A mutation leads to phenomenal effect

A point mutation in a gene leads to a phenomenal effect on the phenotype. It is a classic Biochemistry textbook case study, Sickle Cell Anemia. The mutant hemoglobin has a Valine instead of the Glutamic acid. The change is highly observable in the form of a debilitating condition. But, not all point mutations in the protein sequence are debilitating, and sometimes they give rise to something spectacular. One such example is the White Tiger, frequently mistaken as an albino. The recent publication in Current Biology [1] has been picked up by many newspapers and is creating news. See here, here, and here. There are two reasons as to why this research has become news. For one, it is about the endangered species and Tiger conservation. Second, it is precisely pinpointing to a molecular level change that can now be understood.

In sickle cell anemia, the longer and charged Glutamic acid changes to a uncharged Valine, thereby wrecking havoc.

Screen Shot 2013-05-24 at 12.14.27 PMResearchBlogging.orgThe gene in limelight is SLC45A2, which is present in many vertebrates including Humans. (Uniprot id: Q9UMX9) In humans this “pigmentation related gene in humans, whose polymorphisms are associated with light skin color in modern Europeans and pathogenic mutations known to cause oculocutaneous albinism type 4“. From a structural bioinformatics perspective, the paper provides as to how this mutation can be understood towards its function in the mutant. It is a membrane protein and the solved structure is not available, but the homology modeled structure is available in ModBase [2]. See below the modeled protein structure from ModBase, with the position 477 highlighted. Figure 3 of the paper shows a different way of showing the multiple sequence alignment.

Human SLC45A2 highlighting the Alanine 477

Human SLC45A2 highlighting the Alanine 477

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The residue 477 (Alanine is conserved among many vertebrates) is in the 11th transmembrane helix, and the change from Alanine to Valine, is possibly thought to prevent melanin synthesis therefore the while tiger! In the case of Sickle cell Anemia, one theory is that the mutation could have some evolutionary pressure, that is due to high prevalence of malaria. It so happens that people suffering from sickle cell anemia, do not get malaria, they are resistant to it.

In Tigers, the orange coloration of the fur, helps it to camouflage among the grasslands and forests. But, in the case of white tiger, what could have been the evolutionary pressure? This question remains in my mind after reading this paper.

References

  1. Xu, X., Dong, G., Hu, X., Miao, L., Zhang, X., Zhang, D., Yang, H., Zhang, T., Zou, Z., Zhang, T., Zhuang, Y., Bhak, J., Cho, Y., Dai, W., Jiang, T., Xie, C., Li, R., & Luo, S. (2013). The Genetic Basis of White Tigers Current Biology DOI: 10.1016/j.cub.2013.04.054
  2. http://modbase.compbio.ucsf.edu/modbase-cgi/model_details.cgi?queryfile=1369410401_8612&searchmode=default&displaymode=moddetail&referer=yes&snpflag=&
  3. http://www.uniprot.org/uniprot/Q9UMX9
  4. http://en.wikipedia.org/wiki/SLC45A2
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