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Low Copy RepeatsEdit

Low copy repeats, commonly abbreviated as LCRs, are substantial blocks of DNA that occur in multiple locations in the genome. Also known as segmental duplications, these regions are typically at least 1 kilobase long and share a high degree of sequence identity. In the human genome, LCRs are a major source of structural variation and a key driver of rearrangements that can shape genome architecture over time. They play a dual role: they fuel evolutionary innovation by duplicating genes and regulatory elements, yet they also create vulnerabilities that can lead to disease when misalignment during recombination occurs. The study of LCRs sits at the intersection of evolutionary biology, clinical genetics, and genomics, and continues to illuminate how genomes balance stability with change. For more on the broader context of genomic structure, see Copy number variation and Segmental duplication.

Structure and distribution

LCRs are characterized by their length and high sequence similarity. They typically range from about 1 kb up to several hundred kilobases, and their sequence identity often exceeds 90%, with many regions approaching near-complete identity. This high similarity makes them prone to misalignment during meiosis, which in turn can drive unequal crossing over and the formation of deletions or duplications. For a broader discussion of the mechanism, see non-allelic homologous recombination.

Geographically, LCRs are dispersed throughout the genome, but they cluster in certain hotspots, including pericentromeric and subtelomeric areas and gene-rich regions. Some chromosomes harbor prominent LCR-rich segments that are known to underlie recurrent rearrangements. The architecture of LCRs is a major factor in shaping regional variation in copy number across individuals, a phenomenon studied under the umbrella of copy number variation.

Mechanistically, the creation of new LCRs and the rearrangements they promote can arise from replication-based processes (such as microhomology-mediated events) in addition to classical recombination. The consequence is a dynamic genome in which regions of high identity not only duplicate genes or regulatory elements but also predispose the genome to recurrent, recurrently stable patterns of deletion and duplication.

Roles in genome evolution, health, and disease

LCRs contribute to genome evolution by generating fresh copies of genes and regulatory sequences, which can acquire novel functions or expression patterns over time. A well-known example involves duplications within certain gene families that have been implicated in neural development and brain evolution, such as those connected with the SRGAP2 gene family. See SRGAP2 for related discussion on how segmental duplications may have influenced human neural development.

From a medical perspective, NAHR between LCRs is a major mechanism behind several well-characterized genomic disorders. Deletions or duplications arising from these rearrangements can disrupt genes or perturb regulatory networks, leading to a spectrum of developmental and clinical features. Notable examples include: - Smith–Magenis syndrome, associated with a deletion in the 17p11.2 region, which is flanked by LCRs and arises through NAHR. See Smith–Magenis syndrome. - Charcot–Marie–Tooth disease type 1A, caused by a tandem duplication of the PMP22 gene region on 17p12, a change driven by LCR-mediated misalignment. See Charcot–Marie–Tooth disease and PMP22. - 22q11.2 deletion syndrome (DiGeorge/Velocardiofacial syndrome), a widely studied condition generated by rearrangements between LCRs in that locus. See DiGeorge syndrome. - 1q21.1 deletion and duplication syndromes, which reflect recurrent rearrangements in LCR-rich segments on chromosome 1. See 1q21.1 deletion syndrome and 1q21.1 duplication syndrome. - 16p11.2 deletion and duplication syndromes, another set of rearrangements mediated by LCRs with associations to neurodevelopmental outcomes and body habitus. See 16p11.2 deletion syndrome and 16p11.2 duplication syndrome.

Beyond these named disorders, LCRs are implicated in a range of other pathogenic rearrangements and are a focus of ongoing research into cancer genomics, where rearrangements in LCR-rich regions can disrupt tumor suppressor genes or activate oncogenes. In clinical practice, detecting LCR-associated CNVs relies on complementary methods, including array-based approaches and sequencing technologies, to resolve the structure and breakpoints of rearrangements. See Copy number variation and Non-allelic homologous recombination for additional context on detection and interpretation.

Detection, research methods, and interpretation

Advances in sequencing technologies and mapping methods have improved the ability to characterize LCRs and the rearrangements they mediate. Long-read sequencing platforms, such as those developed for single-molecule sequencing, help span repetitive LCRs that are difficult to resolve with short reads. See Long-read sequencing for details. Optical mapping and high-resolution fluorescence in situ hybridization (FISH) provide complementary views of large structural changes in LCR-rich regions. For comparative analyses across populations, researchers rely on maps of Copy number variation and the underlying architecture provided by Segmental duplication.

Research on LCRs also informs our understanding of human evolution and population history. By tracing duplication events and their maintenance in different lineages, scientists reconstruct how genomes adapt while balancing the risk of deleterious rearrangements. This work sits alongside broader studies of Genome evolution and the functional consequences of gene dosage changes in humans.

See also