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Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage
- Source :
- Nature communications, vol 12, iss 1, Nature Communications 12, 2076 (2021), Nature Communications, Vol 12, Iss 1, Pp 1-13 (2021), Nature communications, Nature Communications, Digital.CSIC. Repositorio Institucional del CSIC, instname, UCrea Repositorio Abierto de la Universidad de Cantabria, Universidad de Cantabria (UC)
- Publication Year :
- 2021
-
Abstract
- Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs. We find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event. Using human brain RNA-sequencing data, we show the intron-3-retaining transcript to be more abundant in Alzheimer’s disease with more severe tau and amyloid pathological burden. Thus, we demonstrate potential association of human-lineage-specific sequences in brain development and neurological disease.<br />Knowledge of genomic features specific to humans may be important for understanding disease. Here the authors demonstrate a potential role for these human-lineage-specific sequences in brain development and neurological disease.
- Subjects :
- 0301 basic medicine
Apolipoprotein E
Aging
Messenger
General Physics and Astronomy
Neurodegenerative
Alzheimer's Disease
Genome
Linkage Disequilibrium
Negative selection
0302 clinical medicine
2.1 Biological and endogenous factors
Aetiology
health care economics and organizations
Conserved Sequence
Phylogeny
Multidisciplinary
Brain
Neurodegenerative Diseases
Single Nucleotide
Alzheimer's disease
Phenotype
International Parkinson’s Disease Genomics Consortium
Neurological
Regression Analysis
Long Noncoding
DNA, Intergenic
RNA, Long Noncoding
Human
Biotechnology
Lineage (genetic)
Science
1.1 Normal biological development and functioning
Computational biology
Biology
Polymorphism, Single Nucleotide
Article
General Biochemistry, Genetics and Molecular Biology
Chromosomes
03 medical and health sciences
Apolipoproteins E
Underpinning research
Alzheimer Disease
Genetic variation
Genetics
Acquired Cognitive Impairment
Humans
RNA, Messenger
Polymorphism
Gene
Whole genome sequencing
Intergenic
Pair 19
Genome, Human
Human Genome
Neurosciences
Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)
Molecular Sequence Annotation
General Chemistry
DNA
Introns
Brain Disorders
030104 developmental biology
Gene Ontology
RNA
Dementia
Chromosomes, Human, Pair 19
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Database :
- OpenAIRE
- Journal :
- Nature communications, vol 12, iss 1, Nature Communications 12, 2076 (2021), Nature Communications, Vol 12, Iss 1, Pp 1-13 (2021), Nature communications, Nature Communications, Digital.CSIC. Repositorio Institucional del CSIC, instname, UCrea Repositorio Abierto de la Universidad de Cantabria, Universidad de Cantabria (UC)
- Accession number :
- edsair.doi.dedup.....8d89fb6c0172da3ad22f71ca50851027