20x a-like genes 5 3 B-like genes 5 3 Hb Gower 1 Hemoglobins Hb Gower 2 Hb F HbA. HbA 022 22 o Hb Portland 52 Developmental moroniC Feta Adult eriod Birth
Globin Gene Developmental Expression and Globin Switching Classical example of ordered regulation of developmental gene expression Genes in each cluster arranged in Same transcriptional orientation Same sequential order as developmental expression Equimolar production of a-like and p like globin chains
Globin Gene Developmental Expression and Globin Switching • Classical example of ordered regulation of developmental gene expression • Genes in each cluster arranged in – Same transcriptional orientation – Same sequential order as developmental expression • Equimolar production of α-like and β- like globin chains
Human Hemoglobins: Prenatal Embryonic Fetal: hbF 02Y2 Predominates 5 wks gestation to birth 70% of total Hb at birth <1%o of total hb in adulthood
Human Hemoglobins: Prenatal • Embryonic – 22 • Fetal: HbF – α2 2 – Predominates 5 wks gestation to birth – ~70% of total Hb at birth – <1% of total Hb in adulthood
Human Hemoglobins Postnatal Adult: hba c 2P2 B chain synthesis increases through birth Nearly all Hb is hba by 3 mos of age HbA2 c26 <2%of adult hb Consequence of continuing synthesis of 8 chains
Human Hemoglobins: Postnatal • Adult: HbA – 22 – chain synthesis increases through birth – Nearly all Hb is HbA by 3 mos of age • HbA2 – 22 – ≤2% of adult Hb – Consequence of continuing synthesis of chains
Clinic disease: influences of gene Dosage and Developmental expression Dosage 4 a-vS 2 B-globin alleles per diploid genome Therefore, mutations required in 4 a-globin alleles compared with 2 B-globin alleles for same 100% loss of function Ontogeny a expressed before vs B expressed after birth Therefore, a-chain mutations have prenatal consequences,but B-chain mutations are not evidenced even in the immediate postnatal period
Clinic Disease: Influences of Gene Dosage and Developmental Expression • Dosage – 4 - vs. 2 -globin alleles per diploid genome – Therefore, mutations required in 4 -globin alleles compared with 2 -globin alleles for same 100% loss of function • Ontogeny – expressed before vs. expressed after birth – Therefore, -chain mutations have prenatal consequences, but -chain mutations are not evidenced even in the immediate postnatal period