The evolutionary genomics of X chromosomes

个体的性别通常是由一对特殊的染色体（携带遗传信息的巨大DNA分子）决定的。它们被称为X染色体和Y染色体。在哺乳动物和果蝇等动物中，雌性携带两个X染色体，雄性携带一个X染色体和一个y染色体。雄性和雌性各携带两个其他染色体，一个来自母亲，另一个来自父亲。X是一条相当典型的染色体，但Y只有少量的功能基因（DNA中指定蛋白质结构的部分）。这意味着大多数发生在X染色体上的新突变和改变基因功能将影响男性，因为没有正常的拷贝来掩盖它们的影响。相反，女性X染色体上的突变将与正常拷贝一起出现，就像另一条染色体上的突变一样。如果有害突变出现在X染色体上，自然选择能更好地清除它们，因为它们部分携带在男性身上，并充分表现出它们的影响。类似地，如果有用的突变发生在X染色体上，那么增加其携带者适应性的有用突变可能会有更好的机会引起进化变化。这些在X染色体和基因组其他部分之间的进化速度差异可能会产生重要的后果，例如在X染色体上发现控制物种差异的基因的更大倾向。确定构成遗传信息的DNA中四个“字母”序列的能力意味着我们可以通过比较物种之间的DNA序列直接测量进化变化的速度。这种比较已经被用来询问X染色体上的基因和基因组中其他地方的基因之间的进化速度是否不同。到目前为止，结果是相互矛盾的。我们计划使用两种不同寻常的有利制度来进一步进行这类比较，这将有助于解决这些冲突。一种是一组果蝇物种（伪果蝇谱系），其中一条常规染色体已经有效地变成了一条额外的X染色体。这使我们能够比较这条染色体上基因的进化速度与其他果蝇物种中相同染色体上相同基因的进化速度，在其他果蝇物种中，它的行为正常。我们将以异常快速进化的基因为目标，因为这些基因最有可能通过自然选择积累有用的突变。我们还将收集这些基因变异的数据，在其中一个物种，果蝇伪眼。这使得通过选择有用的突变来使用统计测试来进行进化，而不是对适应度影响不大的突变的偶然积累。另一个系统是老鼠，它有许多基因的新（重复）拷贝，一些在X染色体上，一些在常规染色体上。这样就可以比较X染色体和基因组其他部分的重复配对之间的进化分歧率。我们将使用公开可用的小鼠及其亲戚大鼠的基因组序列，并询问X上的重复序列是否比其他地方的DNA序列进化率更高。此外，我们将研究另一种不同类型的过程，即DNA小片段的添加和删除。这一过程对基因组大小的进化很重要，但人们对其了解甚少。与基因组的其他部分相比，X似乎具有不同的特性，在自然选择中，X表现出更强的插入模式，而不是缺失。我们将使用公开可用的物种间比较和物种内变异的数据来检验作用于添加和删除的进化力的本质。该研究整合了进化遗传和计算方法，以最大限度地从基因组序列中获得理解，并将为英国研究界提供有关进化机制的新工具和见解。

The sex of an individual is often determined by a pair of specialized chromosomes (the giant DNA molecules that carry the genetic information). These are known as the X and Y chromosomes. In animals like mammals and the fruitfly Drosophila, females carry two copies of the X, and males carry an X and a Y. Both males and females carry two copies of each of the other chromosomes, one derived from the mother and the other from the father. The X is a fairly typical chromosome but the Y has only a small number of functional genes (the portions of the DNA that specify the structures of proteins). This means that most new mutations that occur on the X and alter gene function will affect males, since there is no normal copy to cover up their effects. In contrast, a mutation on the X in a female will be present together with a normal copy, just like a mutation on another chromosome. Natural selection is better at removing harmful mutations if they arise on the X, since part of the time they are carried in males and fully express their effects. Similarly, useful mutations that increase the fitness of their carriers may have a better chance of causing evolutionary change if they arise on the X. These differences in rates of evolution between the X and the rest of the genome can have important consequences, such as a greater tendency for genes controlling species differences to be found on the X chromosome. The ability to determine the sequences of the four 'letters' in DNA that make up the genetic information means that we can directly measure rates of evolutionary change by comparing DNA sequences between species. Such comparisons have been used to ask whether rates of evolution differ between genes on the X chromosome and elsewhere in the genome. The results so far have been conflicting. We plan to use two unusually favourable systems for further comparisons of this kind, which should help to resolve these conflicts. One is a group of Drosophila species (the pseudoobscura lineage), where a regular chromosome has effectively been turned into an additional X chromosome. This allows us to compare rates of evolution of genes on this chromosome with rates for the same genes on the equivalent chromosome in other Drosophila species, where it behaves normally. We will target unusually fast-evolving genes, since these are most likely to be the ones accumulating useful mutations by natural selection. We will also collect data on variation on these genes within one of the species, Drosophila pseudoobscura. This allows the use of statistical tests for evolution by selection for useful mutations, as opposed to the chance accumulation of mutations with little effect on fitness. The other system is in the mouse, which has new (duplicate) copies of many genes, some on the X and some on regular chromosomes. This allows comparisons of the rates of evolutionary divergences among pairs of duplicates between the X chromosome and the rest of the genome. We will use the publicly available genome sequences of the mouse and its relative the rat, and ask whether duplicates on the X have higher rates of DNA sequence evolution than those elsewhere. In addition, we will study a different type of process, the addition and deletion of small pieces of DNA. This process is important for the evolution of genome size, but is poorly understood. It seems to have different properties for the X compared with the rest of the genome, with the X showing a stronger pattern of insertions being favoured by natural selection over deletions. We will use publicly available data on between species comparisons and within species variability to examine the nature of the evolutionary forces acting on additions and deletions. The research integrates evolutionary genetic and computational approaches to maximize the understanding gained from genome sequences, and will provide new tools and insights concerning evolutionary mechanisms to the research community in the UK.