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Genetic basis for divergence in developmental gene expression in two closely related sea urchins

Abstract

The genetic basis for divergence in developmental gene expression among species is poorly understood, despite growing evidence that such changes underlie many interesting traits. Here we quantify transcription in hybrids of Heliocidaris tuberculata and Heliocidaris erythrogramma, two closely related sea urchins with highly divergent developmental gene expression and life histories. We find that most expression differences between species result from genetic influences that affect one stage of development, indicating limited pleiotropic consequences for most mutations that contribute to divergence in gene expression. Activation of zygotic transcription is broadly delayed in H. erythrogramma, the species with the derived life history, despite its overall faster premetamorphic development. Altered expression of several terminal differentiation genes associated with the derived larval morphology of H. erythrogramma is based largely on differences in the expression or function of their upstream regulators, providing insights into the genetic basis for the evolution of key life history traits.

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Fig. 1: Development and gene expression in parents and hybrids.
Fig. 2: Inferred genetic basis for expression divergence among species.
Fig. 3: Developmental changes in genetic basis for expression divergence.
Fig. 4: Inferred genetic basis for expression of genes that interact during development.

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Data availability

The sequence reads for this project are available from the Sequence Read Archive under accession no. SRP229522. The count tables are available from the project’s GitHub repository (https://github.com/Wray-Group-at-Duke/HybridsProject_NEE).

Code availability

The code used in this project is available from the project’s GitHub repository (https://github.com/Wray-Group-at-Duke/HybridsProject_NEE).

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Acknowledgements

D. McClay, P. Davidson, H. Devens, A. Massri and S. Makohon-Moore provided advice and comments. J. Coolon (Wesleyan University) generously shared unpublished code and advice. This study was supported by an Australian Research Council grant to M.B. and National Science Foundation grant nos. IOS1457305 and IOS1929934 to G.A.W.

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L.W., J.W.I. and G.A.W. designed the study. L.W., J.W.I. and A.E. generated the data. L.W., J.W.I., A.E., M.B. and G.A.W. contributed the analysis tools. All authors participated in analysing the results. G.A.W. wrote the paper with input from L.W., J.W.I., A.E., R.A.R., E.C.R. and M.B.

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Correspondence to Gregory A. Wray.

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Extended data

Extended Data Fig. 1 Interpretation of inheritance mode (dominance) classification.

The scatterplot in the center corresponds to Fig. 2d of the main text. Each dot corresponds to a single gene. The x-axis is the difference in expression level in hybrids and H. erythrogramma (He; maternal), while the y-axis is the difference in expression level in hybrids and H. tuberculata (Ht; paternal), both log2 scale for visualization of the full dynamic range. The six bar plots surrounding the scatterplot illustrate hypothetical cases of expression for individual genes that would be classified as different modes of inheritance: expression levels are shown for both parental crosses (He and Ht) and for hybrids (Hy). If expression in hybrids is not statistically distinguishable from He but is statistically distinguishable from Ht, mode of inheritance is classified as He dominant. The reverse case is classified as Ht dominant. If expression in hybrids is intermediate between He and Ht, the case is classified as additive (codominant). If expression in hybrids is higher than both parents, the case is classified as overdominant, while if lower than either parent it is classified as underdominant. Genes not differentially expressed between the parental crosses and are classified as conserved. The formal criteria for these classifications are presented in Supplementary Table 3. Note that although the arrows point to only one cloud of points, He dominant, Ht dominant, and additive each has a counterpart distributed symmetrically around the origin; underdominant and overdominant are symmetrical around the origin along the diagonal.

Extended Data Fig. 2 cis and trans genetic influences on transcript abundance.

Cells in hybrids contain regulatory machinery from both parents (blue and red ovals, representing orthologous transcription factors). Because transcription factors diffuse, they interact with both genomes in hybrids. Genetic differences between species allow assignment of reads in hybrids to parent of origin and indicates whether they are present at equal levels or not (allelic balance or imbalance, respectively). Lower left: allelic imbalance in hybrids indicates a genetic influence on an expression difference, since both alleles are in the same trans environment. Further, the genetic influence must be in linkage disequilibrium with the gene in question or it would not produce a consistent influence due to recombination and independent assortment. Lower center: allelic balance in hybrids indicates the absence of cis genetic effects, because the genetic basis is not in linkage disequilibrium with the gene. If the gene is also consistently expressed at different levels in the two parental species, however, it must have a genetic basis which must therefore be in trans. In such cases, something in the biochemical environment influences expression level independent of any differences in cis-regulatory elements between species. Possibilities include differences binding specificity or expression level of a transcription factor or presence of a co-factor that influences the expression of the gene. Comparing expression in hybrids that in the parental species provides additional information. If expression in hybrids is intermediate between that in the two parental species and there is no allelic imbalance, the case is classified as all trans. Lower right: other cases imply a mix of cis and trans influences, one of which is shown here. The cis and trans influences can reinforce or counteract and may not be of the same magnitude. For additional discussion, see references2,5,6,7,8,9.

Extended Data Fig. 3 Interpretation of regulatory mode (cis/trans) classification.

The scatterplot in the center corresponds to Fig. 2e (main text), with each dot representing a gene. The x-axis is the ratio of expression levels in the two species, while the y-axis is the ratio of expression levels from the two alleles in hybrids (Ae = H. erythrogramma allele, At = H. tuberculata allele); note log2 scales. Bar plots show hypothetical cases illustrating classification of genes by regulatory mode: expression levels are shown for parental crosses (He = H. erythrogramma; Ht = H. tuberculata), hybrids (Hy), and alleles within hybrids (Ae = He allele; At = Ht allele). Cases where allelic expression in hybrids is not statistically different from the parental crosses are classified as all cis. If expression in hybrids is the average of parental crosses and the two alleles are expressed at the same level, the case is classified as all trans. When expression in hybrids is the average of the two parents but that of at least one allele lies closer to the same-species cross, the case is classified as cis + trans. When the case is similar to the previous but alleles in hybrids are closer to the opposite parental cross, it is classified as cis x trans. Compensatory cases involve no difference between same species crosses but alleles in hybrids show differences of similar magnitude and opposite sign. Note that although the arrows point to only one cloud of points, each has a counterpart distributed symmetrically around the origin; in addition, cis x trans has four clouds of points. For each of the two or four clouds of points, one or more of the bars in the hypothetical expression level plots will change (see formal criteria in Supplementary Table 4 for details).

Extended Data Fig. 4 Inference of early paternal influences on transcription.

At the blastula stage, 42 genes in hybrids are classified as having paternal dominant expression with all or partly trans influences. This combination of classifications implies activity of the paternal allele of another gene prior to the blastula stage. Several plausible molecular mechanisms could produce this result. An example is sketched out here involving two genes: gene B, classified as paternal dominant and all or part trans at blastula stage, and gene A, which encodes a transcription factor (rectangles) that activates transcription of gene B at blastula stage. In this scenario, a different transcription factor is present in the pre-blastula embryo (ovals). It binds to a cis-regulatory element to activate transcription of gene A in H. tuberculata (blue ovals), but the orthologous transcription factor in H. erythrogramma (red ovals) cannot bind to the cis-regulatory element due to a mutation (marked X). In hybrids, the transcription factor binds to the cis-regulatory element of the paternal allele and activates its transcription, but still cannot bind to the cis-regulatory element of the maternal allele. As a consequence, the transcription factor produced from gene A is present in blastula stage embryos of H. tuberculata and hybrids (blue rectangles), but not those of H. erythrogramma. The transcription factor from gene A (rectangles) goes on to activate transcription of gene B in embryos of H. tuberculata and hybrids, but not embryos of H. erythrogramma. This transcription factor must interact with the cis-regulatory elements of both the maternal and paternal allele in hybrids, as this case was classified as all or part trans.

Extended Data Fig. 5 Model for transient early embryonic asymmetry of trans effects.

Several situations can produce a trans genetic effect. One, shown here, involves mutations in a transcription factor that alters the level of expression of a target gene. Possibilities include changes in binding affinity, changes in protein:protein interactions that stabilize its interaction with the binding site, and a variety of indirect effects mediated through co-factors or chromatin state. The essential point is that binding of orthologous transcription factors produces different levels of transcription. Since most of the transcriptional machinery in early embryos is maternally derived, the paternal orthologue will likely not be present in early hybrid embryos because the sperm brings few if any transcription factors to the zygote (middle left). Thus, even though the cis-regulatory elements of both species can bind the transcription factor, expression in hybrids is low from both alleles because the only orthologue of the transcription factor present is the maternal version, which activates expression more weakly. Since trans-acting factors such as transcription factors often exert an influence on the expression of many target genes, a few cases like the one outlined here (or scenarios with similar effects such as presence of a more potent repressor in eggs of H. erythrogramma) could readily account for the strong bias towards reduced expression for genes showing trans-only genetic influences in hybrids. By gastrula stage, the paternal genome is being widely transcribed and both orthologues of the transcription factor are present in the cytoplasm. Assuming the simplest and most common case that the gene encoding the transcription factor itself shows allelic balance and the protein has a similar DNA binding characteristics, the two orthologues will bind each cis-regulatory element allele with equal frequency, erasing the asymmetry (right). Again, more complex scenarios are possible.

Extended Data Fig. 6 Model for asymmetry of compensatory cases based on a proposed novel underlying mechanism.

Left: prior studies have generally interpreted the underlying mechanism in compensatory cases as involving equal and opposite cis and trans effects. In one simple scenario (shown here), both orthologues of the transcription factor bind to both orthologues of the cis-regulatory element, but with different kinetics or different consequences for transcriptional activation due to mutations in the transcription factor coding sequence and in the cis-regulatory element. The net level of transcripts remains the same in hybrids and both parents. A variety of specific combinations of cis and trans effects could result in no net difference in transcript abundance. In the scenario shown, the altered regulatory element and altered transcription factor interact with each other but this need not be the case. Right: a different underlying mechanism is possible when considering allelic imbalance in early embryos, due to the possibility of evolutionary changes in the presence or level of maternal transcripts that are loaded into the egg. If zygotic expression of a gene is reduced but maternal transcripts make up the difference, the net result will be conserved gene expression. In the scenario shown here, maternal mRNA is not loaded into the eggs of H. tuberculata but it is loaded in H. erythrogramma. This effect is necessarily asymmetric because the egg contributes vast quantities of transcripts to the zygote while the sperm contributes next to none. This mechanism would generally be possible only in early embryos, as it is a direct effect of evolutionary changes in maternal gene expression and maternal transcripts typically do not persist into later development.

Extended Data Fig. 7 Model for differences among developmental stages in the genetic basis for the evolution of expression of the same gene.

During development, the trans environment (primarily transcription factors and co-factors) changes but the cis-regulatory elements remain the same. Note that transcription factors diffuse and thus can interact with regulatory elements in both genomes (‘and’ indicates both possible states). Often, different transcription factors influence gene expression at different stages. Given that different transcription factors typically interact with different binding sites in the genome or even entirely different cis-regulatory elements, a mutation in one transcription factor binding site may only affect the interaction with one transcription factor at one stage of development. Later, this same mutation has no influence because that particular transcription factor is no longer present and the ones that are present bind to other sites within the same or a nearby cis-regulatory element. The net result is that the mutation only affects development at one stage. This becomes important for thinking about adaptation because a mutation that affects gene expression at one stage of development need not affect other stages – meaning its effects are not highly pleiotropic. Note that the precise scenario sketched out above is just one of many different possible mechanisms for producing an evolutionary difference at one stage of development but not at another. Protein modifications to transcription factors such as phosphorylation, changes in the presence of co-factors, competition with another transcription factor for the same binding site, and local modifications to chromatin are some of these alternative mechanisms. In all cases, the consequences of the mutation for expression of the gene in question is context-dependent, with the context changing during development.

Extended Data Fig. 8 Experimental evidence for evolutionarily conserved linkages within the skeletogenic GRN.

The MEK-ERK pathway, via the transcription factor Ets1/2, is required for expression of the skeletogenic gene alx1. This locus encodes the transcription factor Alx1, which is required for normal expression of the gene msp130, which is a terminal differentiation gene that encodes a structural protein of the biomineral matrix. a and a’: Localization of alx1 transcripts by in situ hybridization in vehicle control-treated (a) and MEK-ERK inhibitor-treated (a’) H. erythrogramma larvae reveal stained cells in the juvenile rudiment (in a but not a’). b and b’: Indirect immunofluorescence localization of the Msp130 protein product in H. erythrogramma larva injected with a standard control morpholino (b) or a translation-blocking morpholino targeting alx1 (b’). c. Diagram showing two key gene regulatory connections that are shared between H. erythrogramma and the ancestral GRN.

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Wang, L., Israel, J.W., Edgar, A. et al. Genetic basis for divergence in developmental gene expression in two closely related sea urchins. Nat Ecol Evol 4, 831–840 (2020). https://doi.org/10.1038/s41559-020-1165-y

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