Tumburu Laxminath, Thein Swee Lay
National Heart, Lung and Blood Institute/NIH, Sickle Cell Branch, Bethesda, Maryland, USA.
Curr Opin Hematol. 2017 May;24(3):173-182. doi: 10.1097/MOH.0000000000000333.
The discovery of several genetic variants associated with erythroid traits and subsequent elucidation of their functional mechanisms are exemplars of the power of the new genetic and genomic technology. The present review highlights findings from recent genetic studies related to the control of erythropoiesis and dyserythropoiesis, and fetal hemoglobin, an erythroid-related trait.
Identification of the genetic modulators of erythropoiesis involved two approaches: genome-wide association studies (GWASs) using single nucleotide polymorphism (SNP) arrays that revealed the common genetic variants associated with erythroid phenotypes (hemoglobin, red cell count, MCV, MCH) and fetal hemoglobin; and massive parallel sequencing such as whole genome sequencing (WGS) and whole exome sequencing (WES) that led to the discovery of the rarer variants (GFI1B, SBDS, RPS19, PKLR, EPO, EPOR, KLF1, GATA1). Functional and genomic studies aided by computational approaches and gene editing technology refined the regions encompassing the putative causative SNPs and confirmed their regulatory role at different stages of erythropoiesis.
Five meta-analysis of GWASs identified 17 genetic loci associated with erythroid phenotypes, which are potential regulators of erythropoiesis. Some of these loci showed pleiotropy associated with multiple erythroid traits, suggesting undiscovered molecular mechanisms and challenges underlying erythroid biology. Other sequencing strategies (WGS and WES) further elucidated the role of rare variants in dyserythropoiesis. Integration of common and rare variant studies with functional assays involving latest genome-editing technologies will significantly improve our understanding of the genetics underlying erythropoiesis and erythroid disorders.
发现多个与红系性状相关的基因变异，并随后阐明其功能机制，是新的遗传和基因组技术强大力量的例证。本综述重点介绍了近期有关红细胞生成调控、异常红细胞生成以及胎儿血红蛋白（一种与红系相关的性状）的遗传研究结果。
红细胞生成遗传调节因子的鉴定涉及两种方法：使用单核苷酸多态性（SNP）阵列的全基因组关联研究（GWAS），该研究揭示了与红系表型（血红蛋白、红细胞计数、平均红细胞体积、平均红细胞血红蛋白含量）和胎儿血红蛋白相关的常见基因变异；以及大规模平行测序，如全基因组测序（WGS）和全外显子组测序（WES），这导致发现了更罕见的变异（GFI1B、SBDS、RPS19、PKLR、EPO、EPOR、KLF1、GATA1）。计算方法和基因编辑技术辅助的功能和基因组研究细化了包含假定致病SNP的区域，并证实了它们在红细胞生成不同阶段的调节作用。
GWAS的五项荟萃分析确定了17个与红系表型相关的基因位点，这些位点是红细胞生成的潜在调节因子。其中一些位点显示出与多种红系性状相关的多效性，提示红系生物学背后存在未被发现的分子机制和挑战。其他测序策略（WGS和WES）进一步阐明了罕见变异在异常红细胞生成中的作用。将常见和罕见变异研究与涉及最新基因组编辑技术的功能测定相结合，将显著提高我们对红细胞生成和红系疾病遗传学基础的理解。
