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Genetics of human hair form diversity

Periodic Reporting for period 1 - HairGen (Genetics of human hair form diversity)

Reporting period: 2016-09-01 to 2018-08-31

We are all enthralled by the human diversity existing around us. Much of what makes us different from each other is our genes. The irony however is that there is not one switch on and off mechanism that makes us distinct but a number of these switches. Studying genes and understanding their complex interactions is important – firstly to unravel the biological adaptations that have occurred in the past and secondly to harness the information for the betterment of public health today and in the future. For this, there is a vital need to carry forward the existing information available from the genome-wide association studies to understand gene function, related biology and influence on disease phenotypes.

Human hair shape varies across geographically distinct populations in its shape, color, texture and growth patterns. It is indeed very intriguing to know why we have different hair shapes across the world, which genes and variants are responsible for this diversity, how they work and whether they influence differences in disease incidence in modern populations with different ancestries. The main objectives of the current project were firstly to perform the downstream elucidation of one of the identified variant in a gene coding for serine protease to gain insight on its role in human hair diversity. Secondly, to perform phenotypic assessment for the skin and gland phenotypes to identify other effects of the variant. Thirdly, to elucidate the molecular mechanism of the gene; by studying its expression and interaction with candidate molecular pathways.

The main advantage of the project that makes it progressive in the state-of-the-art is that it uses the powerful tool of genome editing in generation of mouse models and the fact that this gene is conserved in mice allows us to undertake the functional follow-up of the variant effectively. The team uses integrated approach of functional genomics, molecular biology, developmental biology and population genetics to contribute towards better understanding of the genetic architecture of the human hair shape.
One of the variants in PRSS53 (Serine protease 53) was found to be associated with hair straightness in Latin Americans and ubiquitously present in East Asians leading to about 76% of the individuals carrying this variant. The tests carried out also attested that this variant and its effect was advantageous for the population. Hence, the above facts presented a strong case for the functional follow-up of the variant using mouse models.
We generated two modified Prss53 mouse lines, one representing the exact variant as in humans and the other representing a non-functional form (null) of the gene. Our results showed altered hair phenotype (both for hair coat and whiskers) for the null form of the gene. However, the exact variant did not show any readily identifiable external feature. On extensive analysis, we found that the latter showed a subtler effect on body hair. Both these results together confirmed the role of the gene towards hair shape variation.

Since there was an evidence for the particular variant contributing to its high frequency in East Asians, an obvious question next was to decipher if the modified mouse models also pointed towards any other wide-ranging effects on the body, which could be tested turn in humans. The hypothesis for this was mainly the fact that other hair variants have been associated with multiple traits. For this, skin and gland related features were studied. This led to an important finding of one of the novel phenotypes. Our cell-based experiments to test the interaction of PRSS53 with one of the candidate genes also contributing to hair straightness in East Asians (Ectodysplasin A receptor - EDAR) shows that it is unlikely that their functions intersect, thereby suggesting both of these genes contribute to straight hair phenotype through independent pathways.
This project will help us to illustrate the biological pathways directly influencing the hair shape and texture enabling further understanding of hair biology. The new knowledge generated can be also useful in understanding various human hair and skin disorders. Since, the project confirms the role of the gene in hair shape this variant and is commonly found in East Asians, it can be an important part of hair shape marker set. This can provide new dimensions in forensic science in the context of ancestry and personal identification of individuals. There has been also evidence for the involvement of gene in psoriasis and inter-population variation in the prevalence of the disease. Hence the findings of the project can be further useful in understanding the progression of the disease and its population dynamics. Also, PRSS53 being a serine protease represents a druggable enzyme target approachable through topical means, hence reflecting the potential to contribute towards novel therapeutic targets.

To summarize, in-depth analysis of the population-specific variant using mouse models gives us insight about its effect on hair and beyond and is vital for designing approaches for the betterment of public health.

Societal impact-

HairGen deals with a very important aspect of one’s identity- hair. With the low sequencing costs and the facilities available there has been increasing awareness among people to explore one’s genome to understand their origin, why they appear different, what potential disease risks can they have. Projects like these act as proof of concept to understand why we have different forms of genes existing in different populations and why they are important. These kinds of projects are integral towards understanding human diversity, the adaptations of human populations in the past and mechanism of related diseases. Infact, these kinds of studies form the crux of the upcoming field of personalized genomics. Better knowledge of the mechanism that controls curliness or straightness can be useful for the hair care industry by offering new treatments and hair care products for hair management, useful to people.