George H. Perry - US grants

[unreadable] DESCRIPTION (provided by applicant): [unreadable] The goal of this study is to identify proteins whose expression levels have evolved under natural selection in humans and non-human primates. Variation in gene regulation, both at the transcriptional and translational levels, is thought to be involved in human phenotypic diversity including disease susceptibility, and is hypothesized to have played an important role in human evolution. Although most previous work in this area has focused on mRNA levels, proteins are usually more directly involved in biological processes. Moreover, complex translational regulatory mechanisms can influence protein levels independent of transcript abundance. Therefore, the characterization of variation in protein levels in humans and non-human primates is expected to provide considerable insight into the genomic mechanisms that may have played important roles in our evolutionary history. In this study, I will (i) develop an antibody microarray platform for highthroughput measurements of steady-state protein expression levels in multiple primate species, (ii) use this platform for comparisons of human, chimpanzee (Pan troglodytes), and rhesus macaque (Macaca mulatta) liver, kidney, heart, lung and testis tissues, and (iii) examine ratios of intra- and inter-specific variation to identify proteins whose expression levels have evolved under stabilizing selection across primates or directional selection in the human lineage. These proteins may be involved in human diseases, for example when expression levels are perturbed. Furthermore, proteins with adaptive changes in steady-state expression levels may have been important in the evolution of human-specific traits, which will be explored using analyses of protein functions and patterns of expression and natural selection by tissue. Variation in protein expression levels is thought to be involved in human phenotypic diversity including disease susceptibility, and may have played an important role in human evolution. This study will use highthroughput technologies to compare protein expression levels across five different tissues from humans, chimpanzees, and rhesus macaques, to identify proteins with expression levels that (i) are highly similar among the three primate species, and (ii) have significantly increased or decreased along the human lineage. Such proteins may be involved in human diseases, for example when expression levels are perturbed, and proteins with significant human lineage changes in expression levels may have been important in the evolution of physical traits that are unique to our species. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]

Humans arrived to the island of Madagascar only approximately 2,300 years ago. Since that time, humans have affected the island's environment and its unique biodiversity through deforestation and hunting practices. As a result, many Malagasy animal species are at risk for extinction. For example, over 70% of the island's 100 species of lemurs, the primates of Madagascar, are considered Endangered or Critically Endangered by the International Union for the Conservation of Nature. In addition, from unmineralized skeletal remains, we know of at least 17 now-extinct "subfossil" lemur species, some of which lived as recently as 500 years ago, or less. All of the extinct species were larger than every living lemur species, and some substantially so, up to the size of a male gorilla. This study aims to use ancient DNA methods and massively parallel sequencing technology for genetic studies of the extinct subfossil lemur species, and to make genetic comparisons between the extinct and living lemur species. These comparisons are important for understanding the history of the extinct species themselves, but also for broadening our understanding of the history of human-environment interactions on Madagascar and for identifying primary lemur extinction risk factors - knowledge which may influence the prioritization of conservation efforts for the still surviving lemur species. Researchers will sample bone and teeth from subfossil lemur skeletons to extract DNA and sequence complete mitochondrial genomes from single individuals of 14 of the 17 extinct subfossil lemur species, as well as from population samples of seven of these species. For comparative purposes, the researchers also will sequence complete mitochondrial genomes from populations of 10 living lemur species.

The proposed research will involve international collaborations between US academic institutions and the University of Antananarivo in Madagascar. This work will provide extensive training for both US and Malagasy graduate students, and will help build the capacity for genomics data analysis in Madagascar. In addition to the primary scientific publications resulting from this work, the conservation implications of the study will be summarized in an article submitted to the open access journal Madagascar Conservation & Development, facilitating broad dissemination of the conservation significance of the research results.

This CAREER project will apply new biological and computer science methods to study recent changes in the population sizes of humans, domesticated agricultural species, and endangered native animals all living in the same habitat. The results will help us understand how human population growth affects natural populations of wild species, and the complex interactions among people, domesticated animals, and the environment. The study will advance science through the development of new genomic methods and computational "big data" analyses (bioinformatics) for analyzing genomic data. These methods will initially be applied to a study of people, their cattle, and two endangered lemur species in Madagascar, which is an ideal site because humans first arrived to the island relatively recently (several thousand years ago). Research on human-environment interactions in other regions of the world, including North America where human-environment interaction started earlier, will also benefit from these methods. The educational component of the project will involve the annual delivery of bioinformatics training workshops to diverse audiences; participating students will develop biological and computer science skills that separately and together will have wide scientific and industrial training applicability.

The scientific aims of this proposal include reconstructing high-resolution demographic histories for Malagasy people, their commensal domesticated cattle, and two widely-distributed endemic lemur species, all with temporal resolution relevant to the recent timeline of human history on the island. These results, made possible by the application of novel population genomic methods developed by the principal investigator, will be compared to each other and to available paleoclimate data to develop an integrated empirical model of the history of anthropogenic effects on Madagascar's biodiversity. Madagascar is an important island for studying the processes and consequences of human-environment interaction. The people of Madagascar have an interesting history because of their relatively recent arrival to the island, their mixed Austronesian and African ancestry, and because of their relationship to one of the world's most biologically diverse, endemic and threatened ecologies. This work will empirically transform our understanding of the history of anthropogenic effects on Madagascar's biodiversity and establish an integrative research framework for application to other regions of the world where Holocene resource use intensification and human-environment interaction are likewise topics of major interest. A centerpiece of the educational component of this project is the annual delivery of interactive-style bioinformatics training workshops that build on the integration of biological and computational science that is central to the research. The most advanced workshop will be integrated with the project's scientific aims through ?hackathon?-style development of computational tools for analyses of the genomic data generated in this study. Joint funding for this project is provided by the National Science Foundation's Office of International Science and Engineering (OISE).

? DESCRIPTION (provided by applicant) We propose a functional genomics investigation of differential immune system and growth hormone responses, using a novel comparative population approach with a natural human model. The cultural transition to agriculture that began ~12,000 years ago precipitated a major shift in the burden of human endemic infectious diseases. The vast majority of modern humans now live in agriculture-based societies, with an evolutionary history shaped in part by these relatively recent infectious disease profile changes. Most genetic association studies of disease - or of the related functional genomic response to disease - that have been conducted to date have focused exclusively on agriculture-based populations. Yet direct comparisons between agriculturalist and hunter-gatherer populations would provide important, novel insights into how evolutionary responses to the agricultural transition have influenced human physiology. This is true for both the modern human disease response and other biological traits that differ between agriculturalists and hunter-gatherers, such as body size. In the proposed study we will investigate the differential immune system and growth hormone responses between an agriculturalist and hunter-gatherer population using a powerful in vitro system in which the cells of 50-89 individuals from each population will be challenged with growth hormones and ligands that mimic viral and bacterial infections, followed by RNA-seq to identify genome-wide population differences in the regulatory responses. These results will then be compared to genome-wide SNP genotype and targeted resequencing data to identify and characterize genetic loci with potential functional and evolutionary significance for inter- population immune response and body size differences. These integrated analyses will contribute to our understanding of human growth and development functional genomic pathways and also shed light on how the human immune system has been affected by the cultural transition to agriculture, thereby advancing our understanding of the modern human disease response and medical outcomes.

Syphilis is a sexually transmitted infection (STI) caused by Treponema pallidum subp. pallidum bacteria. It has recently reemerged as an urgent worldwide health crisis. The origin of the disease has been a mystery since its sudden appearance in Europe at the end of the 15th century and its subsequent rapid global spread. It has long been debated whether syphilis was introduced to Europe, perhaps from the Americas, or evolved from a form of treponemal infection that had been in Europe all along. Graduate student Ziyu Wang and collaborators at The Pennsylvania State University will take a multi-faceted approach to investigate the pathogen's genetic diversity over the past 500 years in Europe to explore several possibilities to explain syphilis' origin in Europe. The current T. pallidum pathogens - associated with several related diseases - likely represent only the most successful or recently emerged genetic variants. Examined through an anthropological lens, ancient genomes when considered within the context of human sociocultural systems yield clues about the processes through which pathogens have achieved their evolutionary success. Ultimately a more informed understanding of the factors that contribute to the complex and dynamic interactions between humans and their pathogens provides a deep-time foundation for predicting the evolutionary trajectories of modern infectious pathogens and human responses. Today, as in the past, STI-related stigma has done much to interfere with the development and implementation of effective intervention programs. Lessons learned from historic epidemics and the public response will provide valuable tools for training healthcare professionals, STI high-risk groups, and the public.

To untangle syphilis' origin, its evolution, and its worldwide spread, the research team will sequence T. pallidum genomes from representative specimens sampled from temporally and socially well-characterized European skeletal assemblages dating to the 16th to 19th centuries. Ancient T. pallidum has previously not been well studied because of the limited ability of conventional genetic techniques (e.g., polymerase chain reaction) to recover highly-degraded ancient pathogen DNA. Here a sensitive targeted hybridization capture technique will be used to recover complete, or near-complete, ancient T. pallidum genomes. By comparing temporally known ancient pathogen genomes with their modern equivalents, the research team can track the sequential changes that occurred in the pathogen's genetic history. Doing so will narrow the possible evolutionary scenarios for the origin of syphilis and point to when the pathogen variant that causes syphilis first emerged.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.