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Discovery and functional analysis of novel candidate genes and variants underlying craniofacial diversification in Cyprinodon pupfishes

鲤鱼颅面多样化的新候选基因和变异的发现和功能分析

基本信息

批准号：
10190890
负责人：
Christopher Herbert Martin
金额：
$ 34.2万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10190890
关键词：
1p36 Alleles Biological Assay Biological Models CRISPR/Cas technology Candidate Disease Gene Caribbean region Clinical Congenital Abnormality Craniofacial Abnormalities Cyprinodons Cyprinodontidae Dental Depressed mood Development Diagnosis Disease Embryo Enhancers Evolution Exhibits Face Genes Genetic Genome Genomic Segment Genomics Geography Human Human Genetics Human Pathology In Situ Hybridization Individual Investigation Jaw Knock-out Knowledge Length Link Maps Measures Molecular Morphology Mutation Natural experiment Nose Oral Pathway interactions Phenocopy Phenotype Population Positioning Attribute Prevention Quantitative Genetics Quantitative Trait Loci Research Sampling Scanning Skeleton System Testing Transgenic Organisms Untranslated RNA Variant Vertebrates causal variant craniofacial craniofacial development craniofacial disorder craniofacial structure developmental genetics differential expression experience experimental study forward genetics gene discovery genetic architecture genetic variant genome editing genome-wide human disease improved insight malformation novel public health relevance rhotekin spatiotemporal success therapeutic target trait transcriptome sequencing transcriptomics

项目摘要

Project Summary: Craniofacial abnormalities are the most common form of human birth defects, but their molecular basis remains poorly understood. Highly conserved craniofacial developmental pathways shared across diverse vertebrate species have been shaped by adaptive evolution to produce a tremendous diversity of adaptive craniofacial phenotypes. Fundamental investigation of the genetic basis of these phenotypes will lead to better diagnosis, prevention, and treatment of human birth defects. Indeed, complementary or new information on the genetic basis of many human pathologies in model systems is often obtainable from naturally occurring systems that display analogous divergent phenotypes. These natural systems are now feasible for genomic and transgenic approaches and provide an opportunity for ‘evolutionary’ forward genetics. Here I propose to leverage my lab’s extensive experience developing a new vertebrate system from the ground up: highly divergent craniofacial morphology in Caribbean pupfishes. Our preliminary genome-wide divergence scans and association mapping have identified both well-known craniofacial candidate genes and ten new candidate genes associated with jaw length variation. Divergent genomic regions are often restricted to a single gene with only one or a few candidate variants in upstream regulatory or intronic regions. Our preliminary quantitative trait locus mapping also indicates that some of these regions explain up to 15% of jaw length variation in lab-reared F2 intercrosses. Thus, I hypothesize that fixed mutations in these species control spatiotemporal expression of both known and novel craniofacial genes underlying highly divergent craniofacial features in pupfishes. I propose to investigate the genetic basis of novel adaptive phenotypes in this non-model system using a combination of population genomics, de novo genome assembly, quantitative genetics, transcriptomics, in situ hybridization, and CRISPR-Cas9 genome editing. Our initial success in Caribbean pupfishes demonstrates the power of our approach and potential for expansion. Pupfish exhibit novel craniofacial traits; ongoing gene flow and strong selection provide an ideal natural ‘experiment’ for fine-mapping candidate variants associated with these traits. We are also pioneering in situ hybridization and CRISPR-Cas9 approaches in pupfishes. By integrating candidate gene and variant discovery in a natural system exhibiting diverse craniofacial features with powerful functional assays, the proposed research will demonstrate the feasibility and power of new non-model systems to gain novel insights into the developmental genetics of human diseases. 1

项目总结: