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Genetic and developmental mechanisms of vertebrate craniofacial variation

脊椎动物颅面变异的遗传和发育机制

基本信息

批准号：
9979840
负责人：
Elena Boer
金额：
$ 7.12万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979840
关键词：
Alleles Anatomy Animal Model Animals Beak Biological Models Birds Breeding Candidate Disease Gene Chickens Chromosome Mapping Chromosomes Clinical Markers Columbidae Complement Complex Congenital Abnormality Congenital Disorders Craniosynostosis DNA Sequence Defect Development Developmental Process Diagnosis Dimensions Disease Distant Embryo Embryonic Development Etiology Gene Frequency Genes Genetic Genetic Crosses Genome Genome Scan Genomic Segment Genomics Goals Human In Situ Hybridization Individual Intellectual functioning disability Investigation Knowledge Laboratories Link MADH6 gene Maps Modeling Molecular Morphogenesis Morphology Mutation Organ Pathogenesis Pattern Phenotype Quantitative Trait Loci Regulation Research Robinow syndrome Rock Pigeons Role Shapes Signal Pathway Signal Transduction Skeleton Speech Techniques Testing Therapeutic Tissues Variant Vertebrates Width Zebrafish base bone combinatorial craniofacial craniofacial bone craniofacial complex craniofacial development craniofacial disorder differential expression experimental study falls genetic architecture genome wide association study genomic locus hearing impairment imaging approach imaging study inhibitor/antagonist innovation insight member programs receptor sex trait transcriptome sequencing

项目摘要

PROJECT SUMMARY Craniofacial morphogenesis is a highly orchestrated and evolutionarily conserved developmental process. In some cases, changes to the genes that underlie normal craniofacial variation across vertebrates can cause anatomical defects in humans. Thus, a comprehensive understanding of the genetic and developmental mechanisms of craniofacial diversity will provide important insights into human congenital craniofacial disorders, which account for more than one third of all birth defects and often cause hearing loss, speech impediment and intellectual disability. Among breeds of domestic pigeon, radical variation in beak morphology within a single species has resulted from millennia of artificial selection. Preliminary genomic analyses support the results of classical breeding experiments, which suggest that pigeon beak morphology is controlled by multiple genetic loci, including at least one sex-linked factor. By comparing the genomes of small and medium beak pigeons, I have identified two candidate genes, ROR2 and SMAD6, which encode members of the non-canonical Wnt and BMP signaling pathways, respectively. In humans, mutations in these genes cause congenital craniofacial disorders, including Robinow syndrome and Craniosynostosis. This project utilizes cross-disciplinary approaches and complementary vertebrate models to understand the combinatorial function of specific genes and signaling pathways during patterning of the vertebrate craniofacial skeleton. Furthermore, this project takes advantage of the striking variation in beak morphology within domestic pigeons to identify the genetic architecture of specific dimensions of craniofacial morphology, including the size and shape of individual bones of the craniofacial skeleton. This project will pursue two distinct Aims. Aim 1 will test the individual and integrated molecular functions of ROR2 and SMAD6 during vertebrate craniofacial morphogenesis. I will use a combination of in situ hybridization (ISH) and RNA sequencing (RNA-seq) techniques to determine if differential expression of ROR2 and/or SMAD6 and their respective signaling pathways are associated with variation in beak morphology in avian embryos. In addition, I will employ genetic, developmental and live imaging approaches to test the functional roles of ROR2 and SMAD6 during chick and zebrafish craniofacial morphogenesis. Aim 2 will identify specific genes associated with variation in the size and shape of individual bones of the vertebrate craniofacial skeleton. I will perform quantitative trait locus (QTL) mapping in two pigeon F2 intercrosses to identify genomic loci that underlie variation in pigeon beak morphology. To complement the genetic mapping experiments, I will leverage the Shapiro lab's extensive “pigeonomic” toolkit to fine map the specific genes or DNA sequences within each QTL that are associated with dimensions of beak morphology. These experiments will broadly define the genetic architecture of craniofacial variation in pigeons and will implicate specific candidate genes for further investigation. These complementary genetic, genomic, and developmental approaches will define the precise roles of two genes in vertebrate craniofacial morphogenesis and will identify the molecular basis of astonishing craniofacial variation in an innovative model system. Together, the Aims of this project will open new avenues to understand the roles of specific genes in normal and disease variation among vertebrates in general.

项目摘要颅面形态发生是一个高度协调和进化保守的发育过程，过程在某些情况下，脊椎动物正常颅面变异的基因变化会导致人体的解剖缺陷因此，全面了解遗传和颅面多样性的发育机制将为人类先天性颅面疾病占所有出生缺陷的三分之一以上，通常会导致听力损失，语言障碍和智力残疾。在家鸽的品种中，单个物种内喙形态的根本性变化，几千年来的人工选择初步的基因组分析支持经典的育种实验表明，鸽喙形态受多个遗传位点控制，包括至少一个与性别相关的因素。通过比较中小型喙鸽的基因组，鉴定了两个候选基因ROR 2和SMAD 6，它们编码非典型Wnt的成员， BMP信号通路。在人类中，这些基因的突变导致先天性颅面畸形，疾病，包括Robinow综合征和颅缝早闭。该项目利用跨学科了解特定基因组合功能的方法和补充脊椎动物模型以及脊椎动物颅面骨骼形成过程中的信号通路。此外，该项目利用家鸽喙部形态的显著差异来鉴定颅面形态的特定维度的结构，包括个体骨骼的大小和形状颅面骨骼的结构该项目将追求两个不同的目标。目标1将测试单个和集成分子 ROR 2和SMAD 6在脊椎动物颅面形态发生中的功能。我将结合使用原位杂交（ISH）和RNA测序（RNA-seq）技术，以确定是否差异表达的 ROR 2和/或SMAD 6及其各自的信号通路与喙的变异相关鸟类胚胎的形态学此外，我将采用遗传、发育和活体成像方法，测试ROR 2和SMAD 6在鸡和斑马鱼颅面形态发生中的功能作用。目的2 将确定与个体骨骼大小和形状变化相关的特定基因，脊椎动物的颅面骨骼我将在两个鸽子F2中进行数量性状基因座（QTL）定位杂交以鉴定鸽子喙形态变异的基因组位点。以补充遗传作图实验，我将利用夏皮罗实验室的广泛的“鸽子”工具包，精细地图，每个QTL内与喙形态尺寸相关的特定基因或DNA序列。这些实验将广泛地定义鸽子颅面变异的遗传结构，暗示特定候选基因用于进一步研究。这些互补的遗传学、基因组学和发育学方法将确定两个基因在脊椎动物颅面形态发生，并将确定惊人的分子基础颅面变化的创新模型系统。总之，该项目的目标将开辟新的途径，了解特定基因在脊椎动物正常和疾病变异中的作用。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Two Genomic Loci Control Three Eye Colors in the Domestic Pigeon (Columba livia).

DOI：
10.1093/molbev/msab260
发表时间：
2021-12-09
期刊：
Molecular biology and evolution
影响因子：
10.7
作者：
Maclary ET;Phillips B;Wauer R;Boer EF;Bruders R;Gilvarry T;Holt C;Yandell M;Shapiro MD
通讯作者：
Shapiro MD

Complex genetic architecture of three-dimensional craniofacial shape variation in domestic pigeons.