Functional and Fitness Consequences of Human Genetic Variation

人类遗传变异的功能和健康后果

基本信息

批准号：
10640266
负责人：
Rajiv Champion McCoy
金额：
$ 40.94万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2019-08-21 至 2024-06-30
项目状态：
已结题

项目摘要

Project Summary Along with the environment, genetic differences between cells, individuals, populations, and species drive phenotypic differences at each level of biological organization. My research program develops computational and statistical methods to quantify the functional and fitness effects of natural genetic variation. Using humans as a model, specific research themes include studying the genetic basis, molecular mechanisms, and functional and fitness consequences of 1) human aneuploidy and 2) hominin phenotypic divergence. Aneuploidy affects more than half of human embryos and is the leading cause of pregnancy loss. My lab seeks to understand the extent and phenotypic consequences of various forms of aneuploidy and sub- chromosomal structural variation, scaling from the level of gene expression up to cellular and organismal phenotypes. To this end, I have developed a statistical approach to quantify the relationship between copy number and expression of individual genes. By applying this approach to samples with combined DNA and RNA sequencing data, we will measure the expression consequences of copy number alteration and the possibility that certain genes are “buffered” against its effects. We will also improve methods for detecting mosaic aneuploidy in single-cell data, helping resolve controversy about its incidence and implications for human embryonic development. Extending beyond embryos, we will mine single-cell genomic datasets to profile tissue- wide landscapes of chromosomal mosaicism and cell-type-specific maps of dosage sensitivity. A complementary approach for studying fitness-altering mutations focuses on evolutionary timescales. Previous research has established that regulatory changes influencing gene expression play a primary role in phenotypic divergence. Introgression of Neandertal and Denisovan sequences into modern human genomes provides a unique opportunity to characterize such regulatory substitutions. Through a large-scale analysis of allele-specific expression, I recently demonstrated that one quarter of persisting Neandertal sequences confer significant cis-regulatory effects. We will extend this work to Denisovan introgression by measuring allele-specific expression in cell lines derived from Oceanic individuals. This will allow us to contrast expression effects of mutations that arose in different hominin groups, testing hypotheses about lineage-specific and shared patterns of hominin regulatory evolution. In addition to gene expression levels, genetic variation influencing alternative splicing constitutes a primary link to phenotypic variation and disease. To understand its role in hominin evolution, we will quantify the effects of archaic alleles on patterns of alternative splicing. By contrasting expression and splicing effects of introgressed and control mutations of non-archaic origin, we will seek general insights into the characteristics of regulatory changes that drive phenotypic divergence.

项目概要除了环境之外，细胞、个体、种群和物种之间的遗传差异也驱动着我的研究项目开发了计算能力。和统计方法来量化人类自然遗传变异的功能和适应性影响。作为模型，具体的研究主题包括研究遗传基础、分子机制和功能 1) 人类非整倍性和 2) 人类表型差异的适应性后果。非整倍体影响超过一半的人类胚胎，是导致妊娠失败的主要原因。试图了解各种形式的非整倍性和亚型的程度和表型后果染色体结构变异，从基因表达水平到细胞和生物水平为此，我开发了一种统计方法来量化复制之间的关系。通过将这种方法应用于含有 DNA 和 RNA 组合的样本，可以了解单个基因的数量和表达。测序数据，我们将测量拷贝数改变的表达后果以及可能性某些基因会对其影响进行“缓冲”。我们还将改进检测马赛克的方法。单细胞数据中的非整倍性，有助于解决有关其发生率及其对人类影响的争议超越胚胎，我们将挖掘单细胞基因组数据集来分析组织。染色体嵌合体的广泛景观和剂量敏感性的细胞类型特异性图。研究适应度改变突变的补充方法侧重于进化时间尺度。先前的研究已经证实，影响基因表达的调控变化在表型分歧。尼安德特人和丹尼索瓦人序列渗入现代人类基因组。通过大规模分析来描述此类监管替代提供了独特的机会。等位基因特异性表达，我最近证明四分之一的持久尼安德特人序列赋予我们将通过测量等位基因特异性将这项工作扩展到丹尼索瓦人基因渗入。在来自海洋个体的细胞系中的表达这将使我们能够对比表达效果。不同古人类群体中出现的突变，检验有关谱系特异性和共享模式的假设除了基因表达水平之外，遗传变异也影响着替代性。剪接构成了表型变异和疾病的主要联系。为了了解它在古人类进化中的作用，我们将通过对比表达和可变剪接模式来量化古老等位基因的影响。为了了解基因渗入和非古老起源的控制突变的剪接效应，我们将寻求对驱动表型分歧的监管变化的特征。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Functional divergence among hominins.

古人类之间的功能差异。

DOI：
10.1038/s41559-019-0995-y
发表时间：
2019
期刊：
Nature ecology & evolution
影响因子：
16.8
作者：
Yan,StephanieM;McCoy,RajivC
通讯作者：
McCoy,RajivC

Let the data do the talking: the need to consider mosaicism during embryo selection.

DOI：
10.1016/j.fertnstert.2021.09.008
发表时间：
2021-11
期刊：
Fertility and sterility
影响因子：
6.7
作者：
Viotti M;McCoy RC;Griffin DK;Spinella F;Greco E;Madjunkov M;Madjunkova S;Librach CL;Victor AR;Barnes FL;Zouves CG
通讯作者：
Zouves CG

Human embryo implantation.

DOI：
10.1242/dev.201507
发表时间：
2023-05-15
期刊：
DEVELOPMENT
影响因子：
4.6
作者：
Muter, Joanne;Lynch, Vincent J.;McCoy, Rajiv C.;Brosens, Jan J.
通讯作者：
Brosens, Jan J.

Maternal selection of human embryos in early gestation: Insights from recurrent miscarriage.

DOI：
10.1016/j.semcdb.2022.01.007
发表时间：
2022-11
期刊：
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
影响因子：
7.3
作者：
Brosens, Jan J.;Bennett, Phillip R.;Abrahams, Vikki M.;Ramhorst, Rosanna;Coomarasamy, Arri;Quenby, Siobhan;Lucas, Emma S.;McCoy, Rajiv C.
通讯作者：
McCoy, Rajiv C.

Aberrant landscapes of maternal meiotic crossovers contribute to aneuploidies in human embryos.

母体减数分裂交叉的异常景观导致人类胚胎的非整倍性。

DOI：
10.1101/2023.06.07.543910
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Ariad,Daniel;Madjunkova,Svetlana;Madjunkov,Mitko;Chen,Siwei;Abramov,Rina;Librach,Clifford;McCoy,RajivC
通讯作者：
McCoy,RajivC