Blood disorders are a fascinating viewpoint from which to study human microevolution. Some disorders, perhaps especially hemoglobin S, the abnormal hemoglobin variant responsible for the sickle cell trait and sickle cell disease, represent textbook cases of balancing selection and the ‘heterozygous advantage’. Briefly, balancing selection occurs when a polymorphism is maintained in a population at levels higher than are expected by chance. In the case of hemoglobin S, this occurs because heterozygotes have an adaptive advantage above that of the homozygote. Homozygotes aren’t likely to survive long because blood cells are deformed, leading to various medical problems. Conversely, heterozygotes have a less severe case of the sickle trait while also being protected against severe malaria. In malarious regions the balance is therefore between the benefits of being a heterozygote and the severe costs of being a homozygote.
But the complexity of blood and blood-related disorders, and their interactions with malaria parasites, is usually glossed over. A little background on hemoglobin:
Normal hemoglobin is composed of two α-globin proteins and two β-globin proteins, with each protein being capable of transporting oxygen (which binds to each globin’s heme) throughout the body. ‘Normal’ individuals have two copies each of ‘α’ and ‘β’ genes, located within the α and β gene complexes, each of which contains the genetic information needed to construct four proteins per hemoglobin molecule (a tetramer). The α globin gene complex is located on chromosome 16 while the β globin gene complex is located on chromosome 11, meaning that globin production is nicely synchronized with coordination from two very different genomic locations.
All vertebrates have α and β globins in their blood. Most fish, amphibians, and reptiles appear to have globin genes lumped into one cluster, on the same chromosome. It is thought that, over evolutionary time, gene duplications, changes in regulatory regions, and splitting of the genes onto different chromosomes allowed for developmental and stage specific expression of the globin genes we now see in humans.[1,2]
However, not all hemoglobin is created equal. Adult hemoglobin (as opposed to fetal or embryonic hemoglobin) is heterogeneous, with α chains combining with either β or δ chains (see images below). Fetal hemoglobin is also heterogeneous, with a mixture of α and γ chains, and with the γ chains being either γG (for glycine at position 136) or γA (for alanine at position 136).
For now, I will only focus on the β globin gene complex, which is sandwiched in between some olfactory receptor genes on the short arm of chromosome 11. Moving left to right, we have a locus control region (which is essential for the expression of genes within the β globin complex), the ε globin gene, two γ globin genes (G and A), the ψβ1 ‘pseudogene’ (which is preserved in most mammals that have been studied), the δ globin gene, and finally, the β globin gene.
Which genes are expressed at which time is heavily regulated by the locus control region, which regulates the transcription levels of genes in the β globin gene complex. Both human genetic disease studies and deletion studies in mice have shown this region to be imperative for β globin gene expression, however the exact mechanism through which it promotes expression isn’t fully known. Some studies have indicated that DNAse hypersensitive I sites within the locus control region are what control gene exposure to transcription factories, and/or that the locus control region may form a chromatin loop, actually coming into direct contact with the genes within the β globin complex.[3,4]
Regardless of how the process works, there is a symphony-like succession of instrumental players, which work together but are chronologically switched on and off during the mostly early parts of the lifespan. Hemoglobin switching is what occurs when one gene largely ceases to be expressed while another’s expression is increased. This switch isn’t exactly binary as there are cline-like changes that ultimately lead to shifts in the proportion of globins that are present in hemoglobin.[5]
For example, see the image below. You can see that embryonic (ε) globin is present very early after conception but largely ceases after ~ 6 weeks post-conception. Adult, β or δ, globin is present very early but at low levels. It rises slowly until there is a switch somewhere (probably early) during the first year of life. At that point fetal (γ) globin has reduced in its proportion of total hemoglobin to a level lower than adult hemoglobin, and continues to decrease. γ globin will probably continue to be produced, at very low levels, throughout the lifespan of this individual. Notice that this progression follows the ordering of the genes within the gene complex, which correspond chronologically to developmental stages.
 |
| Image adapted from Weatherall and Clegg 2001 |
There is a lot of natural (unharmful) variation in the β globin genes. Conversely, there are also a lot of hemoglobin pathologies that are associated with the β globin gene complex, especially the β-globin gene (and to some extent the δ globin gene and the expression of fetal hemoglobin).
For example, if the expression of one copy of β-globin isn’t expressed then there is an imbalance in hemoglobin chain production and the result is β thalassemia. Most people with β thalassemia continue to produce higher levels of fetal hemoglobin than do people with normal hemoglobin production. If neither copy of the β-globin gene produces globins then severe disease begins to manifest during the first year after birth, when fetal hemoglobin has decreased and adult hemoglobin has increased to a high proportion of total hemoglobin. In the absence of blood transfusions, the outlook for these individuals is pretty grim. Regular blood transfusions may prolong life.[5]
There are several other things that can go wrong in the β-globin gene. Hemoglobin S (sickle cell), hemoglobin C, and hemoglobin E, for example, are all related to variation in the β globin gene.
While all of these hemoglobin disorders are an interesting story in themselves, our evolutionary history may have influenced their distribution both regionally and globally. β thalassemia, as well as each of the other disorders that I’ve mentioned here, historically occurs in regions with heavy malaria burdens and appear to have protective benefits, in the heterozygous state, against malaria morbidity or infection. [There is still debate about how that actually works and I may return to this in a later post.] β thalassemia, which is quite diverse in its symptoms and genetics, occurs throughout much of Africa, the Mediterranean, Southern and Southeast Asia, and into the Pacific.[6]
But the story isn’t over there. I mentioned that fetal hemoglobin is frequently present at elevated levels in individuals with β thalassemia. However, sometimes it is present in adulthood at the same high levels that you would see in the first weeks of life, a condition known as hereditary persistence of fetal hemoglobin (HPFH). HPFH appears to have no (or at least very minor) side effects, meaning that you could potentially have the genetic susceptibility to severe β thalassemia without ever experiencing it. The same is true for other β globin disorders.
Some forms of HPFH are the result of deletion of the delta and β globin genes. However there is also heterogeneity in HPFH, likely related to different deletions in different populations and potentially in mutations of gene repressors. Perhaps one of the most interesting things about HPFH, aside from its protective effects against harmful variants in the adult hemoglobin genes, is that malaria appears to have a hell of a time getting into fetal hemoglobin blood cells.[7,8]
Furthermore, while the potential protective effects of β thalassemia (with regard to malaria) haven’t really come to light it has been suggested that it is actually the extra production of fetal hemoglobin (especially in early life) that is protective. Most mortality from malaria occurs in early life.
And to add to the complexity, the aforementioned traits can be inherited together. Because you have two copies of each, you could potentially have both hemoglobin S and β thalassemia. The compound hemoglobin E and β thalassemia trait is actually relatively common in Southeast Asia (hemoglobin E doesn’t usually have severe side effects). For that matter, since HPFH can sometimes be the result of over expression of fetal hemoglobin genes, it’s at least possible to have more than two of these hemoglobin disorders at the same time. And we’re only talking about one half of the globin story here, I haven’t even discussed the α globin gene complex. Finally, there are several other blood and blood related disorders that could be simultaneously inherited: G6PD-deficiency, Southeast Asian ovalocytosis, or even compliment receptor 1 polymorphisms. The story with regards to inherited malaria immunity, when you consider all of the potential combinations, is inherently complicated. And we’re not even talking about acquired immunity to malaria here.
After a half century of work on the blood disorders related to this region of the genome, we do know a relatively lot. What is clear, however, is that the story is super complex and that there is still a lot that we don’t know. Given the harmful effects of being a homozygote for most of these traits, and the fact that their distribution largely matches historically malarious regions, I’m fairly certain that they are an example of adaptation to a pretty severe environmental stress. However, I think this is an example of the complexities inherent in understanding ecology and evolution. Even in relatively clear cut cases of human evolution there aren’t simple universal fixes to environmental stressors (like malaria) and in fact, simplistic evolutionary explanations aren’t likely to be fully correct.
References
1. Hardison R (1998) Hemoglobins from bacteria to man: evolution of different patterns of gene expression. The Journal of experimental biology 201: 1099–1117.
2. Gillemans N, McMorrow T, Tewari R, Wai AWK, Burgtorf C, et al. (2003) Functional and comparative analysis of globin loci in pufferfish and humans. Blood 101: 2842–2849.
3. Dean A (2006) On a chromosome far, far away: LCRs and gene expression. Trends in genetics 22: 38–45.
4. Fleetwood MR, Ho Y, Cooke NE, Liebhaber S a (2012) DNase I hypersensitive site II of the human growth hormone locus control region mediates an essential and distinct long-range enhancer function. The Journal of biological chemistry 287: 25454–25465.
5. Weatherall D, Clegg J (2001) The Thalassaemia Syndromes. 4th ed. Wiley-Blackwell. p.
6. Williams TN, Weatherall DJ (2012) World distribution, population genetics, and health burden of the hemoglobinopathies. Cold Spring Harbor perspectives in medicine 2: a011692.
7. Pasvol G, Weatherall DJ, Wilson JM (1977) Effects of foetal haemoglobin on susceptibility of red cells to Plasmodium falciparum. Nature 270: 171 – 173.
8. Shear H, Grinberg L, Gilman J, Fabry M, Stamatoyannopoulos G, et al. (1998) Transgenic mice expressing human fetal hemoglobin are protected from malaria by a novel mechanism. Blood 92: 2520–2526.
No comments:
Post a Comment