Genetic variation contributes to evolution and is also linked to disease-from well-known single-gene disorders to complex multifactorial conditions. Understanding the role of genetic variation is essential for advancing human health and developing strategies to combat disease.
Our lab focuses on understanding how highly conserved regions, including those that have remained unchanged since the divergence of mammals, birds, and reptiles (ultraconserved elements, UCEs), contribute to genome stability, integrity, and human health. While many such regions harbor gene regulatory activity, such activity cannot fully explain extreme conservation [1].
We propose a model in which sequence conservation contributes to genome integrity. Here, maternal and paternal regions compare their sequences such that mismatches trigger disease, infertility, or cell death[2-5]. In this way, strongly conserved sequences would safeguard the genome by recognizing and eliminating harmful rearrangements from the population, thus maintaining genome integrity.
To pursue this idea, we are studying the relationship between sequence conservation and genetic variation on a broad scale. Rather than focusing on individual genes, we analyze the correlation between conserved DNA regions, genetic variation, and health. We have already found that UCEs are unlikely to be deleted or duplicated by copy number variations (CNVs) in healthy individuals[4, 5]. In contrast, UCE copy number is altered by CNVs associated with cancer, autism, and developmental disorders [4, 5].
As our studies have relied primarily on published datasets, we aim now to expand this work by leveraging the UK Biobank’s extensive genetic data. By examining variations such as single nucleotide polymorphisms within or near conserved regions, we aim to identify relationships among these variations, conserved DNA regions, and health.
1. PMID: 33782603. 2. PMID: 16998490. 3. PMID: 18957701. 4. PMID: 25340765. 5. BioRxiv 10.1101-233197.
