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Genetic and functional assessment of human-specific duplicated genes

人类特异性重复基因的遗传和功能评估

基本信息

批准号：
10156595
负责人：
Colin James Shew
金额：
$ 3.82万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-12 至 2023-01-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10156595
关键词：
3-Dimensional Attention Autopsy Base Pairing Biochemical Bioinformatics Biological Assay Brain CRISPR/Cas technology Cell Line Cells Chromatin Chromatin Structure DNA DNA Sequence Rearrangement Data Development Disease Dissection Engineering Enhancers Epigenetic Process Etiology Event Evolution Future Gene Duplication Gene Expression Gene Expression Regulation Genes Genetic Genome Genomics Genotype-Tissue Expression Project Hi-C Human Immune Individual Light Link Maps Molecular Morphology Mutation Neurologic Nucleotides Pan Genus Pathogenicity Pattern Phenotype Play Pongidae Population Primates Recurrence Regulatory Element Repetitive Sequence Reporter Research Resolution Role Single Nucleotide Polymorphism Structure Techniques Technology Testing Tissues Validation Variant Work connectome differential expression epigenomics follow-up genome-wide genomic locus high throughput screening human disease improved innovation insight lymphoblastoid cell line nonhuman primate novel paralogous gene promoter structural genomics trait

项目摘要

PROJECT SUMMARY Recent advances in sequencing technologies and bioinformatics have created an emerging picture of structurally dynamic human and non-human primate genomes. In addition to single-nucleotide variants, larger structural variants (SVs; e.g., deletions, duplications, and inversions) are prolific within and between species but are more difficult to study. SVs are often too large to reliably identify with short-read (e.g., Illumina) data and frequently coincide with repetitive elements, making these loci historically difficult to assemble, annotate, and functionally investigate. Despite this, SV-associated rearrangements are known to cause morphological and neurodevelopmental abnormalities in humans, and a handful of human-specific duplicated (HSD) genes have been linked to innovative neurological features. The potential functional impact of SVs is enormous, as single mutational events can rearrange genes and regulatory elements throughout the genome. However, while the genes themselves have received growing attention, the regulatory landscape of SVs remains poorly characterized. Gene expression differences are known to contribute to a variety of human diseases, and are thought to be a major contributor to phenotypic divergence between species. SVs thus represent an understudied and likely impactful set of loci to examine in this light. This is particularly intriguing in the case of HSD genes, which show distinct expression patterns despite having nearly identical sequences. This work will use genomic techniques to investigate the effect of evolutionarily recent SVs on gene expression between humans and chimpanzees. This will be accomplished via three approaches: (1) high-throughput assay of human-duplicated regulatory element activity; (2) identification of differences in the promoter-enhancer connectome across SV breakpoints; and (3) testing for causal relationships between candidate regulatory features and gene expression at SV loci of functional significance. The findings of this research will be the first to characterize hundreds of loci in parallel and will offer insight into the mechanistic basis for regulatory changes between primate species.

项目总结