Amphioxus SYCP1 : a case of retrogene replacement and co-option of regulatory elements adjacent to the ParaHox cluster

MGG was supported by the University of St Andrews School of Biology Biotechnology and Biological Sciences Research Council DTG and the Wellcome Trust ISSF. Work in the authors’ laboratory is also supported by the Leverhulme Trust.Retrogenes are formed when an mRNA is reverse transcribed and re-inserted into the genome in a location unrelated to the original locus. If this retrocopy inserts into a transcriptionally favourable locus and is able to carry out its original function, it can, in rare cases, lead to retrogene replacement. This involves the original, often multi-exonic, parental copy being lost whilst the newer single-exon retrogene copy ‘replaces’ the role of the ancestral parent gene. One example of this is amphioxus SYCP1, a gene that encodes a protein used in synaptonemal complex formation during meiosis, and which offers the opportunity to examine how a retrogene evolves after the retrogene replacement event. SYCP1 genes exist as large multi-exonic genes in most animals. AmphiSYCP1, however, contains a single coding exon of ~3200bp and has inserted next to the ParaHox cluster of amphioxus, whilst the multi-exonic ancestral parental copy has been lost. Here, we show that AmphiSYCP1 has not only replaced its parental copy, but has evolved additional regulatory function by co- opting a bidirectional promoter from the nearby AmphiCHIC gene. AmphiSYCP1 has also evolved a de novo, multi-exonic 5’untranslated region that displays distinct regulatory states, in the form of two different isoforms, and has evolved novel expression patterns during amphioxus embryogenesis in addition to its ancestral role in meiosis. Absence of ParaHox-like expression of AmphiSYCP1, despite its proximity to the ParaHox cluster, also suggests this gene is not influenced by any potential pan-cluster regulatory mechanisms, which are seemingly restricted to only the ParaHox genes themselves.Publisher PDFPeer reviewe

Dynamic changes in the epigenomic landscape regulate human organogenesis and link to developmental disorders

From Springer Nature via Jisc Publications RouterHistory: received 2019-10-04, accepted 2020-06-18, registration 2020-06-24, pub-electronic 2020-08-06, online 2020-08-06, collection 2020-12Publication status: PublishedFunder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265; Grant(s): CRTF, PhD studentship, MR/J003352/1, MR/L009986/1, MR/L009986/1, MR/S036121/1, MR/000638/1Funder: Academy of Medical Sciences; doi: https://doi.org/10.13039/501100000691; Grant(s): Lecturer starter grantFunder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440; Grant(s): 088566, 097820, 105610Abstract: How the genome activates or silences transcriptional programmes governs organ formation. Little is known in human embryos undermining our ability to benchmark the fidelity of stem cell differentiation or cell programming, or interpret the pathogenicity of noncoding variation. Here, we study histone modifications across thirteen tissues during human organogenesis. We integrate the data with transcription to build an overview of how the human genome differentially regulates alternative organ fates including by repression. Promoters from nearly 20,000 genes partition into discrete states. Key developmental gene sets are actively repressed outside of the appropriate organ without obvious bivalency. Candidate enhancers, functional in zebrafish, allow imputation of tissue-specific and shared patterns of transcription factor binding. Overlaying more than 700 noncoding mutations from patients with developmental disorders allows correlation to unanticipated target genes. Taken together, the data provide a comprehensive genomic framework for investigating normal and abnormal human development

Dynamic changes in the epigenomic landscape regulate human organogenesis and link to developmental disorders

© The Author(s) 2020.How the genome activates or silences transcriptional programmes governs organ formation. Little is known in human embryos undermining our ability to benchmark the fidelity of stem cell differentiation or cell programming, or interpret the pathogenicity of noncoding variation. Here, we study histone modifications across thirteen tissues during human organogenesis. We integrate the data with transcription to build an overview of how the human genome differentially regulates alternative organ fates including by repression. Promoters from nearly 20,000 genes partition into discrete states. Key developmental gene sets are actively repressed outside of the appropriate organ without obvious bivalency. Candidate enhancers, functional in zebrafish, allow imputation of tissue-specific and shared patterns of transcription factor binding. Overlaying more than 700 noncoding mutations from patients with developmental disorders allows correlation to unanticipated target genes. Taken together, the data provide a comprehensive genomic framework for investigating normal and abnormal human development.The work was supported by Wellcome grants 088566, 097820 and 105610, with additional support from MRC project grants MR/L009986/1 to N.B. and N.A.H., MR/ J003352/1 to K.P.H., and MR/000638/1 and MR/S036121/1 to N.A.H. R.E.J. was an MRC clinical research training fellow, and S.J.W. was an MRC doctoral account PhD student. J. L.G.S. was supported by the Marató TV3 Fundacion (Grant No. 201611)

Regulatory de novo mutations underlying intellectual disability

The genetic aetiology of a major fraction of patients with intellectual disability (ID) remains unknown. De novo mutations (DNMs) in protein-coding genes explain up to 40% of cases, but the potential role of regulatory DNMs is still poorly understood. We sequenced 63 whole genomes from 21 ID probands and their unaffected parents. In addition, we analysed 30 previously sequenced genomes from exome-negative ID probands. We found that regulatory DNMs were selectively enriched in fetal brain-specific enhancers as compared with adult brain enhancers. DNM-containing enhancers were associated with genes that show preferential expression in the prefrontal cortex. Furthermore, we identified recurrently mutated enhancer clusters that regulate genes involved in nervous system development (CSMD1, OLFM1, and POU3F3). Most of the DNMs from ID probands showed allele-specific enhancer activity when tested using luciferase assay. Using CRISPR-mediated mutation and editing of epigenomic marks, we show that DNMs at regulatory elements affect the expression of putative target genes. Our results, therefore, provide new evidence to indicate that DNMs in fetal brain-specific enhancers play an essential role in the aetiology of ID.This work was funded by grants from the Wellcome Trust Institute Strategic Support and National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, Institute for Translational Medicine and Therapeutics (P70888) obtained by SS Atanur. J Ferrer and MG De Vas’s work was funded by grants from the Wellcome Trust (WT101033 to J Ferrer), Medical Research Council (MR/L02036X/1 to J Ferrer), and European Research Council Advanced Grant (789055 to J Ferrer). MM Pradeepa’s lab is funded by the UKRI/MRC (MR/T000783/1), and Barts charity (MGU0475) grants. TN Khan was partially supported by the Government of Pakistan under the PSDP project “Development of National University of Medical Sciences (NUMS), Rawalpindi.