Quantifying functional constraints in the mammalian genome

最近，科学界已经获得了几种哺乳动物基因组的完整DNA序列。这些包括人类、黑猩猩、猕猴、狗、小鼠和大鼠的基因组序列。基因组包含编码蛋白质的基因，蛋白质是所有生物的基石。然而，人们早就知道，超过98.5%的哺乳动物基因组由不编码蛋白质的“非编码”DNA组成。非编码DNA仍然很重要，因为它包含控制基因“表达”的序列;也就是说，基因何时以及在什么细胞和组织中产生蛋白质。因此，基因表达控制序列引起了生物学家的极大兴趣，但对基因组中有多少序列由这些序列组成以及它们在基因组中的位置知之甚少。在我们提出的计划中，我们将试图找出重要的基因表达控制序列位于哺乳动物基因组中。我们将通过比较几种哺乳动物的基因组序列来做到这一点。我们将寻找在哺乳动物数千万年的进化过程中，基因组中保持相似的部分，从而保留了共同的功能。作为这些比较的一部分，我们将测量和比较猿和啮齿动物基因组中基因表达控制序列的相似性。我们先前的工作表明，猿类的基因表达控制序列不如啮齿类动物保守，这表明自然选择在猿类中的作用较小。我们还建议获得来自印度野生小鼠种群个体的基因和基因表达控制区的DNA序列。我们建议研究一个印度种群，因为这些老鼠的遗传变异很大。我们希望能在小鼠的DNA序列中发现个体之间的差异。DNA序列差异的数量将使我们能够估计序列差异对个体小鼠繁殖成功的影响程度。

Very recently, the complete DNA sequences of several mammalian genomes have been made available to the scientific community. These include the genome sequences of human, chimpanzee, macaque, dog, mouse and rat. Genomes contain genes that code for proteins, which are the building blocks of all living things. However, it has long been known that more than 98.5% of the mammalian genome consists of 'noncoding' DNA that does not code for proteins. Noncoding DNA is nonetheless important because it contains sequences that control the 'expression' of genes; that is, when and in what cells and tissues genes produce proteins. Gene expression control sequences are therefore of great interest to biologists, yet very little is known about how much of the genome consists of these sequences and where they are located in the genome. In our proposed project, we shall attempt to find out where the important gene expression control sequences are located in mammalian genomes. We will do this by comparing the genome sequences of several mammals. We will search for those parts of the genome that have remained similar to each other, and therefore have retained common functions, over the many tens of millions of years of mammalian evolution. As part of these comparisons, we shall measure and compare the amount of similarity in gene expression control sequences in the genomes of apes and rodents. Our previous work has suggested that gene expression control sequences are less strongly conserved in apes than rodents, suggesting that natural selection has been less effective in apes. We also propose to obtain DNA sequences from genes and gene expression control regions from individuals of a population of wild mice from India. We are proposing to study an Indian population because these mice are highly genetically variable. We expect to find differences between individual mice in their DNA sequences. The numbers of DNA sequence differences will allow us to estimate how much the sequence differences affect the reproductive success of individual mice.