Functional Analysis of Red Hair Colour Using a Humanised Mouse Model
使用人源化小鼠模型对红色头发颜色进行功能分析
基本信息
- 批准号:BB/P017479/1
- 负责人:
- 金额:$ 51.81万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2017
- 资助国家:英国
- 起止时间:2017 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Although much of the normal variation between humans is due to genetics, very little is known about the genes that cause this variation. An exception is the genetics of hair colour for which, largely thanks to studies in mice, a number of genes are known that are associated with both blond hair and red hair. The genetics of red hair is the simplest and this study is addressing the genes and interactions between them which result in red hair.We showed a number of years ago that people with red hair have changes in a gene known as MC1R, but not everyone with a variant MC1R gene has red hair; some variants frequently result in red hair whilst others more often than not do not. There must be other genes that determine whether or not MC1R affects hair colour. We have studied the DNA of tens of thousands of people in the UK Biobank study, and identified genes that appear to affect hair colour. There are many different genes associated with blond hair, but only a handful that result in red hair. To study these genes and their interactions in more detail we plan to study the effect of some of the variants in cells grown in culture. In order to fully understand the impact of these variants in the whole body, we will go on to make mice that carry these genetic changes, and look at the impact of the changes on mouse hair colour. This will act as a model system for the study of other traits controlled by more complex genetic interactions.Mice which lack the MC1R gene have yellow fur rather than the normal black or "agouti" (a grey/brown colour). The human and mouse MC1R proteins have somewhat different properties, and the respective genes are regulated differently to compensate. If we engineer one of the "strong" red hair changes into the mouse gene it has surprisingly little impact on the colour of the mice; the differences in gene regulation mask the effect of the variant. We have produced a mouse strain that lacks its own MC1R gene but contains the human gene, along with all the DNA required for the normal function of the gene, and this gives the mice their normal coloured hair. This human gene will allow us to study changes seen in red haired people by engineering changes in the DNA. We will produce mice with a "strong" and a "weak" change in the coding part of the human MC1R gene and assess their impact on mouse hair colour. We have also found changes in the DNA that control the MC1R gene in red-haired people. We will engineer these changes into our "humanised" mouse model and assess it's impact on hair colour.We have also found that DNA changes near a gene called MSX2 are associated with red hair. This gene codes for a protein that can control other genes, and indirect evidence suggests that it may control a gene called ASIP, which codes for an inhibitor of MC1R. We will investigate where MSX2 interacts with DNA around the ASIP gene, and we will ask what is the effect on hair colour of removing those sites in mice.
虽然人类之间的正常差异很大程度上是由于遗传因素,但人们对导致这种差异的基因知之甚少。一个例外是头发颜色的遗传学,这在很大程度上要归功于对老鼠的研究,已知有许多基因与金发和红发都有关。红发的遗传学是最简单的,这项研究是关于导致红发的基因和它们之间的相互作用。我们几年前就表明,红发的人有一种被称为MC1R的基因的变化,但并不是每个带有变异的MC1R基因的人都有红发;一些变异经常导致红发,而另一些通常不会。一定还有其他基因决定MC1R是否会影响头发的颜色。在英国生物库的研究中,我们研究了数以万计的人的DNA,并确定了似乎影响头发颜色的基因。有许多不同的基因与金发有关,但只有少数几个基因会导致红发。为了更详细地研究这些基因及其相互作用,我们计划研究一些变异对培养细胞的影响。为了充分了解这些变异对全身的影响,我们将继续制造携带这些基因变化的小鼠,并观察这些变化对小鼠毛发颜色的影响。这将作为研究由更复杂的遗传相互作用控制的其他特征的模型系统。缺乏MC1R基因的小鼠皮毛是黄色的,而不是正常的黑色或“刺鼠”(灰色/棕色)。人类和小鼠的MC1R蛋白有一些不同的性质,各自的基因受到不同的调节来进行补偿。如果我们将其中一种“浓密”的红色毛发转变成老鼠的基因,令人惊讶的是,它对老鼠的颜色几乎没有影响;基因调控上的差异掩盖了这种变异的影响。我们已经培育出一种小鼠品系,它没有自己的MC1R基因,但包含人类基因,以及该基因正常功能所需的所有DNA,这使小鼠拥有正常颜色的毛发。这种人类基因将使我们能够通过设计DNA的变化来研究红发人群的变化。我们将培育出人类MC1R基因编码部分“强”和“弱”变化的小鼠,并评估它们对小鼠毛发颜色的影响。我们还在红发人群中发现了控制MC1R基因的DNA的变化。我们将把这些变化引入我们的“人源化”小鼠模型,并评估其对头发颜色的影响。我们还发现,名为MSX2的基因附近的DNA变化与红发有关。该基因编码一种可以控制其他基因的蛋白质,间接证据表明,它可能控制着一种名为ASIP的基因,该基因编码MC1R的一种抑制因子。我们将研究MSX2与ASIP基因周围DNA的相互作用,我们将询问移除这些位点对小鼠头发颜色的影响。
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)
Investigating the genetic architecture of eye colour in a Canadian cohort
研究加拿大人群眼睛颜色的遗传结构
- DOI:10.1101/2021.09.29.462299
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Lona-Durazo F
- 通讯作者:Lona-Durazo F
Expanded Analysis of Pigmentation Genetics in UK Biobank
- DOI:10.1101/2022.01.30.478418
- 发表时间:2022-01
- 期刊:
- 影响因子:0
- 作者:E. Pairo-Castineira;Jaime Cornelissen;K. Rawlik;O. Canela‐Xandri;S. Loftus;W. Pavan;K. Brown;A. Tenesa;I. Jackson
- 通讯作者:E. Pairo-Castineira;Jaime Cornelissen;K. Rawlik;O. Canela‐Xandri;S. Loftus;W. Pavan;K. Brown;A. Tenesa;I. Jackson
A custom capture sequence approach for oculocutaneous albinism identifies structural variant alleles at the OCA2 locus.
眼形白化病的自定义捕获序列方法可以确定OCA2基因座的结构变体等位基因。
- DOI:10.1002/humu.24257
- 发表时间:2021-10
- 期刊:
- 影响因子:3.9
- 作者:Loftus SK;Lundh L;Watkins-Chow DE;Baxter LL;Pairo-Castineira E;Nisc Comparative Sequencing Program;Jackson IJ;Oetting WS;Pavan WJ;Adams DR
- 通讯作者:Adams DR
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Ian Jackson其他文献
07-P020 Identification and characterisation of novel vision loci from a recessive ENU-mutagenesis screen
- DOI:
10.1016/j.mod.2009.06.303 - 发表时间:
2009-08-01 - 期刊:
- 影响因子:
- 作者:
Christine Mulford;Sally Cross;Katrine West;Lisa McKie;Margaret Keighren;Ian Jackson - 通讯作者:
Ian Jackson
16-P019 A cell-based screen for genes involved in mammalian cilia formation and function
- DOI:
10.1016/j.mod.2009.06.710 - 发表时间:
2009-08-01 - 期刊:
- 影响因子:
- 作者:
Emma Hall;Pleasantine Mill;Ian Jackson - 通讯作者:
Ian Jackson
Ismail Jatoi, Manfred Kaufmann, Jean Y. Petit, Atlas of breast surgery Springer-Verlag, 2006, 133 pages, ISBN 3540243518, $169.00 USD
- DOI:
10.1007/s00238-006-0030-9 - 发表时间:
2006-04-26 - 期刊:
- 影响因子:0.800
- 作者:
Ian Jackson - 通讯作者:
Ian Jackson
The onset of anelastic behavior in fine-grained synthetic dunite
细粒合成纯铜岩中迟弹性行为的开始
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:2.3
- 作者:
Tongzhang Qu;Ian Jackson;U. Faul;Emmanuel C. David - 通讯作者:
Emmanuel C. David
SOEPpapers on Multidisciplinary Panel Data Research The German Socio-Economic Panel study She ’ s leaving home : a large sample investigation of the empty nest syndrome
SOEP多学科面板数据研究论文德国社会经济面板研究她要离开家:空巢综合症的大样本调查
- DOI:
- 发表时间:
2017 - 期刊:
- 影响因子:0
- 作者:
Alan Piper;Ian Jackson - 通讯作者:
Ian Jackson
Ian Jackson的其他文献
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{{ truncateString('Ian Jackson', 18)}}的其他基金
Mouse Models of Human Variation and Disease
人类变异和疾病的小鼠模型
- 批准号:
MC_UU_00007/4 - 财政年份:2018
- 资助金额:
$ 51.81万 - 项目类别:
Intramural
Seismic wavespeeds and attenuation in upper-mantle rocks: a laboratory study of the effect of partial melting
上地幔岩石中的地震波速和衰减:部分熔融效应的实验室研究
- 批准号:
ARC : DP0208127 - 财政年份:2002
- 资助金额:
$ 51.81万 - 项目类别:
Discovery Projects
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