Transcription of human-specific duplicate genes

Abstract

In this work, I set out to characterize new genes contained specifically within the human genome but absent from any other, including our closest evolutionary cousins. Our interest in these genes is twofold: First, gene duplication is a fundamental process by which evolutionary innovations at the organismal level arise; and second, we believe that variation in these new genes is an important and unappreciated source of phenotypic differences between individuals, both normal and pathogenic. The ability to interpret observed variation in a gene, such as to determine if a mutation in that gene is likely to be impactful, requires quality annotation. This includes an understanding of gene structure: how the gene is transcribed, processed, and which base pairs code for protein or have other specific roles. The major challenge presented by this category of genes is that they are highly identical to other parts of the genome, and as such, most methods of investigation struggle to tell them apart. As will be expanded upon, this annotation is currently absent or insufficient for genes that are specific to the human genome. Combined with evolutionary and expression analysis, solving this annotation problem enables us to understand how new genes are created in the human genome at the very earliest stages. Combined with surveys of natural occurring and pathogenic variation, it enables us to understand which new genes are functional and which are not, and among those with function, which harbor deleterious variants that can cause disease. With these goals in mind, I set out to solve the annotation of human-specific duplicate genes most promising for functional status. I performed a close study of one such gene, HYDIN2, where I present an evolutionary analysis that gives insight into gene creation and associated disease mechanism, present a survey of naturally occurring variation, and describe the complex transcriptional pattern of a gene that serves as a case study in how duplication and rearrangement of genome segments can lead to rapid gene innovation. Next, I present a technique to more rapidly and rigorously study the transcription of any recently created duplicate gene. I apply this technique to the body of human-specific duplicate genes as well as other expanded gene families. I show that by improving upon current annotations we gain insight into the structural history, expression pattern, and functional status of such genes. I conclude with logical next steps and promising future directions. Ultimately, this work increments our understanding of how gene duplication leads to evolutionary innovation specifically in human, the functional impact of these species-specific differences, and how variation in these genes can contribute to disease.