AUTHOR=Barthelson Karissa , Baer Lachlan , Dong Yang , Hand Melanie , Pujic Zac , Newman Morgan , Goodhill Geoffrey J. , Richards Robert I. , Pederson Stephen M. , Lardelli Michael 

TITLE=Zebrafish Chromosome 14 Gene Differential Expression in the fmr1hu2787 Model of Fragile X Syndrome

JOURNAL=Frontiers in Genetics

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.625466

DOI=10.3389/fgene.2021.625466

ISSN=1664-8021

ABSTRACT=<p>Zebrafish represent a valuable model for investigating the molecular and cellular basis of Fragile X syndrome (FXS). Reduced expression of the zebrafish <italic>FMR1</italic> orthologous gene, <italic>fmr1</italic>, causes developmental and behavioural phenotypes related to FXS. Zebrafish homozygous for the hu2787 non-sense mutation allele of <italic>fmr1</italic> are widely used to model FXS, although FXS-relevant phenotypes seen from morpholino antisense oligonucleotide (morpholino) suppression of <italic>fmr1</italic> transcript translation were not observed when hu2787 was first described. The subsequent discovery of transcriptional adaptation (a form of genetic compensation), whereby mutations causing non-sense-mediated decay of transcripts can drive compensatory upregulation of homologous transcripts independent of protein feedback loops, suggested an explanation for the differences reported. We examined the whole-embryo transcriptome effects of homozygosity for <italic>fmr1<sup><italic>h</italic><italic>u</italic>2787</sup></italic> at 2 days post fertilisation. We observed statistically significant changes in expression of a number of gene transcripts, but none from genes showing sequence homology to <italic>fmr1</italic>. Enrichment testing of differentially expressed genes implied effects on lysosome function and glycosphingolipid biosynthesis. The majority of the differentially expressed genes are located, like <italic>fmr1</italic>, on Chromosome 14. Quantitative PCR tests did not support that this was artefactual due to changes in relative chromosome abundance. Enrichment testing of the “leading edge” differentially expressed genes from Chromosome 14 revealed that their co-location on this chromosome may be associated with roles in brain development and function. The differential expression of functionally related genes due to mutation of <italic>fmr1</italic>, and located on the same chromosome as <italic>fmr1</italic>, is consistent with R.A. Fisher’s assertion that the selective advantage of co-segregation of particular combinations of alleles of genes will favour, during evolution, chromosomal rearrangements that place them in linkage disequilibrium on the same chromosome. However, we cannot exclude that the apparent differential expression of genes on Chromosome 14 genes was, (if only in part), caused by differences between the expression of alleles of genes unrelated to the effects of the <italic>fmr1<sup><italic>h</italic><italic>u</italic>2787</sup></italic> mutation and made manifest due to the limited, but non-zero, allelic diversity between the genotypes compared.</p>