Functional Analysis of Red Hair Colour Using a Humanised Mouse Model

虽然人类之间的正常变异大部分是由于遗传学，但对导致这种变异的基因知之甚少。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，已知一些基因与金发和红发都有关。红头发的遗传学是最简单的，这项研究是解决基因和它们之间的相互作用，导致红头发。我们显示了数年前，红头发的人有一个基因称为MC 1 R的变化，但不是每个人都有变异MC 1 R基因有红头发;一些变异经常导致红头发，而其他人往往不是。一定有其他基因决定MC 1 R是否影响头发颜色。我们研究了英国生物银行研究中数万人的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，但只有少数导致红头发。为了更详细地研究这些基因及其相互作用，我们计划研究培养细胞中某些变体的影响。为了充分了解这些变异对整个身体的影响，我们将继续制造携带这些遗传变化的小鼠，并观察这些变化对小鼠毛色的影响。这将作为一个模型系统，用于研究由更复杂的遗传相互作用控制的其他性状。缺乏MC 1 R基因的小鼠具有黄色的皮毛，而不是正常的黑色或“agglomerate”（灰色/棕色）。人类和小鼠的MC 1 R蛋白质具有不同的特性，并且相应的基因受到不同的调节以进行补偿。如果我们将其中一种“强烈”的红色毛发变化设计到小鼠基因中，它对小鼠的颜色几乎没有影响;基因调控的差异掩盖了变异的影响。我们已经培育出一种小鼠品系，它缺乏自己的MC 1 R基因，但含有人类基因，沿着该基因正常功能所需的所有DNA，这使小鼠具有正常颜色的毛发。这种人类基因将使我们能够通过DNA的工程变化来研究红头发人的变化。我们将生产出人类MC 1 R基因编码部分发生“强”和“弱”变化的小鼠，并评估它们对小鼠毛色的影响。我们还发现了红头发人群中控制MC 1 R基因的DNA的变化。我们将把这些变化设计到我们的“人性化”小鼠模型中，并评估它对头发颜色的影响。我们还发现，一个名为MSX 2的基因附近的DNA变化与红色头发有关。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一种名为ASIP的基因，该基因编码MC 1 R的抑制剂。我们将研究MSX 2在哪里与ASIP基因周围的DNA相互作用，我们将询问在小鼠中去除这些位点对头发颜色的影响。

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.