Shaoline Sheppard

Bio: Shaoline Sheppard is an academic researcher from École Polytechnique Fédérale de Lausanne. The author has contributed to research in topics: Synteny. The author has an hindex of 1, co-authored 3 publications receiving 4 citations.

Transposable elements and their KZFP controllers are drivers of transcriptional innovation in the developing human brain.

Abstract: Transposable elements (TEs) account for more than 50% of the human genome and many have been co-opted throughout evolution to provide regulatory functions for gene expression networks. Several lines of evidence suggest that these networks are fine-tuned by the largest family of TE controllers, the KRAB-containing zinc finger proteins (KZFPs). One tissue permissive for TE transcriptional activation (termed "transposcription") is the adult human brain, however comprehensive studies on the extent of this process and its potential contribution to human brain development are lacking. To elucidate the spatiotemporal transposcriptome of the developing human brain, we have analyzed two independent RNA-seq data sets encompassing 16 brain regions from eight weeks postconception into adulthood. We reveal a distinct KZFP:TE transcriptional profile defining the late prenatal to early postnatal transition, and the spatiotemporal and cell type-specific activation of TE-derived alternative promoters driving the expression of neurogenesis-associated genes. Long-read sequencing confirmed these TE-driven isoforms as significant contributors to neurogenic transcripts. We also show experimentally that a co-opted antisense L2 element drives temporal protein relocalization away from the endoplasmic reticulum, suggestive of novel TE dependent protein function in primate evolution. This work highlights the widespread dynamic nature of the spatiotemporal KZFP:TE transcriptome and its importance throughout TE mediated genome innovation and neurotypical human brain development. To facilitate interactive exploration of these spatiotemporal gene and TE expression dynamics, we provide the "Brain TExplorer" web application freely accessible for the community.

Transposable elements and their KZFP controllers are drivers of transcriptional innovation in the developing human brain

Abstract: Transposable elements (TEs) constitute 50% of the human genome and many have been co-opted throughout human evolution due to gain of advantageous regulatory functions controlling gene expression networks. Several lines of evidence suggest these networks can be fine-tuned by the largest family of TE controllers, the KRAB-containing zinc finger proteins (KZFPs). One tissue permissive for TE transcriptional activation (termed transposcription) is the adult human brain, however comprehensive studies on the extent of this process and its potential contribution to human brain development are lacking. In order to elucidate the spatiotemporal transposcriptome of the developing human brain, we have analysed two independent RNA-seq datasets encompassing 16 distinct brain regions from eight weeks post-conception into adulthood. We reveal an anti-correlated, KZFP:TE transcriptional profile defining the late prenatal to early postnatal transition, and the spatiotemporal and cell type specific activation of TE-derived alternative promoters driving the expression of neurogenesis-associated genes. We also demonstrate experimentally that a co-opted antisense L2 element drives temporal protein re-localisation away from the endoplasmic reticulum, suggestive of novel TE dependent protein function in primate evolution. This work highlights the widespread dynamic nature of the spatiotemporal KZFP:TE transcriptome and its potential importance throughout neurotypical human brain development.

Homoeolog Inference Methods Requiring Bidirectional Best Hits or Synteny Miss Many Pairs.

Abstract: Homoeologs are pairs of genes or chromosomes in the same species that originated by speciation and were brought back together in the same genome by allopolyploidization. Bioinformatic methods for accurate homoeology inference are crucial for studying the evolutionary consequences of polyploidization, and homoeology is typically inferred on the basis of bidirectional best hit (BBH) and/or positional conservation (synteny). However, these methods neglect the fact that genes can duplicate and move, both prior to and after the allopolyploidization event. These duplications and movements can result in many-to-many and/or nonsyntenic homoeologs-which thus remain undetected and unstudied. Here, using the allotetraploid upland cotton (Gossypium hirsutum) as a case study, we show that conventional approaches indeed miss a substantial proportion of homoeologs. Additionally, we found that many of the missed pairs of homoeologs are broadly and highly expressed. A gene ontology analysis revealed a high proportion of the nonsyntenic and non-BBH homoeologs to be involved in protein translation and are likely to contribute to the functional repertoire of cotton. Thus, from an evolutionary and functional genomics standpoint, choosing a homoeolog inference method which does not solely rely on 1:1 relationship cardinality or synteny is crucial for not missing these potentially important homoeolog pairs.

Integrative Genomics Viewer

Abstract: Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Meta-QTLs, ortho-meta-QTLs and candidate genes for grain yield and associated traits in wheat (Triticum aestivum L.)

Abstract: In wheat, 2852 major QTLs of 8998 QTLs available for yield and related traits were used for meta-analysis; 141 meta-QTLs were identified, which included 13 breeder's MQTLs and 24 ortho-MQTLs; 1202 candidate genes and 50 homologues of genes for yield from other cereals were also identified. Meta-QTL analysis was conducted using 2852 of the 8998 known QTLs, retrieved from 230 reports published during 1999-2020 (including 19 studies on tetraploid wheat) for grain yield (GY) and the following ten component traits: (i) grain weight (GWei), (ii) grain morphology-related traits (GMRTs), (iii) grain number (GN), (iv) spikes-related traits (SRTs), (v) plant height (PH), (vi) tiller number (TN), (vii) harvest index (HI), (viii) biomass yield (BY), (ix) days to heading/flowering and maturity (DTH/F/M), and (x) grain filling duration (GFD). The study resulted in the identification of 141 meta-QTLs (MQTLs), with an average confidence interval (CI) of 1.4 cM as against a CI of > 12.1 cM (8.8 fold reduction) in the QTLs that were used. The corresponding physical length of CI ranged from 0.01 Mb to 661.9 Mb (mean, 31.5 Mb). Seventy-seven (77) of these 141 MQTLs overlapped marker-trait associations (MTAs) reported in genome-wide association studies. Also, 63 MQTLs (each based on at least 10 QTLs) were considered stable and robust, with 13 MQTLs described as breeder's MQTLs (selected based on small CI, large LOD, and high level of phenotypic variation explained). Thirty-five yield-related genes from rice, barley, and maize were also utilized to identify 50 wheat homologues in MQTLs. Further, the use of synteny and collinearity allowed the identification of 24 ortho-MQTLs which were common among the wheat, barley, rice, and maize. The results of the present study should prove useful for wheat breeding and future basic research in cereals including wheat, barley, rice, and maize.

Developmental dynamics of RNA translation in the human brain

Abstract: The precise regulation of gene expression is fundamental to neurodevelopment, plasticity and cognitive function. Although several studies have profiled transcription in the developing human brain, there is a gap in understanding of accompanying translational regulation. In this study, we performed ribosome profiling on 73 human prenatal and adult cortex samples. We characterized the translational regulation of annotated open reading frames (ORFs) and identified thousands of previously unknown translation events, including small ORFs that give rise to human-specific and/or brain-specific microproteins, many of which we independently verified using proteomics. Ribosome profiling in stem-cell-derived human neuronal cultures corroborated these findings and revealed that several neuronal activity-induced non-coding RNAs encode previously undescribed microproteins. Physicochemical analysis of brain microproteins identified a class of proteins that contain arginine-glycine-glycine (RGG) repeats and, thus, may be regulators of RNA metabolism. This resource expands the known translational landscape of the human brain and illuminates previously unknown brain-specific protein products. Duffy et al. profiled mRNA translation in 73 human prenatal and adult cortex samples and identified thousands of previously unknown translation events, including small open reading frames that give rise to human-specific and/or brain-specific microproteins.

Primate-specific transposable elements shape transcriptional networks during human development

Abstract: Abstract The human genome contains more than 4.5 million inserts derived from transposable elements (TEs), the result of recurrent waves of invasion and internal propagation throughout evolution. For new TE copies to be inherited, they must become integrated in the genome of the germline or pre-implantation embryo, which requires that their source TE be expressed at these stages. Accordingly, many TEs harbor DNA binding sites for the pluripotency factors OCT4, NANOG, SOX2, and KLFs and are transiently expressed during embryonic genome activation. Here, we describe how many primate-restricted TEs have additional binding sites for lineage-specific transcription factors driving their expression during human gastrulation and later steps of fetal development. These TE integrants serve as lineage-specific enhancers fostering the transcription, amongst other targets, of KRAB-zinc finger proteins (KZFPs) of comparable evolutionary age, which in turn corral the activity of TE-embedded regulatory sequences in a similarly lineage-restricted fashion. Thus, TEs and their KZFP controllers play broad roles in shaping transcriptional networks during early human development.