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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：
10408072
负责人：
Christopher Herbert Martin
金额：
$ 33.73万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408072
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：颅面畸形是人类最常见的出生缺陷形式，但它们的分子人们对此仍知之甚少。高度保守的颅面发育途径在不同的脊椎动物物种之间共享是由适应性进化塑造的，以产生适应性颅面表型的巨大多样性。对中国的基础调查这些表型的遗传基础将导致更好的诊断、预防和治疗人类的先天缺陷。事实上，关于许多人的遗传基础的补充或新信息模型系统中的人类病理通常可以从自然发生的系统中获得，该系统表现出相似的不同表型。这些自然系统现在可以用于基因组和转基因方法，并为“进化”的前向遗传学提供了机会。在这里，我建议利用我的实验室开发一种新的脊椎动物的丰富经验自下而上的系统：加勒比海鲤鱼的高度分化的头面部形态。我们初步的全基因组差异扫描和关联图谱已经确定了这两个已知的头面部候选基因和与颌骨相关的10个新候选基因长度变化。不同的基因组区域通常局限于只有一个基因的单个基因。或者一些上游调控区域或内含子区域的候选变体。我们的预赛数量性状基因座图谱还表明，这些区域中的一些可以解释高达15%的实验室饲养的F2代杂交后代的颌长变异。因此，我假设固定的突变在这些物种控制着已知和新的颅面部的时空表达鲤鱼高度分化的头面部特征的基因。我提议在这个非模型系统中研究新的适应性表型的遗传基础群体基因组学、从头组装基因组学、数量遗传学、转录学、原位杂交和CRISPR-Cas9基因组编辑。我们在加勒比海鲤鱼上的初步成功证明了我们的方法和有扩张的潜力。瓢虫鱼显示出新的头面部特征；持续的基因流动和强大的选择为精细定位候选变异提供了一个理想的自然“实验” 有了这些特点。我们还在首创原位杂交和CRISPR-Cas9方法鲤鱼。通过在自然系统中整合候选基因和变体发现来展示不同的头面部特征和强大的功能分析，拟议的研究将展示新的非模型系统的可行性和威力，以获得对人类疾病的发育遗传学。 1

项目成果

期刊论文数量（25）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Multiple performance peaks for scale-biting in an adaptive radiation of pupfishes.

河豚鱼适应性辐射中咬鳞的多个性能峰值。

DOI：
10.1101/2023.12.22.573139
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Tan,Anson;StJohn,Michelle;Chau,Dylan;Clair,Chloe;Chan,HoWan;Holzman,Roi;Martin,ChristopherH
通讯作者：
Martin,ChristopherH

Jaw size variation is associated with a novel craniofacial function for galanin receptor 2 in an adaptive radiation of pupfishes.

下颌尺寸的变化与甘丙肽受体 2 在河豚鱼适应性辐射中的一种新的颅面功能有关。

DOI：
10.1101/2023.06.02.543513
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Palominos,MFernanda;Muhl,Vanessa;Richards,EmilieJ;Miller,CraigT;Martin,ChristopherH
通讯作者：
Martin,ChristopherH

Corrigendum to: Hydrodynamic simulations of the performance landscape for suction-feeding fishes reveal multiple peaks for different prey types.

勘误表：吸食性鱼类性能景观的水动力模拟揭示了不同猎物类型的多个峰值。