I am generally curious on how structural variants commonly found in human genomes contribute to evolution and disease susceptibility. Along this thread, I am interested whether there are certain evolutionary tradeoffs that exist, where some structural mutations may provide a benefit in one tissue, and detrimental health consequences in another- this process could result in a maintenance of variation observed between human individuals.
Contribution to Science
1. Skin Barrier Evolution.
Skindirectly interacts with the environment at multiple levels, and as such, evolves under various adaptive forces. Skin plays as the first barrier against pathogens and nonbiological external agents and helps regulate internal body temperature. We argue that structural variants likely have a stronger functional impact than single nucleotide variants due to their size. In a study I led, we found that a common, 32kb deletion of LCE3B and LCE3C genes that is associated with psoriasis, is ancient, predating Human Denisovan divergence. However, it was not clear why negative selection had not removed this deletion from the population. Here, we have shown that the haplotype block that harbors the deletion (i) retains high allele frequency among extant and ancient human populations; (ii) harbors unusually high nucleotide variation (π, P < 4.1 × 10−3); (iii) contains an excess of intermediate frequency variants (Tajima’s D, P < 3.9 × 10−3); and (iv) has an unusually long time to coalescence to the most recent common ancestor (TSel, 0.1 quantile). Our results are most parsimonious with the scenario where the LCE3BC deletion has evolved under balancing selection in humans. More broadly, this is consistent with the hypothesis that a balance between autoimmunity and natural vaccination through increased exposure to pathogens maintains this deletion in humans. In this study, I led the bioinformatic interrogation of the variation at this locus in modern and ancient human populations. My most profound influence on this work came with the theoretical concept of the link between autoimmunity and natural vaccination.
2. Salivary Amylase Evolution.
Saliva is the first stop for food, microorganisms, and other xenobiotic molecules entering our bodies. It regulates microbial composition, helps with predigestion, taste perception, and overall hemostasis of the oral cavity. This direct environmental interaction makes saliva an ideal candidate for evolutionary pressures. An amazing example of this is the amylase gene (AMY), which codes for a starch-digesting enzyme in animals. Previous studies have found that AMY underwent several gene copy number gains in humans, dogs and mice, possibly along with increased starch consumption during the evolution of these species. In this study, we present comprehensive evidence for AMY copy number expansions that independently occurred in several mammalian species which consume diets rich in starch. We also provided correlative evidence that AMY gene duplications may be an essential first step for amylase to be expressed in saliva. Our findings underscore the overall importance of gene copy number amplification as a flexible and fast evolutionary mechanism that can independently occur in different branches of the phylogeny. In this study, I led the collaborative effort to collect mammalian DNA and saliva samples from across the globe, including wolves, African pouched rats, wild boars, and non-human primates, to name a few. Additionally, during this effort I was able to deduce that the likely mechanism for independent AMY duplication was through retrotransposon events. Overall, the experience in this project connected my training in bioinformatics to the wet-lab bench involving enzymatic activity in saliva, providing me with project I was able to take full circle.
3. Novel Mechanism for Mucin Evolution.
Mucin proteins are highly glycosylated molecules critical for mucus generation, cellular signaling, and microbial interactions on epithelial surfaces. Functionally, mucins share proline-, serine-, and threonine-rich (PTS) repeats that serve as O-glycosylation sites. However, unlike several other homologous gene families, several mucin subfamilies have evolved independently. The mechanisms through which these mucins evolved remain mostly unknown. In this on-going study we did a genome-wide analysis to find how conserved mucins are in other mammalian species. We identified that the secretory calcium-binding phosphoprotein (SCPP) gene locus is a hotspot for de novo mucin evolution in mammals. Further bioinformatic analysis of this locus documented 27 hitherto undescribed mucins, highlighting 15 instances of independent mucin evolution. We confirmed the expression of a subset of these mucins in saliva using gel electrophoresis and subsequent mass-spectrometric analysis. We constructed a plausible model arguing that the secretory and proline-rich nature of proteins encoded by genes in the SCPP locus provides fodder for recurrent mucinization. Our results have broad implications for understanding the evolution of gene families coding for O-glycosylated secreted multiple-repeat-domain proteins.
Collectively, in a world where communication between medical doctors, scientists, and the general public is often inefficient, I aim to bridge this gap as a scientist in medical and evolutionary genetics and make it mutually understandable across fields. With current treatments being tailored to individuals in things like precision medicine and gene therapy, my hope is to one day generate basic research-based breakthroughs that may lead to foundational treatments.