FETAL GLOBIN GENES; EVOLUTION OF ONTOGENETIC PROGRAMS

本项目的重点是人类进化分子遗传学。 哺乳动物的β-珠蛋白基因簇中有伽马基因 发生。一个重要的目标是发展系统发育足迹。 程序，当应用于足够多的 比较序列数据可以在范围内区分 进化上保守的元件的非编码序列 中性DNA。实现这一目标将有助于实现 该项目的主要目标：即阐明基因 在人类和其他猿类灵长类动物中进化的程序 从胚胎(zeta2 sigma2；alpha2 sigma2)切换到胎儿 (Alpha2 Gamma2)到成人(Alpha2 delta2；Alpha2 Beta2) 血红蛋白的合成。发现了不同的发育模式 在小鼠、兔子和原猴灵长类动物中(胚胎但 非胎儿γ-珠蛋白基因的表达与全开关 从伽玛到贝塔的表达在胎儿时期而不是之后 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 从西格玛到伽马，再到增量和贝塔表达 人类β-珠蛋白基因簇。遗传程序用于 灵长类动物中进化的血红蛋白转换提供了一个模型 对于任何发育受控的人类基因系统来说 调节元件的突变会导致临床疾病。这个 关于β-珠蛋白基因簇的DNA测序正在进行中 源自Galago，tarsier(最接近猿猴的原猴)，蜘蛛 猴子、恒河猴、长臂猿、红毛猩猩、大猩猩和 黑猩猩将被扩大到不仅包括大多数基因 在这些簇内，但大多数侧翼和基因间 地区。β-珠蛋白基因的广泛DNA测序 其他猿类和原猴物种的集群以及几个 非灵长类胎盘哺乳动物(飞狐猴、树鼠和 )也在计划之中。这一物种的系统发育足迹 扩大排序数据的主体，帮助确定 胎儿的伽马表达程序是在 Haplorhini(塔西尔和猿猴)或在 人类，可以识别自适应序列元件 在前猿猴中出现后，猴的基因是保守的 集群。红系细胞培养的补充性研究 系统将测试含有伽马的DNA克隆的表达 来自胚胎伽马计划的原猴(例如Galago) 并用它们的胎儿伽马程序形成类人猿 进一步评估反式因子和顺式因子各自的作用- 伽马在胎儿体内的进化募集要素 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.