Evolution of hemoglobin and its genes
by Hardison RC
Cold Spring Harb Perspect Med. 2012 Dec 1;2(12):a011627. doi: 10.1101/cshperspect.a011627.
Abstract
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Insights into the evolution of hemoglobins and their genes are an abundant source of ideas regarding hemoglobin function and regulation of globin gene expression. This article presents the multiple genes and gene families encoding human globins, summarizes major events in the evolution of the hemoglobin gene clusters, and discusses how these studies provide insights into regulation of globin genes. Although the genes in and around the α-like globin gene complex are relatively stable, the β-like globin gene clusters are more dynamic, showing evidence of transposition to a new locus and frequent lineage-specific expansions and deletions. The cis-regulatory modules controlling levels and timing of gene expression are a mix of conserved and lineage-specific DNA, perhaps reflecting evolutionary constraint on core regulatory functions shared broadly in mammals and adaptive fine-tuning in different orders of mammals.
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深入探究血紅蛋白（hemoglobins）與其基因的演化，提供我們對血紅蛋白的功能與基因表現調節的豐富題材。本論文主要針對幾種人類 globin 基因與基因家族，歸納血紅蛋白基因簇演化過程中的主要歷程，並討論這些研究如何深入闡明血紅蛋白的調節。座落於 alpha-like globin 基因複合集（α-like globin gene complex）內或周圍的基因相對地比較穩定，而beta-like globin 則有較大的變動，這可能是基因移動到一個新位置的證據，以及常見的族系專有（lineage-specific）的增多或刪減。控制基因表現量與表現時機的順位調節模組（cis-regulatory module）是保守性的與族系特有的DNA 綜合效果，這或許能反映出哺乳類廣泛共有的核心調控功能的演化限制，以及哺乳綱不同目別物種的適應性微調。
What is Hemoglobin ?
- transport/bind oxygen
- it is an abundant proteins in red blood cells of mammals and other jawed vertebrates (gnathostomes).
- In human, Hb is known as a heterotetramer : two α-globin and two β-globin, each with an associated heme group.
The model of evolution of vertebrate globin genes. Figure 1 of this reference.
- Myoglobin: monomeric heme-bound globin protein found predominantly in skeletal and heart muscle. It has long been described as an oxygen storage protein.
- Cytoglobin: found in many tissues.
- neuroglobin: Its mRNA is abundant in brain tissue but also is present in many other tissues. It is related to invertebrate nerve globins.
- Physiological function of the heme-bearing proteins are "oxygen binding". But, CYGB showing nitric oxide dioxygenase activity (converting NO to NO3-) and NGB showing nitrite reductase activity to form nitric oxide (converting NO3- to NO. This catalytic capability also found in MB and deoxy-Hb). Thus, the nitrite reductase activity could provide a means to produce nitric oxide under hypoxic conditions, signaling from which could regulate mitochondrial respiration and protect tissues (nerves by NGB, heart muscle by MB) from damage under ischemic conditions (Dietz 2011).
- MB, CYGB, and NGB are present as single-copy genes, whereas HBB and HBAs are in clusters with multiple related genes.
- cyclostomes (represented by hagfish and lampreys), also use a heme-containing globin for oxygen transport, but surprisingly, it is more closely related to CYGB than to the gnathostome hemoglobins. This suggests that the oxygen transport function of heme-containing globins arose by independent, convergent evolution in the two major branches of vertebrates. (((Is there sure, solid evidences for these conclusions, or just speculation by the authors?)))
- Human: alpha-, beta-, delta-, tau-, epsilon- globin. expressed in different locations / different dev stage. The hemoglobins produced at distinct developmental stages have different affinities for oxygen and are subject to complex regulation by cofactors, favoring an overall movement of oxygen from the maternal bloodstream to that of the fetus or embryo.
- In human, the separation of α-like and β-like globin gene clusters in amniotes requires coordination of expression between different chromosomes. 人類 （有羊膜類）的α-like and β-like globin gene clusters 分別在不同的染色體，需要協同控制表現。
- Fish species show an interesting contrast, in that the gene cluster orthologous (homologous genes generated by a speciation event) to that of the mammalian α-globin gene cluster contains both α-like and β-like globin genes ((((((the expression level is not like to be in this guess))))))))) 魚類的 α 與 β globins 則在同一個 cluster 中 （MN type)
- MN: found in all gnathostomes being examined. flanked on one side by the genes MPGNPRL3
- LA (or LCA): The globin genes in this locus are flanked by the genes LCMT1 and AQP8, and the locus can be called “LA.” The gene ARHGAP17 is also part of this locus in many species. These three nonglobin genes are in the same arrangement and order in the tetrapods (human, platypus, chicken, and frog), but the globin genes is devoid.
- DS: DCHS1 on one side and STIM1 on the other; the RRM1 gene is adjacent to STIM1 in many species. In placental mammals, hundreds of OR genes are in this locus, with additional multigene families such as TRIM genes. (DCHS1 and STIM1 are spanned by many many genes==>several megabases away). Found in "amniotes" (water-tighted environment for embryo. reptiles, birds, mammals) but absent in fish and amphibians.
b-like globin only.
Models for evolution of hemoglobin gene complexes in jawed vertebrates. Figure 2 from the reference. The gene maps are not complete, nor are they to scale. (This diagram is adapted fromHardison 2008.)
Maps of orthologous α-like globin genes and expression timing in amniotes. Figure 2 from the reference.
The history of the gene clusters encoding hemoglobins is dynamic and complex. (((inferred to be a more adaptive to the environment).
The ortholog of the μ-globin gene is expressed in adult erythroid cells in birds, producing αD-globin
Hemoglobin gene expression is restricted to erythroid cells.
===================... contents in the further section discuss the gene regulation, gene origins, ...... are majorly in "mammal", not my interesting subject now. so I skipped
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