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

项目概要：颅面畸形是人类出生缺陷最常见的形式，但其分子缺陷高度保守的颅面发育途径的基础仍然知之甚少。不同脊椎动物物种之间共享的基因已通过适应性进化而形成，从而产生了适应性颅面表型的巨大多样性。这些表型的遗传基础将有助于更好地诊断、预防和治疗事实上，许多遗传基础上的补充或新信息。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这些自然系统现在对于基因组来说是可行的。和转基因方法，并为“进化”正向遗传学提供机会。在这里，我建议利用我的实验室开发新脊椎动物的丰富经验从头开始的系统：加勒比海鱼的颅面形态高度分化。我们初步的全基因组分歧扫描和关联图谱已经识别出两者著名的颅面候选基因和十个与下颌相关的新候选基因不同的基因组区域通常仅限于只有一个基因。或我们初步的上游监管或内含子区域的一些候选变体。数量性状基因座作图还表明，其中一些区域解释了高达 15% 的实验室饲养的 F2 杂交中下颌长度的变化因此，我捕获了固定突变。这些物种控制已知和新的颅面的时空表达我建议研究河豚鱼颅面特征高度分化的基因。使用非模型系统研究新的适应性表型的遗传基础群体基因组学、从头基因组组装、定量遗传学的组合，转录组学、原位杂交和 CRISPR-Cas9 基因组编辑。我们在加勒比海鲳鱼中的初步成功证明了我们方法的力量和鳉鱼表现出新颖的颅面特征和强大的基因流动；选择为精细映射相关候选变体提供了理想的自然“实验” 凭借这些特征，我们还在原位杂交和 CRISPR-Cas9 方法方面处于领先地位。通过将候选基因和变异发现整合到自然系统中多样化的颅面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力量，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）

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。

DOI：
10.1093/icb/icaa122
发表时间：
2020
期刊：
Integrative and comparative biology
影响因子：
2.6
作者：
Olsson,KarinH;Martin,ChristopherH;Holzman,Roi
通讯作者：
Holzman,Roi

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

The behavioral origins of novelty: did increased aggression lead to scale-eating in pupfishes?

新奇的行为起源：攻击性的增加是否会导致鳉鱼吃鳞？