
F2 segregation analysis: the ‘Formula 1 grand prix' of experiments to establish genotype-phenotype correlations
Selected by Girish Kale, Jennifer Ann BlackBackground
As humans, we know that most of our genome is conserved, and yet it is quite obvious that we are not all the same: we don’t look the same, we don’t think the same way, and this individuality is something we cherish. Since our genome is almost completely conserved, we need to focus on the subtle differences that form the basis of our individuality. Trying to understand these genomic differences, and linking that understanding to the differences in individual characteristics and susceptibility is an active area of research.
The subtle differences in our genomes are heritable. Again, this is a piece of common knowledge, as looking at our parents or grandparents we can tell where our characteristics come from. Of course, this also extends to various diseases: often doctors ask for a history of certain illnesses in our family. However, such correlations are only limited, as many subtle mutations in our genomes often produce a unique combined output, forming the basis of our individual differences. Linking any subtle mutation to a characteristic or disease susceptibility is really challenging. To tackle this, scientists can exploit high-resolution whole-genome sequencing to pick up even the most subtle mutations, and combine it with unique experimental systems where these mutations in the genome can be easily tracked over generations. The two preprints highlighted here share a unique experimental system where this approach is applied: the inbred lines of Japanese rice fish, also called medaka.
Inbred lines are an interesting resource for the scientific community and exist for other model organisms as well, such as mice and fruit flies. Essentially, an inbred line has individuals with extremely similar genomes: even the most subtle mutations are the same. As a result, they all have the same features and characteristics, including their susceptibility to various diseases, almost as if they are all clones of each other. If the individuals from such an inbred line are mated with others from a different inbred line, then in the next generation (called F1), we will see a difference in characteristics and susceptibilities due to a mixture of the parental genomes (the parents are called F0). In the F1 generation, meiotic recombination shuffles the genomes, and when these individuals mate with each other, the following generation (called F2) will include individuals with genomes that randomly segregate the subtle mutations present in the F0 inbred lines. Now the effects of various subtle mutations in the genome can be teased apart using whole genome sequencing and correlated with quantifications of various characteristics and susceptibilities.
The two preprints highlighted here use this same technique to address two completely different questions. One study tries to identify genes involved in the timing and size of segment formation during embryo development, while the other tries to identify genes leading to heart defects. Both of these studies used medaka species due to various additional experimental advantages including, the possibility to have genetic cross-species hybrids (besides in-bred lines), their small genome size and genetic tractability, and ease of in-vivo imaging during embryo development.
The preprint on Segment formation
Background
Segment formation, or segmentation, is an important process during embryo development. The process is regulated by hundreds of genes. Here, individual somites, the precursors of segments, are derived from pre-somitic mesoderm, and are added one after the other. The number of somites, the initial size of somites and the rate of somite addition is specific to a species. As we can imagine, the number, size, and rate of somite addition will depend on each other: fewer somites will require less time to form, larger somites will need more time to form, etc. Due to such interdependence, it is hard to tease apart how a certain gene influences somitogenesis. In their manuscript, Seleit and colleagues use inbred lines from 2 closely-related medaka species Oryzias sakaizumii and Oryzias latipes to understand the spatial and temporal control of somite formation in these species.
Key Findings
In their experiments, the authors decided to exploit the spatial and temporal differences in somitogenesis between the medaka species. They imaged the process of somitogenesis in live embryos in both Oryzias sakaizumii and Oryzias latipes and found that Oryzias sakaizumii has smaller somites which are added faster than Oryzias latipes. After mating the individuals from these species, in the next F1 generation, the pace of somitogenesis was intermediate to the F0 parent. Then the authors quantified PSM, somite size and somitogenesis pace using quantitative imaging of endogenous her7-venus oscillations in-vivo in about 600 F2 individuals and obtained an expanded (and continuous) phenotypic space for all three traits. They found that while PSM size and somite size are corelated in the F2s (with the same slope as was present in the F0s!), the pace of somitogenesis was not correlated with either PSM or somite size in F2s. This data argues that a developmental constraint mechanism underlies the link between PSM and somite size, while there is modular control of timing and size. The authors used the same phenotyped individuals for whole-genome sequencing, to identify regions of the genome which correlated with somite size or somitogenesis pace. This allowed them to using devQTL mapping to identify novel candidate genes, which might be regulators of the tempo of the somitogenesis clock/ the size of the tissue giving rise to somites.
After identifying interesting candidate genes, the authors introduced CRISPR-Cas9-mediated mutations to functionally test the activity of these candidate genes and to check whether/how they affect somitogenesis. The authors could show that the candidates associated with somite size don’t affect the pace of somitogenesis and vice versa, clearly demonstrating the independence of their genetic regulation. This demonstrated, for the first time in vivo, that somite size and the pace of somitogenesis can be uncoupled.
What we liked about this preprint
This preprint really demonstrates the power of the use of inbred lines. The authors could clearly demonstrate that the regulation of spatial and temporal aspects of somitogenesis are independent, and their genetic basis can be uncoupled. The study also uses strong quantitative and statistical approaches to test their hypothesis, allowing them to make clear statements about how somitogenesis is spatially and temporally regulated. With their approach, the authors can further comment on regulation of time and space in embryonic development in general, as similar mechanisms are expected to also regulate the developmental tempo of a species, which varies similarly across species.
The preprint on Heart defects
Background
In this study, the authors use inbred Medaka fish to examine early cardiac changes in the embryo and how these impact upon adult fish. Specifically, they examined changes to the heart rate of these fish by examining defined features of their hearts and their genomes. They find similar changes to those found in studies performed in humans but additionally, report novel genes that affect heartbeat and could have implications for managing and detecting heart problems in humans.
Key Findings
- Changes in embryo heart rate impact the health of the adult heart
The authors predominantly used two inbred Medaka lines for their studies: HdrR and HO5 (species: Oryzias latipes). By measuring the dynamics across development from the embryonic heart to adulthood, they revealed notable differences between the two inbred fish lines. These two fish lines represent two extremes; slowest heartbeat (HrdR) and fastest heartbeat (HO5). HdrR fish with the slow heart rate performed well in swimming tests, whereas HO5 fish, which have a fast heart rate and show signs of heart alterations early in development, swam poorly in comparison. Thus, the early heart changes affected both the fish’ heart performance and fitness when they developed into adults, with fast heart beat correlating with pathology.
- 59 loci in Medaka embryos correlated with alterations to heart rate
Next, the authors looked for changes in the genomes of these two inbred fish lines when environmental conditions changed. In this instance, they opted for water temperature, which coincides with higher heart rate when temperatures increase. They then crossed individuals from these two lines (HdrR X HO5) to generate a representative spectrum of heart changes, and examined the genomes of over 1000s individuals from this F2 generation. Overall, they identified 59 loci associated with heart rate changes. Within these 59 loci, they identified genes previously associated with pathogenic heart changes in humans.
To confirm their genome-wide studies and to ask if some of the genes identified played a role in heart disease development in these fish, they selected a representative cohort of previously known and novel genes and generated individual CRISPR/Cas9-modified Medaka fish. They show that inactivating genes within this cohort resulted in changes to fish’ heartbeats.
What we liked about this preprint
This preprint, like the other one discussed earlier, shows the power of using inbred (fish) lines. In this specific case, to identify complex pathologies that can be translated to human health. We found it interesting that the authors identified a cohort of genes that previously were not linked to changes in human heart health. Future studies will hopefully reveal if they contribute to human pathologies.
Questions to the authors
specifically for Segment formation manuscript
1) The segmentation and axis elongation process is supposed to be highly robust, as it occurs during the phylotypic stage of embryonic development. How is it that you can see so much variability in the F2? wouldn’t you have expected the “dominant” species to drive the process?
2) You have reported differences in the size and timing of segmentation. Do you think the dataset also includes genes that have changed the onset of when the segments begin to form during the time course of embryonic development?
specifically for Heart defects manuscript
1) Do you think the higher BMI observed in Ho5 is a cause or a consequence of hypoplastic ventricles and faster heart rate?
2) Galectins are promiscuous – how easy is it to target them in terms of translating your findings into the clinic?
for both
1) How important is it to see that the phenotypic spread in the F2 goes beyond the F0 parental extremes? How would the interpretation of the data change if the F2 extremes are the same as, or within, the F0 extremes?
2) How easy is it to generate CRISPR-modified medaka?
3) Why use fish for these models? What about mice or fruit flies, which also have inbred lines?
4) We (the preLighters) assume that all of you (the authors) believe in open science. Are there plans to create a searchable database of the candidate genes, as a resource for the scientific community?
5)What are the challenges of crossing these organisms – what’s the success rate? how does it affect their fitness overall?
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