{"doi":"10.7302/25008","title":"The Evolution of Large Genomic Amplicons and Their Contribution to Selfish Transmission","abstract":"Mendel’s law of segregation describes how parents have two copies of each gene (i.e., alleles), and one copy is transmitted randomly to offspring. To achieve random allele transmission, gametes (sperm or egg) carrying one parental allele must be equally capable of producing offspring. Selfish alleles break Mendel’s law of segregation by producing more fit gametes that are transmitted to >50% of offspring. Selfish alleles on mammalian ex chromosomes (XY) favor either X or Y transmission, resulting in unequal ratios of male versus female offspring. X- or Y-linked genes with selfish alleles are found in multiple copies on a single chromosome within large (>10kb), nearly identical (>99%) duplications, termed amplicons. Whether autosomal amplicons and their genes contribute to selfish transmission requires elucidation. I investigated the evolution of amplicons on the X chromosome and autosomes in mouse and whether autosomal amplicons contribute to selfish transmission. Mammalian sex chromosome evolution is characterized by suppressed meiotic crossing over (i.e., recombination) and an accumulation amplicons. Since suppressed recombination leads to an accumulation of deleterious mutations, initial studies of primate Y chromosomes proposed that Y-linked amplicons protect genes from deleterious mutations via gene conversion. Gene conversion is a “copy and paste” DNA repair mechanism that homogenizes sequences between duplications. Unlike the Y chromosome, X chromosomes freely recombine in females (XX) and are less likely to accumulate deleterious mutations. Thus, I asked whether X-amplicons undergo gene conversion despite recombining in females. I generated sequence assemblies of X-linked amplicons in closely related mouse species and compared sequences within and between mouse species (Chapter 2). Gene conversion between ampliconic duplications is evidenced by a higher sequence identity between duplications within a species relative to between species. My evolutionary sequence comparisons demonstrate that gene conversion between X-linked amplicon duplications is ongoing and can facilitate sequence evolution. I speculate that ampliconic gene conversion moderates the evolution of selfish alleles on the X chromosome. The t-haplotype (t) is a variant of mouse chromosome 17 where recombination is suppressed and capable of selfish transmission. At least four large inversions suppress recombination between the proximal half of the t and wt chromosome 17. Heterozygous male mice (wt/t) exhibit >99% transmission of the t. Whether amplicons evolved on the t and harbor selfish alleles is not known. Long molecule sequencing was used to generate the first sequence assembly of a t-haplotype. My most prominent discovery is the accumulation of t amplicons harboring selfish gene families (Chapter 3). Deletion of a ~1.8Mb t-ampliconic region reduces t transmission, supporting the contribution of t-amplicons to selfish transmission. By comparing the sequence order and copy number across chromosome 17 of closely related Mus species, I reveal three conserved amplicons harboring selfish t gene families mapping to the oldest inversions, implicating ampliconic genes in the origin of the t. I propose amplicons are critical to the evolution of selfish t-haplotype transmission. My studies highlight the crucial role of amplicons in the evolution of selfish transmission. Suppressed recombination of mammalian X and Y chromosomes led to an enrichment of amplicons that can influence selfish transmission. In many ways, t-haplotype evolution mirrors mammalian X and Y chromosome evolution. These findings suggest recombination suppression and amplicon acquisition may be genome-wide signatures of selfish transmission. Importantly, my research paves the way for future studies to explore the implications of selfish transmission on genome evolution.","journal":"Deep Blue (University of Michigan)","year":2024,"id":508290,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9444,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":415695,"name":"Callie M. Swanepoel","orcid":"0000-0003-3857-626X","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:11:06.395600Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}