FETAL GLOBIN GENES--EVOLUTION OF ONTOGENETIC PROGRAMS

该项目的重点是进化的分子遗传学的 哺乳动物的β-珠蛋白基因簇中， 发生. 一个重要的目标是发展系统发育足迹 这些程序在适用于足够的机构时， 比较序列数据可以区分 非编码序列的进化上保守的元素， 中性DNA 实现这一目标将有助于实现 项目的主要目标：即，阐明遗传 在人类和其他猿类灵长类动物中进化的程序， 从胚胎（zeta 2 sigma 2; alpha 2 sigma 2）转换为胎儿 （α 2 γ 2）至成体（α 2 δ 2; α 2 β 2） 血红蛋白合成 发现的不同发育模式 在小鼠、兔子和原猴纲灵长类动物galago（胚胎期， 胎儿不表达γ-珠蛋白基因和完全开关 在胎儿期形成γ到β的表达，而不是在 出生）表明系统发育足迹将有助于识别 参与发育的顺式作用DNA序列 从sigma到gamma到delta和beta表达式的转换， 人类β-珠蛋白基因簇 基因工程 在灵长类动物中进化的血红蛋白转换提供了一个模型， 对于任何发育控制的人类基因系统， 调节元件的突变引起临床病症。 的 β-珠蛋白基因簇的DNA测序正在进行中 源自galago，tarsier（最接近猿类的原猿类），spider 猴子，恒河猴，长臂猿，猩猩，大猩猩，和 黑猩猩的基因将被扩展到不仅包括大多数基因 在这些集群内，但大多数侧翼和基因间 地区 β-珠蛋白基因的广泛DNA测序 其他猿类和原猿类物种的集群， 非灵长类胎盘哺乳动物（飞狐猴，树鼩， Armadillo）也在计划中。 这种生物的进化足迹 扩大排序数据的主体，以帮助确定是否 胎儿的伽马表达程序是在 Haplorhini（Tarsier和simians）或在随后的茎 类，可以识别适应性序列元件， 出现后在前猿类中是保守的猿类基因 集群 使用红系细胞培养的补充研究 系统将测试含有γ的DNA克隆的表达， 来自原猴亚目的胚胎伽马程序（例如galago） 用他们的胎儿伽马程序形成猿类， 进一步评估反式因子和顺式因子各自的作用， 在伽马射线向胎儿进化过程中的元素 发展计划。

This project focuses on the evolutionary molecular genetics of the mammalian beta-globin gene clusters in which gamma genes occur. An important aim is to develop phylogenetic footprinting procedures which when applied to sufficient bodies of comparative sequence data can distinguish within stretches of non-coding sequence the evolutionarily conserved elements from neutral DNA. Achieving this aim will facilitate accomplishing the project's major objective: namely, to elucidate the genetic program that evolved in humans and other simian primates for switching from embryonic (zeta2 sigma2; alpha2 sigma2) to fetal (alpha2 gamma2) to adult (alpha2 delta2; alpha2 beta2) hemoglobin synthesis. The differing developmental pattern found in mice, rabbits, and the prosimian primate galago (embryonic but not fetal expression of gamma-globin genes and the full switch form gamma to beta expression in fetal life rather than after birth) indicates that phylogenetic footprinting will help identify cis-acting DNA sequences involved in the developmental switching from sigma to gamma to delta and beta expression in the human beta-globin gene cluster. The genetic program for hemoglobin switching that evolved in primates provides a model for any developmentally controlled human gene system in which mutations in regulatory elements cause clinical disorders. The DNA sequencing now in progress on beta-globin gene clusters from galago, tarsier (the prosimian closest to simians), spider monkey, rhesus monkey, gibbon, oragnutan, gorilla, and chimpanzee will be extended to include not only most genes within these clusters but the majority of flanking and intergenic regions. Extensive DNA sequencing of the beta-globin gene clusters of additional simian and prosimian species and of several non-primate placental mammals (flying lemur, tree shrew, and armadillo) is also planned. Phylogenetic footprinting of this enlarge body of sequenced data, in helping to establish whether the fetal program of gamma expression evolved on the stem of Haplorhini (Tarsier and simians) or in the succeeding stem of Anthropoidea, could identify adaptive sequence elements that after emergence in the pre-simians were conserved in simian gene clusters. Complementary studies using erythroid cell culture systems will test expression of gamma-containing DNA clones from prosimians which embryonic gamma programs (e.g. galago) and form simians with their fetal gamma program in order to further assess the respective roles of trans-factors and cis- elements in the evolutionary recruitment of gamma to a fetal development program.