Editing Hemoglobin (section)

== Genetics ==
Hemoglobin consists of [[protein subunit]]s ([[globin]] molecules), which are [[polypeptide]]s, long folded chains of specific [[amino acid]]s which determine the protein's chemical properties and function. The amino acid sequence of any polypeptide is [[translation (biology)|translated]] from a segment of DNA, the corresponding [[gene]].

There is more than one hemoglobin gene. In humans, [[hemoglobin A]] (the main form of hemoglobin in adults) is coded by genes ''[[HBA1]]'', ''[[HBA2]]'', and ''[[HBB]]''.<ref name="Hardison-2012"/> Alpha 1 and alpha 2 subunits are respectively coded by genes ''HBA1'' and ''HBA2'' close together on chromosome 16, while the beta subunit is coded by gene ''HBB'' on chromosome 11. The amino acid sequences of the globin subunits usually differ between species, with the difference growing with evolutionary distance. For example, the most common hemoglobin sequences in humans, bonobos and chimpanzees are completely identical, with exactly the same alpha and beta globin protein chains.<ref>{{cite journal |last=Offner |first=Susan |date=2010-04-01 |title=Using the NCBI Genome Databases to Compare the Genes for Human & Chimpanzee Beta Hemoglobin |journal=The American Biology Teacher |language=en |volume=72 |issue=4 |pages=252–56 |issn=0002-7685 |doi=10.1525/abt.2010.72.4.10 |s2cid=84499907 |url=https://abt.ucpress.edu/content/72/4/252 |access-date=2019-12-26 |url-status=live |archive-url=https://web.archive.org/web/20191226155117/https://abt.ucpress.edu/content/72/4/252 |archive-date=2019-12-26}}</ref><ref>{{cite web |title=HBB – Hemoglobin subunit beta – Pan paniscus (Pygmy chimpanzee) – HBB gene & protein |website=uniprot.org |url=https://www.uniprot.org/uniprot/P68872 |access-date=2020-03-10 |url-status=live |archive-url=https://web.archive.org/web/20200801122023/https://www.uniprot.org/uniprot/P68872 |archive-date=2020-08-01}}</ref><ref>{{cite web |title=HBA1 – Hemoglobin subunit alpha – Pan troglodytes (Chimpanzee) – HBA1 gene & protein |website=uniprot.org |url=https://www.uniprot.org/uniprot/P69907 |access-date=2020-03-10 |url-status=live |archive-url=https://web.archive.org/web/20200801122008/https://www.uniprot.org/uniprot/P69907 |archive-date=2020-08-01}}</ref> Human and gorilla hemoglobin differ in one amino acid in both alpha and beta chains, and these differences grow larger between less closely related species.{{citation needed|date=November 2023}}

[[Mutation]]s in the genes for hemoglobin can result in [[hemoglobin variants|variants of hemoglobin]] within a single species, although one sequence is usually "most common" in each species.<ref name="Huisman-1996">{{cite web |title=A Syllabus of Human Hemoglobin Variants |author=Huisman THJ |year=1996 |website=Globin Gene Server |publisher=Pennsylvania State University |url=https://globin.cse.psu.edu/html/huisman/variants/ |access-date=2008-10-12 |url-status=live |archive-url=https://web.archive.org/web/20081211113441/https://globin.cse.psu.edu/html/huisman/variants/ |archive-date=2008-12-11}}</ref><ref>[https://www.labtestsonline.org/understanding/analytes/hemoglobin_var/glance-3.html Hemoglobin Variants] {{Webarchive |url=https://web.archive.org/web/20061105162948/https://www.labtestsonline.org/understanding/analytes/hemoglobin_var/glance-3.html |date=2006-11-05}}. Labtestsonline.org. Retrieved 2013-09-05.</ref> Many of these mutations cause no disease, but some cause a group of [[hereditary disease]]s called ''[[hemoglobinopathy|hemoglobinopathies]]''. The best known hemoglobinopathy is [[sickle-cell disease]], which was the first human disease whose [[mechanism (biology)|mechanism]] was understood at the molecular level. A mostly separate set of diseases called [[thalassemia]]s involves underproduction of normal and sometimes abnormal hemoglobins, through problems and mutations in globin [[gene regulation]]. All these diseases produce [[anemia]].<ref>{{cite web |title=Hemoglobinopathies and Thalassemias |last=Uthman |first=Ed |url=https://web2.airmail.net/uthman/hemoglobinopathy/hemoglobinopathy.html |access-date=2007-12-26 |url-status=dead |archive-url=https://web.archive.org/web/20071215043423/https://web2.airmail.net/uthman/hemoglobinopathy/hemoglobinopathy.html |archive-date=2007-12-15}}</ref>

[[File:HemoglobinABDAlignment.png|thumb|Protein alignment of human hemoglobin proteins, alpha, beta, and delta subunits respectively. The alignments were created using [[UniProt]]'s alignment tool available online. |right |upright=1.5]]

Variations in hemoglobin sequences, as with other proteins, may be adaptive. For example, hemoglobin has been found to adapt in different ways to the thin air at high altitudes, where lower partial pressure of oxygen diminishes its binding to hemoglobin compared to the higher pressures at sea level. Recent studies of deer mice found mutations in four genes that can account for differences between high- and low-elevation populations. It was found that the genes of the two breeds are "virtually identical—except for those that govern the oxygen-carrying capacity of their hemoglobin. . . . The genetic difference enables highland mice to make more efficient use of their oxygen."<ref>Reed, Leslie. "Adaptation found in mouse genes." ''Omaha World-Herald'', 11 Aug. 2009: EBSCO. {{page needed|date=December 2021}}</ref> [[Mammoth]] hemoglobin featured mutations that allowed for oxygen delivery at lower temperatures, thus enabling mammoths to migrate to higher latitudes during the [[Pleistocene]].<ref>{{cite news |title=Mammoths had 'anti-freeze' blood |publisher=BBC |date=2010-05-02 |url=https://news.bbc.co.uk/2/hi/science/nature/8657464.stm |access-date=2010-05-02 |url-status=live |archive-url=https://web.archive.org/web/20100504162118/https://news.bbc.co.uk/2/hi/science/nature/8657464.stm |archive-date=2010-05-04}}</ref> This was also found in hummingbirds that inhabit the Andes. Hummingbirds already expend a lot of energy and thus have high oxygen demands and yet Andean hummingbirds have been found to thrive in high altitudes. Non-synonymous mutations in the hemoglobin gene of multiple species living at high elevations (''Oreotrochilus, A. castelnaudii, C. violifer, P. gigas,'' and ''A. viridicuada'') have caused the protein to have less of an affinity for [[phytic acid|inositol hexaphosphate]] (IHP), a molecule found in birds that has a similar role as 2,3-BPG in humans; this results in the ability to bind oxygen in lower partial pressures.<ref>{{cite journal |title=Repeated elevational transitions in hemoglobin function during the evolution of Andean hummingbirds |journal=Proceedings of the National Academy of Sciences |date=2013-12-17 |issn=0027-8424 |pages=20669–74 |volume=110 |issue=51 |last1=Projecto-Garcia |first1=Joana |last2=Natarajan |first2=Chandrasekhar |last3=Moriyama |first3=Hideaki |last4=Weber |first4=Roy E. |last5=Fago |first5=Angela |last6=Cheviron |first6=Zachary A. |last7=Dudley |first7=Robert |last8=McGuire |first8=Jimmy A. |last9=Witt |first9=Christopher C. |bibcode=2013PNAS..11020669P |pmid=24297909 |doi=10.1073/pnas.1315456110 |doi-access=free |pmc=3870697}}</ref>

Birds' unique [[bird anatomy|circulatory lungs]] also promote efficient use of oxygen at low partial pressures of O<sub>2</sub>. These two adaptations reinforce each other and account for birds' remarkable high-altitude performance.{{citation needed|date=November 2023}}

Hemoglobin adaptation extends to humans, as well. There is a higher offspring survival rate among Tibetan women with high oxygen saturation genotypes residing at 4,000 m.<ref>{{cite journal |title=Higher offspring survival among Tibetan women with high oxygen saturation genotypes residing at 4,000 m |journal=Proceedings of the National Academy of Sciences of the United States of America |date=2004-09-28 |issn=0027-8424 |pages=14300–04 |volume=101 |issue=39 |last1=Beall |first1=Cynthia M. |last2=Song |first2=Kijoung |last3=Elston |first3=Robert C. |last4=Goldstein |first4=Melvyn C. |bibcode=2004PNAS..10114300B |pmid=15353580 |doi=10.1073/pnas.0405949101 |doi-access=free |pmc=521103}}</ref> Natural selection seems to be the main force working on this gene because the mortality rate of offspring is significantly lower for women with higher hemoglobin-oxygen affinity when compared to the mortality rate of offspring from women with low hemoglobin-oxygen affinity. While the exact genotype and mechanism by which this occurs is not yet clear, selection is acting on these women's ability to bind oxygen in low partial pressures, which overall allows them to better sustain crucial metabolic processes.{{citation needed|date=November 2023}}