1
Three Human Mutations: Origins, Genes, and Phenotypic Consequences
Department of Health Science, University of the People
HS 4212-01: Genetics
Instructor: Kaushal Sharma
May 06, 2025
2
Introduction
Mutations, often misunderstood as purely harmful changes, are in fact the engine of
genetic diversity. While some may result in disease or reduced fitness, others provide
advantages or are neutral, contributing to the variability we see across human
populations. This paper explores three human mutations: the CCR5-Δ32 deletion, the
Sickle Cell mutation (HbS), and the lactase persistence mutation (C/T -13910),
examining their molecular nature, gene location, phenotypic outcomes, estimated
emergence, and persistence in human populations.
1. CCR5-Δ32 Mutation
Type of mutation: The CCR5-Δ32 mutation is a 32 base pair deletion in the CCR5 gene.
Gene involved: This mutation occurs in the CCR5 gene, which encodes a chemokine
receptor involved in immune cell trafficking and HIV viral entry (Samson et al., 1996).
Phenotypic result and classification: Individuals homozygous for this deletion are highly
resistant to HIV-1 infection. It is considered a beneficial mutation due to its protective
effect (Liu et al., 1996).
Estimated origin: The mutation is believed to have originated approximately 700 to 2,900
years ago, likely in Northern Europe (Galvani & Slatkin, 2003).
Population persistence explanation: The mutation remains prevalent (around 10% allele
frequency in some European populations) possibly because it offered a survival
3
advantage against past epidemics, such as smallpox or the plague, maintaining its
presence through positive selection.
2. Sickle Cell Mutation (HbS)
Type of mutation: The HbS mutation is a single nucleotide substitution (missense
mutation) in the beta-globin gene (HBB), where adenine is replaced with thymine (GAG
→ GTG), resulting in the substitution of valine for glutamic acid at position 6.
Gene involved: The mutation occurs in the HBB gene, which encodes the beta chain of
hemoglobin.
Phenotypic result and classification: This mutation causes sickle cell disease in
homozygous individuals and sickle cell trait in heterozygotes. It is both deleterious and
beneficial, the latter due to protection from severe malaria in heterozygotes (Allison,
1954).
Estimated origin: The mutation likely arose 4,000–10,000 years ago in Sub-Saharan
Africa, coinciding with the spread of agriculture and increased malaria exposure (Piel et
al., 2010).
Population persistence explanation: Natural selection maintains the allele in populations
where malaria is endemic, as heterozygous carriers have a survival advantage over non-
carriers and those with the disease.
4
3. Lactase Persistence (C/T -13910)
Type of mutation: The lactase persistence trait results from a single nucleotide
polymorphism (SNP), specifically a C to T substitution located 13,910 base pairs
upstream of the LCT gene.
Gene involved: The regulatory mutation affects the MCM6 gene, which influences
expression of the LCT gene responsible for lactase production.
Phenotypic result and classification: This is a beneficial mutation, as it allows continued
digestion of lactose into adulthood—a trait known as lactase persistence (Enattah et al.,
2002).
Estimated origin: The mutation likely originated around 7,500–10,000 years ago in
Central Europe or the Middle East, correlating with the rise of dairy farming (Burger et
al., 2007).
Population persistence explanation: Positive selection favored individuals with this
mutation in dairy-consuming cultures. Today, the mutation is prevalent in European
populations and some African pastoralist groups, demonstrating gene-culture co-
evolution.
Conclusion
These three examples demonstrate that mutations can yield a variety of outcomes, from
disease resistance to metabolic advantages. Rather than being purely harmful, mutations
like CCR5-Δ32, HbS, and lactase persistence illustrate how genetic variation can confer
5
survival benefits and persist in human populations due to selective pressures shaped by
history, environment, and culture.
6
References
Allison, A. C. (1954). Protection afforded by sickle-cell trait against subtertian malarial
infection. British Medical Journal, 1(4857), 290–294.
https://doi.org/10.1136/bmj.1.4857.290
Burger, J., Kirchner, M., Bramanti, B., Haak, W., & Thomas, M. G. (2007). Absence of
the lactase-persistence-associated allele in early Neolithic Europeans. Proceedings of the
National Academy of Sciences, 104(10), 3736–3741.
https://doi.org/10.1073/pnas.0607187104
Enattah, N. S., Sahi, T., Savilahti, E., Terwilliger, J. D., Peltonen, L., & Järvelä, I. (2002).
Identification of a variant associated with adult-type hypolactasia. Nature Genetics,
30(2), 233–237. https://doi.org/10.1038/ng826
Galvani, A. P., & Slatkin, M. (2003). Evaluating plague and smallpox as historical
selective pressures for the CCR5-Δ32 HIV-resistance allele. Proceedings of the National
Academy of Sciences, 100(25), 15276–15279. https://doi.org/10.1073/pnas.2435085100
Liu, R., Paxton, W. A., Choe, S., Ceradini, D., Martin, S. R., Horuk, R., ... & Landau, N.
R. (1996). Homozygous defect in HIV-1 coreceptor accounts for resistance of some
multiply-exposed individuals to HIV-1 infection. Cell, 86(3), 367–377.
https://doi.org/10.1016/S0092-8674(00)80110-5
Piel, F. B., Patil, A. P., Howes, R. E., Nyangiri, O. A., Gething, P. W., Dewi, M., ... &
Hay, S. I. (2010). Global distribution of the sickle cell gene and geographical
7
confirmation of the malaria hypothesis. Nature Communications, 1(8), 104.
https://doi.org/10.1038/ncomms1104
Samson, M., Libert, F., Doranz, B. J., Rucker, J., Liesnard, C., Farber, C. M., ... &
Parmentier, M. (1996). Resistance to HIV-1 infection in Caucasian individuals bearing
mutant alleles of the CCR-5 chemokine receptor gene. Nature, 382(6593), 722–725.
https://doi.org/10.1038/382722a0
