HDBR Expression: A Unique Resource for Global and Individual Gene Expression Studies during Early Human Brain Development

Lindsay, Susan; Xu, Yaobo; Lisgo, Steven; Harkin, Lauren F.; Copp, Andrew J.; Gerrelli, Dianne; Clowry, Gavin J.; Talbot, Aysha; Keogh, Michael J.; Coxhead, Jonathan; Santibanez‐Koref, Mauro; Chinnery, Patrick F.

doi:10.3389/fnana.2016.00086

Cited by 78 publications

(116 citation statements)

References 19 publications

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“…26 YY1200712MaleLindsay et al . 26 YYYY192313FemaleLindsay et al . 26 YYY

* BG = basal ganglia, CC = cerebral minus temporal cortex, CP = choroid plexus of the lateral ventricles, DE = diencephalon, TC = temporal cortex, FB = forebrain, MB = midbrain.

Figure 1Relation between effects of age and side on gene expression (as t-values) for the brain structures aged 5–5.5pcw and aged 7.5–13pcw.…”

Section: Resultsmentioning

confidence: 99%

“…As described previously 26 , the temporal lobe had been dissected from the rest of the cerebral cortex.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, the Human Developmental Biology Resource (UK) recently released a transcriptomic dataset in which various structures of the developing brain, in the age range 7.5–14pcw, had been separated into left and right prior to RNA sequencing 26 , which included cerebral cortex separated into temporal and non-temporal lobe, basal ganglion, diencephalon, and choroid plexus of the lateral ventricles. No laterality-related analysis of these data had been performed prior to that which we report here.…”

Section: Introductionmentioning

confidence: 99%

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Subtle left-right asymmetry of gene expression profiles in embryonic and foetal human brains

Kovel

Lisgo

Fisher

et al. 2018

Sci Rep

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Left-right laterality is an important aspect of human –and in fact all vertebrate– brain organization for which the genetic basis is poorly understood. Using RNA sequencing data we contrasted gene expression in left- and right-sided samples from several structures of the anterior central nervous systems of post mortem human embryos and foetuses. While few individual genes stood out as significantly lateralized, most structures showed evidence of laterality of their overall transcriptomic profiles. These left-right differences showed overlap with age-dependent changes in expression, indicating lateralized maturation rates, but not consistently in left-right orientation over all structures. Brain asymmetry may therefore originate in multiple locations, or if there is a single origin, it is earlier than 5 weeks post conception, with structure-specific lateralized processes already underway by this age. This pattern is broadly consistent with the weak correlations reported between various aspects of adult brain laterality, such as language dominance and handedness.

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“…26 YY1200712MaleLindsay et al . 26 YYYY192313FemaleLindsay et al . 26 YYY

* BG = basal ganglia, CC = cerebral minus temporal cortex, CP = choroid plexus of the lateral ventricles, DE = diencephalon, TC = temporal cortex, FB = forebrain, MB = midbrain.

Figure 1Relation between effects of age and side on gene expression (as t-values) for the brain structures aged 5–5.5pcw and aged 7.5–13pcw.…”

Section: Resultsmentioning

confidence: 99%

“…As described previously 26 , the temporal lobe had been dissected from the rest of the cerebral cortex.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Subtle left-right asymmetry of gene expression profiles in embryonic and foetal human brains

Kovel

Lisgo

Fisher

et al. 2018

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…While our analyses were based on transcript expression aware annotation from the GTEx v7 dataset, we provide necessary files for pext annotation with the Human Brain Development Resource (HBDR) fetal brain dataset (51) in gs://gnomad-public/papers/2019-tx-annotation/data/HBDR_fetal_RNAseq. HBDR includes 558 samples from varying brain subregions across developmental time points.…”

Section: Transcript Expression Aware Annotation With Fetal Isoform Exmentioning

confidence: 99%

Transcript expression-aware annotation improves rare variant discovery and interpretation

Cummings

Karczewski

Kosmicki

et al. 2019

Preprint

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The acceleration of DNA sequencing in patients and population samples has resulted in unprecedented catalogues of human genetic variation, but the interpretation of rare genetic variants discovered using such technologies remains extremely challenging. A striking example of this challenge is the existence of disruptive variants in dosage-sensitive disease genes, even in apparently healthy individuals. Through manual curation of putative loss of function (pLoF) variants in haploinsufficient disease genes in the Genome Aggregation Database (gnomAD)(1), we show that one explanation for this paradox involves alternative mRNA splicing, which allows exons of a gene to be expressed at varying levels across cell types. Currently, no existing annotation tool systematically incorporates this exon expression information into variant interpretation. Here, we develop a transcript-level annotation metric, the proportion expressed across transcripts (pext), which summarizes isoform quantifications for variants. We calculate this metric using 11,706 tissue samples from the Genotype Tissue Expression project(2) (GTEx) and show that it clearly differentiates between weakly and highly evolutionarily conserved exons, a proxy for functional importance. We demonstrate that expressionbased annotation selectively filters 22.8% of falsely annotated pLoF variants found in haploinsufficient disease genes in gnomAD, while removing less than 4% of high-confidence pathogenic variants in the same genes. Finally, we apply our expression filter to the analysis of de novo variants in patients with autism spectrum disorder (ASD) and developmental disorders and intellectual disability (DD/ID) to show that pLoF variants in weakly expressed regions have effect sizes similar to those of synonymous variants, while pLoF variants in highly expressed exons are most strongly enriched among cases versus controls. Our annotation is fast, flexible, and generalizable, making it possible for any variant file to be annotated with any isoform expression dataset, and will be valuable for rare disease diagnosis, rare variant burden analyses in complex disorders, and curation and prioritization of variants in recall-by-genotype studies.

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“…Gene expression-GTEx RNA seq (13) was used to analyse gene expression in adult tissues. BrainSpan data (14) for specific genes were viewed in GenTree (15); the Human Developmental Biology Resource (16) was accessed via Expression Atlas (17). Both resources were used to analyse gene expression in neural tissues during various developmental stages.…”

Section: Methodsmentioning

confidence: 99%

Characterization of an enhancer element that regulates FOXP2 expression in human cerebellum

Madurga

Novo

2019

Preprint

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Human cerebellum is involved not only in motor control but also in several cognitive skills. In this work, our goal was to identify genomic enhancers responsible for the regulation of genes implicated in the development of this brain region. From an initial collection of Vista elements showing specific enhancer activity in mouse hindbrain, we found an enhancer element located within the final intron of FOXP2, a gene expressed in cerebellum and implicated in vocal communication and speech and language disorders in humans. Analysis of this enhancer using various computational resources suggests that it is a strong candidate to account for FOXP2 expression during cerebellar development. Two blocks within this region are deeply conserved in vertebrates; they are separated by a microsatellite sequence present only in eutherian mammals, and expanded in human genomes.

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HDBR Expression: A Unique Resource for Global and Individual Gene Expression Studies during Early Human Brain Development

Cited by 78 publications

References 19 publications

Subtle left-right asymmetry of gene expression profiles in embryonic and foetal human brains

Subtle left-right asymmetry of gene expression profiles in embryonic and foetal human brains

Transcript expression-aware annotation improves rare variant discovery and interpretation

Characterization of an enhancer element that regulates FOXP2 expression in human cerebellum

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