Genetic Studies of Large Palindromes

Arrays of large, nearly identical, palindromic DNA sequences in mammals are rare in the genome. What benefit large palindrome arrays have to the genome, or an organism remains unclear. A few studies of large palindrome arrays on the mouse X and Y chromosomes reveal they can result in selfish chromosome transmission and be necessary for male fertility. Due to the large megabase size, high levels of nucleotide identity between palindrome arms, and multicopy nature, large palindrome arrays have been challenging to resolve and study experimentally. Moreover, our understanding of large palindrome arrays on autosomes is largely nonexistent. Here, we propose to overcome these barriers by using recent haplotype-resolved genome assemblies to identify, genome-wide, and comprehensively characterize seven of the 14 large palindrome arrays in mice. We hypothesize large palindrome arrays evolve to favor their own inheritance and are necessary for fertility. We will test our hypothesis via two aims. Aim 1 will determine whether two autosomal large palindrome arrays contribute to selfish chromosome transmission when heterozygous and are necessary for fertility when homozygous. Aim 2 will determine whether the five large palindrome arrays on the X chromosome cooperate or compete to influence selfish chromosome transmission or fertility. The simultaneous characterization of large palindrome arrays on autosomes and the sex chromosomes can provide a unifying view of palindrome arrays in selfish chromosome transmission and necessity in fertility. Our studies will enable new studies of these largely overlooked genomic regions and their associated genes in all species, including humans. Our research efforts will provide the foundation for mechanistic insights into their associated genes’ roles in influencing fertility, chromosome evolution, and speciation. Project Number: 1R01HD119706-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Jacob Mueller | Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR, ANN ARBOR, MI | Award Amount: $2,207,672 | Activity Code: R01 | Study Section: Genetic Variation and Evolution Study Section[GVE] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HD11970601A1