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Copy number variation

Copy number variation (CNV) is a form of structural genetic variation in which the number of copies of one or more sections of the genome differs among individuals, typically involving DNA segments larger than 1,000 base pairs (bp) and including such as duplications and deletions.^[1]^[2]^[3] CNVs are prevalent across human populations, collectively accounting for approximately 12% of an individual's genomic variation when considering both germline and somatic changes, and they contribute significantly to inter-individual differences beyond single nucleotide polymorphisms (SNPs).^[4]^[5] These variations play a crucial role in human evolution by driving genetic diversity and adaptation, such as through gene dosage effects that influence phenotypic traits and species divergence.^[3]^[6] In health and disease, CNVs are implicated in a wide array of conditions, including neurodevelopmental disorders like autism and schizophrenia, congenital anomalies, and cancers, where altered gene copy numbers can disrupt normal cellular function or promote oncogenesis.^[3]^[7]^[8] Advances in genomic technologies, such as array comparative genomic hybridization (aCGH) and next-generation sequencing, have facilitated the identification and characterization of CNVs, enhancing our understanding of their functional impacts.^[5]

Fundamentals

Definition and Characteristics

Copy number variation (CNV) is a form of structural variation in the genome characterized by deletions, duplications, or insertions of DNA segments, typically ranging from 1 kilobase (kb) to several megabases (Mb) in length, that result in abnormal copy numbers—such as 0, 1, or more than 2 copies—of genes or regulatory elements compared to a reference genome.^[9] These variations alter the genomic architecture without necessarily changing the DNA sequence itself, distinguishing them as a key contributor to inter-individual differences.^[10] CNVs are widespread across the human genome, collectively spanning approximately 12% of its sequence and affecting hundreds of genes.^[11] They can occur as germline variants, present in all cells and heritable across generations, or as somatic variants, arising post-zygotically in specific tissues and thus non-inheritable.^[12] By definition, CNVs represent unbalanced structural changes that lead to a net gain or loss of genetic material, in contrast to balanced rearrangements like inversions or translocations that preserve overall dosage.^[13] This imbalance often modifies gene dosage—the relative amount of gene product—potentially disrupting expression levels, regulatory networks, or protein function, with effects ranging from neutral to pathogenic depending on the affected region.^[14] In comparison to other genetic variants, CNVs differ markedly from single nucleotide polymorphisms (SNPs), which involve substitutions at single base positions and primarily affect sequence specificity rather than quantity, and from insertions/deletions (indels), which are smaller events usually under 1 kb that may cause frameshifts but seldom span multiple genes.^[15] The larger scale of CNVs enables them to influence broader genomic contexts, such as gene families or enhancers, amplifying their potential for dosage-related impacts.^[16] Fundamentally, CNVs enhance genetic diversity by providing a mechanism for rapid evolutionary adaptation and phenotypic variation, as their duplication events can expand gene repertoires without the constraints of point mutations.^[17]

Historical Discovery

Prior to the 2000s, copy number variations (CNVs) were largely viewed as rare, pathogenic structural alterations in the genome, often associated with congenital syndromes detectable through cytogenetic techniques. For instance, the 22q11.2 deletion linked to DiGeorge syndrome was first identified in the early 1980s using cytogenetic methods, with submicroscopic deletions confirmed via fluorescence in situ hybridization in the early 1990s.^[18] These early observations framed CNVs primarily as disease-causing anomalies rather than common polymorphisms.^[19] The paradigm shifted dramatically between 2004 and 2006 with the application of array-based comparative genomic hybridization (array CGH) and single nucleotide polymorphism (SNP) arrays, which enabled genome-wide detection of structural variants. Sebat et al. (2004) demonstrated the existence of large-scale copy number polymorphisms (>100 kb) in the human genome, identifying dozens of such variants among normal individuals using representational oligonucleotide microarray analysis (ROMA). Building on this, Redon et al. (2006) cataloged 1,447 CNV regions spanning over 12% of the genome across diverse populations, establishing CNVs as a major source of genetic diversity comparable to SNPs.^[9] These studies marked the recognition of CNVs as widespread, benign polymorphisms rather than solely pathological events. Following these breakthroughs, CNVs were integrated into large-scale genomic projects starting around 2010, providing deeper insights into their prevalence and impact. The 1000 Genomes Project, launched in 2008 and yielding key results from 2010 onward, systematically characterized CNVs alongside other variants in over 1,000 individuals from multiple ancestries, revealing the prevalence and diversity of CNVs and their contribution to human genetic variation through altered gene dosage and regulatory elements. This effort expanded the known CNV catalog to thousands of loci, highlighting their role in population diversity and facilitating downstream association studies.^[20] By 2024–2025, advancing sequencing technologies and diverse cohort analyses have further emphasized CNVs as key drivers of complex traits and phenotypic variation. Studies using large biobanks like the UK Biobank and SPARK have shown that CNV frequencies vary significantly across genetic ancestry groups, with specific recurrent CNVs exhibiting up to twofold differences that influence trait heritability and disease risk.^[21] This recent recognition underscores the need for ancestry-aware CNV mapping to refine understandings of human genomic diversity.^[22]

Types and Mechanisms

Classification of CNVs

Copy number variations (CNVs) are classified based on the nature of the copy number change, which can involve gains, losses, or more intricate combinations. Gains, also known as duplications or amplifications, refer to genomic segments with more than two copies, leading to increased gene dosage in affected regions.^[3]^[23] Losses, or deletions, occur when fewer than two copies are present, resulting in reduced or absent gene function.^[3]^[23] Complex CNVs encompass multiallelic combinations where multiple copy number states coexist within a single variant, often involving both gains and losses in close proximity or through intricate rearrangements.^[24]^[25] CNVs are further categorized by size and resolution, reflecting their detectability and biological impact. Typically, CNVs range from 1 kilobase (kb) to several megabases (Mb) in length; variants smaller than 1 kb are generally classified as insertions or deletions rather than CNVs and are often overlooked by standard detection methods.^[1] Segmental duplications, a subset of CNVs, involve larger duplicated blocks (often 10-300 kb) that can be tandem (adjacent repeats) or dispersed (non-adjacent across chromosomes), contributing to genomic instability.^[26]^[27] Inheritance patterns distinguish germline CNVs, which are heritable and polymorphic (varying across populations), from de novo CNVs that arise anew in the offspring and are not present in parental genomes.^[28]^[25] Germline CNVs are transmitted through generations and can be benign polymorphisms, while de novo events often carry higher pathogenic potential, particularly in neurodevelopmental disorders.^[29]^[25] The genomic context of CNVs provides additional classification based on location and orientation. CNVs can occur in intergenic regions (between genes), intragenic regions (within genes, affecting exons or introns), or regulatory elements (such as promoters or enhancers), influencing gene expression variably.^[30]^[31] They may be tandem, where duplicated segments are contiguous, or non-tandem (dispersed or insertional), where copies are separated by other genomic material, with tandem forms more prone to disrupting gene structure.^[32]^[33] Standard nomenclature for CNVs follows guidelines from the Database of Genomic Variants (DGV) and Human Genome Variation Society (HGVS), using formats like "chr1:1000000-2000000 dup" to denote a tandem duplication on chromosome 1 from position 1,000,000 to 2,000,000, or "del" for deletions, ensuring precise description of location, type, and size.^[34]^[35] This system facilitates consistent reporting and integration across databases, aiding in the interpretation of CNV diversity.^[36]^[35]

Molecular Mechanisms of Formation

Copy number variations (CNVs) arise primarily through error-prone DNA repair and replication processes that generate structural rearrangements in the genome. These mechanisms include homologous recombination errors, double-strand break (DSB) repair pathways, and replication fork instabilities, often mediated by repetitive genomic elements such as low-copy repeats (LCRs) or segmental duplications (SDs). Recurrent CNVs, which occur at specific hotspots, are typically produced by precise misalignment events, while non-recurrent CNVs result from more variable, error-prone processes.^[37] Non-allelic homologous recombination (NAHR) is a key mechanism for recurrent CNVs, occurring when highly similar but non-allelic sequences, such as LCRs, misalign during meiosis or mitosis, leading to deletions or duplications of the intervening genomic segment. This process is facilitated by the homology length of LCRs, with longer repeats (typically >1 kb and >95% identity) increasing recombination frequency by promoting strand invasion and crossover resolution. NAHR hotspots are enriched in regions with clustered SDs, which constitute about 5-10% of the human genome and are a primary mechanism underlying many disease-associated recurrent CNVs.^[37] Non-homologous end joining (NHEJ) and microhomology-mediated break-induced replication (MMBIR) contribute to non-recurrent CNVs by repairing DSBs through error-prone pathways that often involve short stretches of microhomology (2-15 bp) at breakpoints. NHEJ directly ligates broken ends with minimal processing, frequently introducing small insertions or deletions, and is prevalent in post-replicative cells where DSBs arise from environmental insults like ionizing radiation, which can elevate DSB rates by up to 10-fold. MMBIR, an extension of break-induced replication, initiates at stalled forks or DSBs, using microhomology to switch templates and copy distant sequences, resulting in complex rearrangements like inversions or tandem duplications observed in up to 50% of non-recurrent CNV junctions.^[38]^[39]^[40] Replication-based mechanisms, such as fork stalling and template switching (FoSTeS), generate CNVs during S-phase when replication forks encounter obstacles like repetitive sequences or secondary structures, causing temporary stalling and subsequent template switching to nearby homologous regions. This process, akin to MMBIR but focused on active replication, produces non-recurrent CNVs with junction microhomologies and is implicated in about 30% of complex genomic rearrangements in the human genome. FoSTeS is particularly active in SD-rich regions, where fork collapse rates can be 5-10 times higher than in unique sequences.^[41]^[37] Additional mechanisms include transposon-mediated events, where mobile elements like LINEs or Alu sequences facilitate unequal recombination or excision, contributing to ~10% of CNVs through insertion-induced breaks or NAHR between homologous repeats. Viral integrations can similarly induce CNVs by creating DSBs at integration sites, though this is rarer in germline contexts. CNV frequency is highest in genomic hotspots defined by SDs and LCRs, which account for over 70% of recurrent events and correlate with elevated mutation rates due to their repetitive nature.^[42]^[43]^[44]

Detection Methods

Traditional Techniques

Traditional techniques for detecting copy number variations (CNVs) predate next-generation sequencing and primarily relied on cytogenetic and molecular methods to identify large-scale chromosomal imbalances. These approaches, developed in the late 20th century, enabled the visualization and quantification of CNVs at resolutions sufficient for clinical diagnostics but were limited in detecting smaller variants. Karyotyping, a foundational cytogenetic method, involves culturing cells to arrest them in metaphase, staining chromosomes with Giemsa to produce banding patterns, and microscopically examining for structural abnormalities such as deletions or duplications.^[45] This technique can detect CNVs larger than 5–10 Mb across the entire genome, providing a broad overview of chromosomal architecture in a single cell analysis.^[45] Its strengths include the ability to identify aneuploidies and balanced translocations in individual cells, making it valuable for prenatal and cancer diagnostics since its introduction in the 1950s.^[45] However, limitations include low resolution for submicroscopic CNVs, labor-intensive cell culturing (taking several days), and subjectivity in interpretation, restricting its utility to large-scale events.^[45]^[46] Fluorescence in situ hybridization (FISH) enhances karyotyping by using fluorescently labeled DNA probes that hybridize to specific chromosomal loci, allowing visualization of targeted regions under a microscope without requiring metaphase spreads.^[45] It detects CNVs in the 100 kb to 1 Mb range for known loci, offering higher specificity for confirming abnormalities identified by karyotyping.^[46] Strengths lie in its applicability to non-dividing cells and rapid turnaround (hours to days), which facilitated its widespread adoption in the 1990s for diagnosing microdeletion syndromes.^[45] Limitations include its targeted nature, requiring prior knowledge of suspect regions, and inability to scan the whole genome, making it unsuitable for de novo discoveries.^[45]^[46] Comparative genomic hybridization (CGH), introduced in 1992, compares test DNA from a sample with reference DNA by differentially labeling them with fluorescent dyes and hybridizing to normal metaphase chromosomes, where ratio imbalances indicate copy number gains or losses.^[47] This genome-wide method detects CNVs greater than 5–10 Mb without cell culturing for the test sample, marking a shift toward molecular cytogenetics in the 1990s.^[45] Its strengths include comprehensive scanning for imbalances in solid tumors and constitutional disorders, but limitations such as reliance on metaphase resolution and poor detection of small or low-level mosaics constrained its precision.^[45] Array-based CGH (aCGH), an evolution from 1998, replaces metaphase spreads with microarrayed genomic probes (e.g., BAC clones or oligonucleotides), enabling ratio-based detection of CNVs at resolutions of 50–100 kb depending on probe density. This high-throughput platform revolutionized CNV analysis in the 2000s by allowing simultaneous interrogation of thousands of loci, with strengths in unbiased genome-wide coverage and improved sensitivity for submegabase variants compared to traditional CGH.^[45] Limitations include potential biases from probe hybridization efficiency and challenges in distinguishing benign polymorphisms from pathogenic CNVs, often requiring validation.^[45] SNP microarrays, adapted for CNV detection in the mid-2000s, utilize genotyping platforms like those from Affymetrix or Illumina to measure signal intensities and B-allele frequencies (BAF) at polymorphic sites, inferring copy number states from deviations in these metrics.^[45] With resolutions of 10–40 kb, they excel in integrating CNV calling with genotyping for population studies, as demonstrated in early applications that identified thousands of common variants.^[45] Strengths include cost-effectiveness for large cohorts and detection of loss of heterozygosity alongside CNVs, but limitations involve sparse coverage in repetitive regions and reduced sensitivity for rare or small events.^[45] Multiplex ligation-dependent probe amplification (MLPA), introduced around 2002, is a targeted molecular technique that uses multiple probes to detect copy number changes in up to 50 specific genomic loci in a single reaction by comparing probe amplification products via capillary electrophoresis.^[48] It achieves resolution at the single exon to multi-gene level, making it ideal for clinical confirmation of known CNVs in diagnostic panels for genetic disorders like Duchenne muscular dystrophy or hereditary cancers. Strengths include high throughput, low cost per locus, and no need for custom probe design for commercial kits, enabling rapid analysis (1-2 days). Limitations are its reliance on predefined targets, potential for probe failures in GC-rich regions, and need for orthogonal validation for novel variants.^[49] Quantitative PCR (qPCR) provides a targeted approach for validating or detecting CNVs at specific loci by amplifying test and reference regions and comparing amplification efficiencies via the ΔΔCt method, where fold change in copy number is calculated as $2^{-\Delta\Delta C_t}.^[50] This real-time PCR technique, refined for CNV in the early 2000s, offers high sensitivity for known regions with resolutions down to single-copy changes using standard curves or relative quantification.^[50] Its strengths are speed (hours), low cost, and precision for confirmation studies, but it is limited to predefined targets, introducing biases from primer efficiency and inability to discover novel CNVs genome-wide.^[50] Overall, these traditional methods drove key CNV discoveries in the 2000s, such as population-wide variant catalogs, but their low resolution for small CNVs (<50 kb) and reliance on known regions highlighted the need for higher-throughput alternatives.^[45]

Advanced Sequencing-Based Approaches

Whole-genome sequencing (WGS) has become a cornerstone for high-resolution CNV detection since the early 2010s, leveraging read depth analysis to infer copy number states by comparing observed sequencing coverage to expected levels in a diploid reference genome. The core principle relies on the formula for expected depth ratio in diploid contexts:

\text{Expected depth ratio} = \frac{\text{copy number}}{2}

where deviations from this ratio indicate gains or losses, after normalization for sequencing biases.^[51] Tools like CNVnator, introduced in 2011, apply mean-shift segmentation to binned read depths, achieving sensitivities of 86–96% for CNVs larger than 1 kb while minimizing false positives through noise reduction via total variation penalty.^[52] Control-FREEC, developed around the same period, complements this by using circular binary segmentation and kernel density estimation to call both copy number changes and allelic imbalances, performing robustly on tumor-normal pairs with tunable parameters for varying coverage depths.^[53] These methods have been benchmarked extensively, showing improved precision for germline CNVs when integrated with discordant read-pair signals, though they require at least 30× coverage for reliable small-event detection.^[54] Exome sequencing (WES) extends CNV calling to targeted datasets by exploiting off-target reads—those aligning outside exonic capture regions—to achieve sparse genome-wide coverage, enabling detection of intergenic and intronic variants often missed by on-target analysis alone.^[55] Advances in 2024, such as the ECOLE deep learning caller, utilize transformer architectures to denoise read depth signals from WES, outperforming traditional hidden Markov models in sensitivity for somatic and germline events across heterogeneous cohorts.^[56] By 2025, ensemble approaches integrating CNV callers into WES pipelines have boosted diagnostic yields in rare diseases, with retrospective analyses showing additional diagnoses in 1–10% of unsolved cases, raising overall yields from approximately 25% to 30–40% in diverse pediatric populations.^[57] For instance, tools like SavvyCNV normalize off-target depths via principal component analysis, facilitating scalable genome-wide profiling without full WGS costs.^[58] Long-read sequencing platforms, including PacBio's highly accurate circular consensus sequencing (HiFi) and Oxford Nanopore Technologies (ONT), have revolutionized CNV detection post-2015 by spanning repetitive and homologous regions that confound short-read assembly, directly resolving complex structural variants like nested duplications or inversions with insertions.^[59] Benchmarking in 2024 revealed PacBio HiFi modes yielding higher recall rates (up to 95%) for CNVs in challenging loci compared to ONT or short-read baselines, with error rates below 1% enabling precise breakpoint delineation even in low-complexity DNA.^[59] These technologies excel for variants missed by short reads, such as those in centromeric or segmental duplications, and have been pivotal in de novo assemblies revealing novel CNVs in clinical genomics.^[60] Tools like cuteSV and SVIM integrate long-read alignments for phased CNV calling, supporting applications in population-scale studies where short-read methods achieve only 70–80% concordance.^[61] Single-cell and low-pass WGS approaches address heterogeneity in tissues like tumors, using shallow coverage (0.1–1×) to profile CNVs across thousands of cells without amplification artifacts. The 2025 SCICoNE tool employs a Bayesian MCMC framework to infer copy number profiles and evolutionary event histories from single-cell DNA sequencing, particularly for somatic CNVs, by modeling branching phylogenies from read depth bins.^[62] A 2024 benchmarking study in Genome Biology evaluated NGS-based somatic CNV callers, demonstrating sensitivities exceeding 90% for events larger than 10 kb at low coverage, with ensemble strategies reducing false discovery rates to under 5% in simulated and real tumor datasets.^[63] These methods, often combined with scRNA-seq for multimodal validation, enable high-throughput subclonal reconstruction but demand robust noise models to handle cell cycle variations.^[64] Ensemble methods aggregate outputs from multiple callers to mitigate individual tool biases, with the 2025 EMcnv framework using meta-learning on heterogeneous graphs to fuse read depth, split-read, and paired-end signals, achieving up to 15% gains in F1-score over single algorithms in diverse WGS cohorts.^[65] Addressing population stratification, 2024 studies incorporated ancestry-aware adjustments, such as principal component-based normalization, to correct for allele frequency differences in non-European genomes, reducing false positives in CNV burden analyses by 20–30%.^[21] Despite these innovations, persistent challenges include GC bias correction—often via LOESS or lowess smoothing to equalize coverage in AT/GC-rich regions—and high computational demands, with segmentation algorithms requiring GPU acceleration for terabyte-scale datasets to maintain runtime under 24 hours.^[66]^[67]

Evolutionary Roles

Natural Selection and Adaptation

Copy number variations (CNVs) serve as a key evolutionary substrate due to their polymorphic nature and elevated mutation rates, which are estimated to be 100 to 10,000 times higher than those of single nucleotide polymorphisms (SNPs), facilitating rapid generation of genetic diversity for adaptation.^[68] This higher mutability allows CNVs to respond quickly to selective pressures, particularly in regions prone to structural changes. Analysis of the 1000 Genomes Project phase 3 data from 2,504 human genomes revealed that common CNVs are enriched in immune-related genes, such as those encoding immunoglobulin domains, indicating their role in diversifying immune responses across populations.^[69] Positive selection has acted on specific CNVs to enhance adaptation to environmental challenges, including dietary shifts and pathogen exposure. For instance, copy number increases in the AMY1 gene, which encodes salivary amylase for starch digestion, show signatures of positive selection in populations reliant on high-starch diets, such as agricultural societies, where higher copy numbers correlate with improved enzymatic efficiency.^[70] Similarly, higher copy numbers of CCL3L1, a chemokine gene that inhibits HIV entry into cells, have been reported to confer resistance to HIV-1 acquisition, with individuals possessing more than two copies exhibiting up to an 80% reduced risk after controlling for confounders like age and CCR5 genotype, though this association remains controversial due to conflicting replication studies.^[71]^[72] Recent population-level studies highlight ongoing adaptive roles of CNVs, with differences in frequency across ancestries suggesting historical selection. A 2024 analysis in HGG Advances found that deleterious CNVs are less prevalent in non-European ancestry groups compared to Europeans in large cohorts like the UK Biobank, implying purifying selection may vary by ancestry to maintain fitness in diverse environments.^[73] Analogously, in plants like apple during domestication, CNVs contribute to genetic diversity and adaptation to cultivation pressures, mirroring potential human patterns where ancestry-specific CNV frequencies could underpin local adaptations.^[74] Neutral evolution and balancing selection also maintain CNV diversity, particularly in gene families where multiple alleles persist due to heterozygote advantages in complex traits. Balancing selection on deletion polymorphisms, for example, preserves ancient variants with exonic impacts identified in genome-wide association studies (GWAS), promoting polymorphism in traits like immune function.^[75] Integrated GWAS-CNV analyses further describe selection coefficients for these variants as stronger on average than for SNPs, underscoring CNVs' disproportionate evolutionary influence despite their lower overall frequency.^[76]

Impact on Gene Families

Copy number variations (CNVs) play a pivotal role in the expansion of gene families through mechanisms such as tandem duplications, which generate paralogous genes that can evolve new functions. In the human olfactory receptor (OR) gene family, the largest in the mammalian genome, tandem duplications have contributed to extensive copy number diversity, with approximately 50% of identified CNVs spanning multiple OR loci. This expansion facilitates subfunctionalization, where duplicate copies partition ancestral functions, and neofunctionalization, enabling adaptation to novel odorants, thereby enhancing sensory capabilities across populations.^[77]^[78] Conversely, CNVs involving deletions lead to gene family contraction, effectively pruning redundant or non-essential copies to streamline genomic architecture. In the major histocompatibility complex (MHC), structural variations including CNVs modulate immune response diversity while mitigating potential autoimmune risks from excessive variation. The classical MHC loci (HLA-A, B, C for class I; DR, DQ, DP for class II) are fixed, but allelic diversity and variations in non-classical genes influence pathogen resistance without compromising overall fitness.^[79] Natural selection acts on CNV-driven copy number differences within gene families, often correlating higher copy numbers with improved fitness in specific environments. For instance, populations under selective pressure exhibit elevated copies of certain paralogs, as seen in adaptive expansions linked to ecological challenges. Recent 2025 analyses demonstrate how CNVs enable rapid toggling between ecological niches by altering gene dosage, a dynamic observed in both human and plant systems, such as during apple domestication where CNVs in enzyme families parallel human sensory adaptations.^[80]^[81]^[74] These CNV-induced variations in family size, typically ranging from 1 to 20 copies, exert dosage effects that modulate expression networks, influencing downstream phenotypic traits without disrupting core functions. In expanded families, increased dosage amplifies signaling pathways, while contractions fine-tune regulatory balance, underscoring CNVs' contribution to evolutionary plasticity across taxa.^[82]

Biological and Clinical Implications

Associations with Human Diseases

Copy number variations (CNVs) are strongly implicated in a range of human diseases, particularly those involving neurodevelopmental and psychiatric disorders, where they disrupt gene dosage and contribute to pathogenicity through mechanisms such as haploinsufficiency. Recurrent pathogenic CNVs, such as the 22q11.2 deletion, are associated with DiGeorge syndrome (also known as 22q11.2 deletion syndrome), a condition characterized by congenital heart defects, immune deficiency, and developmental delays, with a prevalence of approximately 1 in 4,000 live births. This deletion typically spans 30-40 genes, leading to dosage imbalances that underlie the syndrome's multisystem effects. Similarly, de novo CNVs—those arising anew in the affected individual—are identified in 5-10% of cases of autism spectrum disorder (ASD), often involving large deletions or duplications that alter neurodevelopmental pathways.^[83]^[84] Many pathogenic CNVs exhibit incomplete penetrance, meaning not all carriers develop the associated phenotype, with penetrance estimates for neurodevelopmental CNVs often below 10% for intellectual disability based on updated analyses of recurrent variants. This variability complicates clinical interpretation and highlights the influence of modifier factors, such as second-hit mutations or environmental interactions. Recent studies have also revealed ancestry-related biases in CNV distribution; for instance, deleterious CNVs appear less prevalent in non-European ancestry groups compared to European groups in large cohorts like the UK Biobank, potentially due to ascertainment biases in population sampling rather than true biological differences. These findings underscore the need for diverse genomic datasets to accurately assess CNV risks across ancestries.^[85]^[86] Advancements in 2024-2025 have expanded understanding of CNV roles in adult-onset diseases. In Parkinson's disease, large-scale CNV analysis identified potentially disease-causing variants in 0.9% of patients versus 0.1% of controls, with an odds ratio (OR) of 1.67, particularly involving genes like PRKN and LRRK2. For psychiatric disorders, CNVs confer substantial risks, with recurrent deletions and duplications linked to schizophrenia, bipolar disorder, and ASD through shared neurodevelopmental disruptions, as detailed in comprehensive reviews emphasizing their high-impact contributions to multifactorial etiology. Diagnostic approaches have benefited from integrating CNV calling into whole-exome sequencing (WES), boosting yield by approximately 5-10% in rare disease cohorts previously undiagnosed by single-nucleotide variant analysis alone, enabling more precise identification of structural contributors.^[87]^[88]^[89] The primary mechanisms of CNV pathogenicity involve gene dosage alterations: deletions often cause haploinsufficiency, where reduced expression of one gene copy impairs function, while duplications may lead to toxic gain-of-function or imbalance in dosage-sensitive pathways. In schizophrenia, specific recurrent CNVs, such as those at 22q11.2 or 16p11.2, elevate risk with ORs ranging from 10 to 20, reflecting their disruption of critical synaptic and neuronal development genes. These dosage effects provide a conceptual framework for understanding CNV-driven diseases, prioritizing genes intolerant to copy number change in clinical genomics.^[90]^[91]

Somatic CNVs in Brain Development

Somatic copy number variations (CNVs) arise de novo during neurogenesis in the developing brain, primarily through replication errors such as double-strand breaks and non-allelic homologous recombination, leading to mosaic patterns in neural tissues.^[92] These post-zygotic events occur in neuronal progenitor cells, resulting in subpopulations of neurons with altered genomic content that persist into adulthood. In healthy human brains, studies using single-cell whole-genome sequencing have revealed that 10-25% of cortical neurons harbor at least one megabase-scale somatic CNV, with recent analyses reporting approximately 20.6% of brain cells affected across various amplification methods.^[93] This prevalence is higher in neurons (4-23.1%) compared to non-neuronal cells (4.7-8.7%), underscoring the role of proliferative divisions during corticogenesis in generating such mosaicism.^[94] Detecting these low-frequency mosaic CNVs presents significant challenges due to their subclonal nature and the technical limitations of bulk sequencing, which often masks variants present in fewer than 10% of cells. Breakthroughs in single-cell sequencing during the 2010s, including studies by McConnell et al. demonstrating CNVs in 13-41% of frontal cortex neurons and Cai et al. identifying clonal mosaic CNVs in pyramidal neurons, first revealed this widespread genomic heterogeneity.^[95]^[96] More recent advances, such as 2024 analyses integrating multiple amplification protocols (e.g., PicoPLEX and primary template-directed amplification), have improved resolution for megabase-scale events even at low coverage (~0.6x).^[93] In 2025, tools like SCICoNE, a statistical model using Markov chain Monte Carlo for copy number calling from shallow whole-genome sequencing data, enable accurate reconstruction of CNV histories in single cells, outperforming prior methods in handling amplification biases and low-input samples.^[62] Functionally, somatic CNVs contribute to neuronal diversity by altering gene dosage in key neurodevelopmental pathways, fostering variability in synaptic connectivity and excitability among otherwise identical neurons. For instance, megabase-scale duplications or deletions can modify expression of genes involved in neuronal migration and synaptogenesis, enhancing circuit-level adaptability without compromising overall brain function in healthy individuals.^[97] In pathological contexts, these variants link to neurodevelopmental disorders; somatic deletions, for example, are implicated in up to 29% of focal cortical dysplasia type II cases associated with epilepsy, where they disrupt mTOR signaling and promote malformed cortical architecture.^[98] From an evolutionary standpoint, somatic CNVs may enhance brain plasticity by introducing genomic variability that supports adaptive responses to environmental demands, potentially buffering against uniform vulnerability in neural populations. This mosaicism likely stems from elevated somatic mutation rates during neurogenesis, estimated at approximately 8-9 SNVs per cell division, reflecting the trade-off between proliferative demands and fidelity in progenitor cells.^[99] Recent 2024-2025 single-cell studies, including those mapping recurrent CNV hotspots near segmental duplications, further highlight how these variants drive tissue-specific evolution in the brain, with sub-telomeric enrichments suggesting mechanisms that promote functional diversification over generations.^[100]

Case Studies

Alpha-Amylase Gene Family

The alpha-amylase gene family exemplifies copy number variation (CNV) in humans, particularly at the AMY1 locus on chromosome 1p21.1, where tandem duplicates of the salivary amylase gene (AMY1) range from 2 to 17 copies per individual, with an average of about 6 copies.^[101]^[102] This contrasts with the nearby pancreatic amylase genes (AMY2A and AMY2B), which exhibit less extensive CNV and are primarily expressed in the pancreas rather than saliva.^[103] The structural complexity arises from repeated duplication events, creating a variable cluster that influences starch digestion efficiency.^[104] This CNV demonstrates adaptive significance tied to dietary shifts, as higher AMY1 copy numbers correlate with populations consuming starch-rich diets. For instance, agricultural groups like European Americans and Japanese average 6-8 copies, compared to 4-5 in low-starch hunter-gatherer populations such as the Biaka Pygmies or Yakut.^[105] Evidence from Perry et al. (2007) indicates positive selection favoring increased copies in high-starch contexts, enhancing the breakdown of complex carbohydrates into simpler sugars for better energy extraction.^[105] East Asian populations, including Japanese, often show elevated averages, reflecting historical reliance on starchy staples like rice.^[105] Functionally, greater AMY1 copies lead to higher salivary amylase protein levels and enzyme activity, improving initial starch hydrolysis in the mouth.^[105] Genome-wide association studies (GWAS) further link low AMY1 copies to increased body mass index (BMI) and obesity risk, with each additional copy reducing obesity odds by about 1.2-fold, potentially due to altered glycemic responses.^[106] Similar associations appear with type 2 diabetes susceptibility, where reduced copies may impair starch metabolism and elevate postprandial glucose.^[107] Detection of AMY1 CNV typically employs quantitative PCR (qPCR) for high-throughput estimation or array comparative genomic hybridization (aCGH) for structural mapping, though qPCR can underestimate copies due to primer biases—digital PCR offers higher accuracy.^[108] Population-level variation persists, with even higher averages in some groups like Indigenous Peruvians, underscoring ongoing adaptation.^[109] Recent research ties AMY1 CNV to microbiome adaptation, showing that copy number influences oral and gut microbial communities' response to starch, potentially modulating biofilm formation and fermentation efficiency in starch-dependent ecosystems.^[110]^[111]

Other Prominent Examples

Copy number variations (CNVs) in immune-related genes provide a clear example of adaptive dosage effects. The CCL3L1 gene, encoding the chemokine macrophage inflammatory protein-1α (MIP-1α), exhibits variable copy numbers. An initial 2005 study reported an inverse correlation with HIV-1 susceptibility and progression, suggesting that lower copy numbers (below the population median of typically 2–4 copies) increase risk due to reduced MIP-1α production, which inhibits HIV entry via the CCR5 co-receptor, and that higher copies confer protection, with each additional copy potentially reducing infection risk by 4–10%.^[112] However, subsequent research has produced inconsistent results, with many studies failing to replicate the association and questioning the original assay's accuracy, leaving the role of CCL3L1 CNV in HIV debated.^[113]^[114] In neurodevelopment, CNVs at the 16p11.2 chromosomal locus represent a prominent pathogenic example with bidirectional effects and variable expressivity. Deletions spanning approximately 600 kb in this region, affecting 25–29 genes including MVP and KCTD13, are strongly associated with autism spectrum disorder (ASD), intellectual disability, and macrocephaly, increasing ASD risk up to ninefold. Duplications of the same interval, in contrast, link to schizophrenia, bipolar disorder, and microcephaly, with penetrance varying by genetic background and environmental factors, underscoring how reciprocal CNVs disrupt dosage-sensitive pathways in brain development and connectivity.^[115]^[116] CNVs in the olfactory receptor (OR) gene family highlight evolutionary and functional diversity in sensory systems. This largest human gene superfamily, comprising over 400 loci, shows extensive structural variation, with roughly 50% of identified CNVs encompassing multiple OR genes and contributing to inter-individual differences in copy number that explain up to 30% of variation in olfactory perception. Such polymorphisms, often involving duplications or deletions of gene clusters on chromosomes 11 and 1, influence odor detection thresholds and receptor repertoire, reflecting neutral genomic drift and selection pressures that fine-tune olfaction across populations without overt disease associations.^[77] Recent investigations into CNVs in Parkinson's disease (PD) have identified rare structural variants in the GBA gene, encoding glucocerebrosidase, as modifiers of risk. While loss-of-function variants in GBA represent the strongest common genetic risk factor for PD, affecting lysosomal function and α-synuclein accumulation.^[117] These cases collectively exemplify CNV-driven dosage sensitivity, where altered gene copy numbers modulate protein expression to yield protective adaptations (e.g., in immunity and olfaction), pathological vulnerabilities (e.g., in neurodevelopment and neurodegeneration), or evolutionary flexibility, distinct from broader disease associations or gene family expansions.

References

[1]
Copy Number Variation (CNV)
A copy number variation (CNV) is when the number of copies of a particular gene varies from one individual to the next.
[2]
Definition of copy number variant - NCI Dictionary of Genetics Terms
A variation in the number of copies of a particular sequence of DNA present in the genome of an individual. Copy number variants include insertions, deletions, ...
[3]
Copy Number Variation and Human Disease - Nature
The term "copy number variation" refers to an intermediate-scale genetic change, operationally defined as segments greater than 1,000 base pairs in length but ...
[4]
What are copy number variants? - Genomics Education Programme
Aug 12, 2020 · Copy number variants (CNVs) are where the number of repeats varies between individuals, and may account for almost 10% of an individual's genome.
[5]
Copy Number Variation in Human Health, Disease, and Evolution
Copy number variation (CNV) is a source of genetic diversity in humans. Numerous CNVs are being identified with various genome analysis platforms.
[6]
Copy-number changes in evolution: rates, fitness effects ... - Frontiers
Gene copy-number differences due to gene duplications and deletions are rampant in natural populations and play a crucial role in the evolution of genome ...
[7]
Copy-Number Variants Impact on Human Traits
Mar 2, 2022 · Hence, CNVs have been acknowledged to play an important role in human diseases and were identified as the genetic etiology of 65 rare and ...
[8]
Rare CNVs Modulate Common Disease Susceptibility
Jan 8, 2024 · Our results shed light on the prominent role of rare CNVs in determining common disease susceptibility within the general population.
[9]
Global variation in copy number in the human genome | Nature
Nov 23, 2006 · Copy number variation (CNV) of DNA sequences is functionally significant but has yet to be fully ascertained. We have constructed a ...A Genome-Wide Map Of Copy... · Copy Number Variation Of... · Imprint Of Cnv On Snp...
[10]
https://www.nature.com/scitable/topicpage/copy-number-variation-445
[11]
Global variation in copy number in the human genome - PMC - NIH
1,447 copy number variable regions covering 360 megabases (12% of the genome) were identified in these populations; these CNV regions contained hundreds of ...
[12]
Constitutional (germline) vs somatic (tumour) variants
Constitutional variants are in all cells and can be passed on, while somatic variants arise in non-germ cells and are not passed on.
[13]
Types of structural variants. Unbalanced SVs represented in the top ...
Balanced SVs are represented in the third row and include inversions and translocations. ... These variants include CNVs (deletions and duplications) ...
[14]
https://www.nature.com/scitable/topicpage/copy-number-variation-and-human-disease-741737
[15]
Human Genomic Variation
Feb 1, 2023 · Note that CNVs are distinguished from other structural variants, such as inversions and translocations, because the latter types often do not ...
[16]
Sequencing 101: Structural variation - PacBio
Dec 19, 2023 · Copy number variants (CNVs): Regions of the genome where the number of copies may vary among individuals, giving rise to genomic imbalances.
[17]
Copy Number Variation Disorders - PMC - NIH
Thus, CNVs have become increasingly recognized as a significant source not only of genetic diversity within the general population, but also the mutational ...
[18]
22q11.2 deletion syndrome - PMC - PubMed Central - NIH
Over time, multiple aetiologies for DiGeorge syndrome were identified, beginning with a cytogenetically apparent 22q11. 2 deletion in the early 1980s12,13. In ...
[19]
22q11.2 deletion syndrome: A tiny piece leading to a big picture - NIH
In the early 1990s, fluorescence in situ hybridization (FISH) studies using probes within the commonly deleted region identified submicroscopic 22q11.2 ...
[20]
Impact of the 1000 Genomes Project on the next wave of ... - NIH
The 1000 Genomes Project aims to provide a much more detailed map of genetic variation on more than 1000 samples from worldwide populations. Some bioinformatics ...
[21]
Copy-number variants differ in frequency across genetic ancestry ...
Copy-number variants differ in frequency across genetic ancestry groups ... A comprehensive analysis of common copy-number variations in the human genome.
[22]
Copy-number variants differ in frequency across genetic ancestry ...
Oct 10, 2024 · We also identified specific recurrent CNVs that consistently differ in frequency across ancestry groups in both the UKBB and SPARK. These ...
[23]
An accurate and powerful method for copy number variation detection
Copy number variations (CNVs) are deletions (<2) or duplications (>2) in DNA copies at a specific chromosomal location in the genome. According to their ...
[24]
Determining multiallelic complex copy number and sequence ...
Nov 2, 2015 · Copy number variation (CNV) is a major component of genomic variation, yet methods to accurately type genomic CNV lag behind methods that ...
[25]
Review Article DNA copy number variation: Main characteristics ...
They are common features of the human genome that play an important role in evolution, contribute to population diversity, development of certain diseases, and ...
[26]
American College of Medical Genetics standards and guidelines for ...
A copy number variant (CNV) is defined as a segment of DNA at least 1 kb in size that differs in copy number compared with a representative reference genome.
[27]
Copy Number Variation: Methods and Clinical Applications - MDPI
Copy number variants (CNVs) are gains or losses of large DNA segments, including deletions, insertions, duplications, or multiplications of DNA.
[28]
Segmental Duplication - an overview | ScienceDirect Topics
Duplications can result in sequence copies at the same locus, referred to as tandem duplications, or sequence duplication in trans at physically separated loci, ...
[29]
Mouse Segmental Duplication and Copy-Number Variation - NIH
Here we present a detailed analysis of the recent duplication content of the mouse clone-based finished genome assembly and assess copy-number variation (CNV) ...
[30]
De novo rates and selection of large copy number variation - PMC
While copy number variation (CNV) is an active area of research, de novo mutation rates within human populations are not well characterized.
[31]
Identification and characterisation of de novo germline structural ...
Apr 18, 2023 · De novo mutations arising in the germline are a source of genetic variation and their discovery broadens our understanding of genetic disorders ...
[32]
A Systematic Review of the Advances and New Insights into Copy ...
Intragenic CNVs occur within the coding regions of genes and directly affect gene function. Intergenic CNVs occur in the non-coding regions between genes ...
[33]
Prevalence and properties of intragenic copy-number variation in ...
Jun 12, 2018 · CNVs accounted for ~3% of all reported variants but a notable ~9% of clinically significant LP/P variants in different gene panels across ...
[34]
Rethinking the pathogenicity of intragenic DMD duplications ...
Apr 14, 2025 · Intragenic duplications can be either tandem or interspersed (also known as non-tandem or insertional). In tandem duplications, the duplicated ...
[35]
Rethinking the pathogenicity of intragenic DMD duplications ...
Tandem duplications often disrupt reading frames and cause gene loss of function, whereas interspersed (nontandem) duplications are largely benign.
[36]
The Database of Genomic Variants: a curated collection of structural ...
The Database of Genomic Variants (DGV) was launched following the publication of the inaugural CNV articles that described the genome-wide prevalence of CNV ...
[37]
HGVS Nomenclature
The HGVS Nomenclature is an internationally-recognized standard for the description of DNA, RNA, and protein sequence variants.
[38]
Database of Genomic Variants [*** v107 ***]
Find DGV Variants. by Study · by Sample · by Method · by Variant · by Platform · by Chromosome. Summary Statistics. Stat, Merged-level, Sample-level. CNVs: ...About the Project · Downloads · Links · FAQ
[39]
Mechanisms of change in gene copy number - PMC - NIH
This is known as copy number variation (CNV). A high proportion of the genome, currently estimated at up to 12%, is subject to CNV-,, which can arise ...Missing: unbalanced | Show results with:unbalanced
[40]
A Microhomology-Mediated Break-Induced Replication Model for ...
Jan 30, 2009 · We derive a model of microhomology-mediated break-induced replication (MMBIR) for the origin of CNV and, ultimately, of LCRs.
[41]
Review The role of microhomology in genomic structural variation
Germline rearrangements, including CNVs, arise from different mechanisms, including nonallelic homologous recombination (NAHR), the end-joining mechanisms NHEJ ...
[42]
The DNA replication FoSTeS/MMBIR mechanism can generate ...
Jun 21, 2009 · Here we provide evidence that human genomic rearrangements ranging in size from several megabases to a few hundred base pairs can be generated by FoSTeS/MMBIR.
[43]
Replication Stress and Mechanisms of CNV Formation - PMC - NIH
In the FoSTeS model, replication forks encountering low-copy repeats or areas that are difficult to replicate are prone to stalling, leading to a switch to ...Replication Stress And... · Mechanisms Of Cnv Formation · Replication Stress Induces...
[44]
Transposable element-mediated rearrangements are prevalent in ...
Nov 19, 2022 · Transposable elements constitute about half of human genomes, and their role in generating human variation through retrotransposition is broadly studied and ...
[45]
Genome-wide analyses of LINE–LINE-mediated nonallelic ... - NIH
Jan 22, 2015 · Nonallelic homologous recombination (NAHR), occurring during meiosis, is the most common mechanism underlying the formation of recurrent CNVs in ...
[46]
Segmental Duplications and Copy-Number Variation in the Human ...
May 15, 2025 · Our study demonstrates that segmental duplications define hotspots of chromosomal rearrangement, likely acting as mediators of normal variation ...
[47]
Methods and strategies for analyzing copy number variation using ...
In this article I review the current microarray technologies being used for genome-wide CNV detection and for the association of CNVs with normal and disease ...Missing: traditional | Show results with:traditional
[48]
[PDF] Karyotyping, FISH and CGH array - Eurofins Biomnis Connect
Karyotyping examines chromosomes for abnormalities. FISH uses fluorescent probes for high resolution. CGH array compares genomes to find copy number variations.
[49]
Comparative genomic hybridization for molecular cytogenetic ...
Oct 30, 1992 · Comparative genomic hybridization produces a map of DNA sequence copy number as a function of chromosomal location throughout the entire genome.
[50]
Quantitative Analysis of Copy Number Variants Based on Real-Time ...
qPCR involves amplification of a test locus with unknown copy number and a reference locus with known copy number. This method has been used in the ...
[51]
Sensitive and accurate detection of copy number variants using read ...
Our results suggest that analysis of read depth is an effective approach for the detection of CNVs, and it captures structural variants that are refractory to ...Missing: formula | Show results with:formula
[52]
CNVpytor: a tool for copy number variation detection and analysis ...
Nov 18, 2021 · CNVnator is a method for CNV analysis based on read depth (RD) of aligned reads. It has been determined to have high sensitivity (86–96%), low ...
[53]
Control-FREEC: Copy number and allelic content caller - Boeva Lab
Control-FREEC is a tool for detection of copy-number changes and allelic imbalances (including LOH) using deep-sequencing data.Missing: CNVnator | Show results with:CNVnator
[54]
Whole-genome sequencing analysis of CNV using low-coverage ...
Jul 30, 2018 · For read-depth analysis, we used CNVnator with 5 kb bin size. Discordant read-pair analysis was performed using LUMPY with segmental ...
[55]
SavvyCNV: Genome-wide CNV calling from off-target reads - NIH
Mar 16, 2022 · We present SavvyCNV, a tool which uses off-target read data from exome and targeted sequencing data to call germline CNVs genome-wide.
[56]
ECOLE: Learning to call copy number variants on whole exome ...
Jan 2, 2024 · We present a deep learning-based somatic and germline CNV caller for WES data, named ECOLE. Based on a variant of the transformer architecture.
[57]
Copy number variant analysis improves diagnostic yield in a diverse ...
Feb 21, 2025 · Our study demonstrates the feasibility and increased yield of CNV analysis of exome data, across multiple phenotypes, referral sources, and ancestries.
[58]
SavvyCNV: Genome-wide CNV calling from off-target reads
Mar 16, 2022 · The ability to use off-target reads to call CNVs across the genome increases the diagnostic utility of targeted next-generation sequencing ...
[59]
Comprehensive assessment of long-read sequencing platforms and ...
Sep 10, 2024 · Specifically, the PacBio CCS sequencing platform outperformed PacBio CLR and Nanopore platforms regarding CNV detection recall rates. A ...
[60]
Full characterization of unresolved structural variation through long ...
Nov 25, 2024 · Long-read sequencing (LRS) and optical genome mapping (OGM) can aid as their molecules span multiple kilobases and capture SVs in full.
[61]
Long read whole genome sequencing-based discovery of structural ...
Aug 20, 2025 · Benchmarking long-read aligners and SV callers for structural variation detection in Oxford nanopore sequencing data. Sci Rep. 2024;14(1): ...
[62]
Single-cell copy number calling and event history reconstruction
We developed SCICoNE, a statistical model and MCMC algorithm tailored to single-cell copy number profiling from shallow whole-genome DNA sequencing data.
[63]
Evaluation of somatic copy number variation detection by NGS ...
Jun 20, 2024 · Somatic copy number variants (CNVs) represent variations in the copy numbers of a DNA sequence during cancer development, differing from an ...
[64]
Benchmarking scRNA-seq copy number variation callers - Nature
Oct 2, 2025 · Single-cell whole-genome sequencing is considered the gold-standard technique to obtain per-cell CNV profiles, as changes in DNA copy number ...Missing: SCICoNE | Show results with:SCICoNE
[65]
EMcnv: enhancing CNV detection performance through ensemble ...
Mar 31, 2025 · We propose EMcnv, a novel deep ensemble framework based on meta-learning. EMcnv combines multiple CNV detection strategies through a three-step approach.
[66]
Whole-genome CNV analysis: advances in computational approaches
It implements an HMM framework to perform CNV segmentation. In addition, it utilizes LOESS smoothing and GC correction to mitigate sequencing biases. Clever ...
[67]
Computational tools for copy number variation (CNV) detection ...
Sep 13, 2013 · Despite improvements to NGS technologies and CNV-detecting tools, the identification of low coverage CNVs still remains a challenge. Although ...
[68]
Identification of Copy Number Variation Hotspots in Human ... - NIH
The locus-specific mutation rates for CNV have been observed to be ∼100 to 10,000 times higher than those for nucleotide substitution rates, which not only ...
[69]
An integrated map of structural variation in 2,504 human genomes
Sep 30, 2015 · We constructed this resource by analysing 1000 Genomes Project phase 3 whole-genome sequencing (WGS) data along with data from orthogonal ...
[70]
Diet and the evolution of human amylase gene copy number variation
This example of positive selection on a copy number-variable gene is, to our knowledge, one of the first discovered in the human genome. Higher AMY1 copy ...
[71]
CCL3L1 copy number is a strong genetic determinant of HIV ...
A high CCL3L1 copy number (>2) associated with a 80% reduced risk of acquiring HIV, after adjusting for age, gender, HCV/HBV status, CCR5-Δ32 polymorphism and ...
[72]
Population-level gene copy number variations reveal distinct genetic ...
Jul 23, 2025 · In this study, we explored how CNVs contribute to genetic diversity, evolution, and adaptation during apple domestication.
[73]
Balancing selection on genomic deletion polymorphisms in humans
Jan 10, 2023 · Our results suggest that balancing selection resulted in ancient deletions harboring disproportionately more exonic variants with GWAS (genome-wide association ...
[74]
Global diversity, population stratification, and selection of human ...
However, copy-number variants (CNVs) affect more base pairs of DNA among humans, and yet our understanding of CNV diversity among human populations is limited.Cnv Discovery · Cnv Diversity And Selection · Denisovan Cnvs Are Retained...<|control11|><|separator|>
[75]
High-Resolution Copy-Number Variation Map Reflects Human ...
Olfactory receptors (ORs), which are involved in odorant recognition, form the largest mammalian protein superfamily. The genomic content of OR genes is ...
[76]
The Birth and Death of Olfactory Receptor Gene Families in ... - NIH
When both daughter ORs have retained function after a duplication event, this may suggest subfunctionalization or neofunctionalization, and differ across taxa ( ...
[77]
Evolution of major histocompatibility complex gene copy number
May 16, 2019 · For example, in humans, there are 6–7 classical MHC loci, allowing for up to 12–14 different variants in a fully heterozygous individual, while ...
[78]
Copy number variation contributes to parallel local adaptation in an ...
Copy number variation (CNV) is thought to be an important source of adaptive genetic variation, as indicated by decades of candidate gene studies that point to ...
[79]
Copy number variation facilitates rapid toggling between ecological ...
By integrating CNVs into a specialist-generalist ecological framework, our findings highlight how gene dosage plasticity contributes to ecological adaptation.
[80]
Widespread modulation of gene expression by copy number ...
Jan 23, 2018 · Copy number variation (CNV) is a frequently observed deviation from the diploid state due to duplication or deletion of genomic regions.
[81]
DiGeorge syndrome (22q11.2 deletion syndrome)
2 deletion syndrome), which is also referred to as velocardiofacial syndrome, is one of the most common genetic syndromes with a prevalence of 1:4000 [1]. With ...
[82]
Copy number variants in autism spectrum disorders - ScienceDirect
Of note, about 4–10% of individuals with ASD show de novo events (deletions or duplications), a higher percentage than that observed in neurotypical siblings ( ...
[83]
Updated penetrance estimates for recurrent copy number variants
Oct 15, 2025 · This theoretical example demonstrates how incidental pathology can be misattributed to low penetrant CNVs (with a rate of up to 30% in this ...
[84]
Copy-number variants differ in frequency across genetic ancestry ...
Aug 12, 2024 · We found that deleterious CNVs are less prevalent in non-European ancestry groups than they are in European ancestry groups of both the UK ...
[85]
Large-scale copy number variant analysis in genes linked to ...
Aug 1, 2025 · Despite the growing recognition of CNVs in PD genetics, most studies to date have been limited by small sample sizes or targeted approaches ...Cnvs In Other Pd-Related... · Genome-Wide Cnv Burden... · Genome-Wide Cnv Analysis And...<|control11|><|separator|>
[86]
Copy Number Variants: Deletion and Duplication Syndromes
Aug 25, 2025 · A deletion in chromosome 22 can cause DiGeorge syndrome. ... early-onset dementia in a man with 22q11 deletion syndrome and Huntington's disease.
[87]
Diagnostic yield of exome sequencing-based copy number variation ...
Sep 30, 2024 · In this study, we evaluated the diagnostic yield of exome sequencing-based CNV analysis in 449 patients with suspected Mendelian disorders.Missing: off- 2025 ensemble
[88]
Dosage sensitivity is a major determinant of human copy number ...
Feb 8, 2017 · When the dosage of these genes is changed by an overlapping CNV, the function of the gene is disrupted in a way that we may observe as disease.
[89]
Genetic copy number variants, cognition and psychosis - Nature
Jul 27, 2020 · ... schizophrenia are not carriers. However, schizophrenia-associated CNVs have odds ratios ranging from 2 to 30 [12, 14] and thus constitute ...
[90]
Submegabase copy number variations arise during cerebral cortical ...
Sep 27, 2018 · Somatic copy number variations (CNVs) exist in the brain, but their genesis, prevalence, forms, and biological impact remain unclear, ...
[91]
Single-cell somatic copy number variants in brain using different ...
Oct 9, 2024 · We find that 20.6% of brain cells have at least one Mb-scale CNV, with some supported by bulk sequencing or single-cells from other brain regions.
[92]
Somatic copy number variant load in neurons of healthy controls ...
Nov 30, 2022 · Chronister and colleagues recently reported that CNV frequencies in neurons (4%–23.1%) are higher than non-neuronal cells (4.7%–8.7%) [6].
[93]
The Brain Somatic Mosaicism Network | Science
Apr 28, 2017 · Somatic mosaicism represents a potential mechanism that may contribute to neuronal diversity and the etiology of numerous neuropsychiatric disorders.
[94]
Somatic mutation involving diverse genes leads to a spectrum of ...
Dec 29, 2021 · We demonstrate that FCD types I, II, and III, are associated with somatic gene variants across a broad range of genes, many associated with epilepsy.
[95]
Different mutational rates and mechanisms in human cells at pre ...
Our estimated average mutation rate of 5.1 SNVs per day per neuronal progenitor during neurogenesis implies that neurons generated at early and later stages of ...
[96]
Mapping recurrent mosaic copy number variation in human neurons
May 17, 2024 · C Neuronal genomes (n = 2097) are arranged in a cells-by-chromosome matrix, ranked by the total percentage of their genome containing deletions.<|separator|>
[97]
276 - Gene ResultAMY1A amylase alpha 1A [ (human)] - NCBI
Sep 9, 2025 · Salivary amylase gene (AMY1) copy number variation has only a minor correlation with body composition in Chinese adults. Associations of SLC6A4 ...Missing: locus chromosome
[98]
Copy number variation of human AMY1 is a minor contributor to ...
Feb 20, 2017 · AMY1 copy number was significantly correlated with the variation observed in salivary amylase production (11.7% of variance, P < 0.0005) and enzyme activity ( ...Missing: selection | Show results with:selection
[99]
Recurrent evolution and selection shape structural diversity ... - Nature
Sep 4, 2024 · Amylase genes facilitate starch digestion, and increased amylase copy number has been observed in some modern human populations with high-starch ...
[100]
Reconstruction of the human amylase locus reveals ... - Science
Genomic studies have found substantial variation in the number of amylase gene copies, which is believed to be an adaptive response to dietary changes among ...
[101]
Diet and the evolution of human amylase gene copy number variation
Sep 9, 2007 · Individuals from populations with high-starch diets have, on average, more AMY1 copies than those with traditionally low-starch diets.
[102]
Low copy number of the salivary amylase gene predisposes to obesity
The OR of 1.19 per-copy of AMY1 translates to about an eight-fold difference in risk of obesity between subjects in the top (CN>9) and bottom (CN<4) 10% of the ...
[103]
Impact of salivary and pancreatic amylase gene copy numbers on ...
May 10, 2022 · Our findings can partly explain the mechanism underlying obesity and diabetes in populations with high amylase copy numbers.
[104]
association between copy number variants at human salivary (AMY1 ...
The human salivary amylase genes display extensive copy number variation (CNV), and recent work has implicated this variation in adaptation to starch-rich diets ...
[105]
Rapid Adaptive Increase of Amylase Gene Copy Number in ...
Aug 15, 2025 · Here, we analyzed AMY1 copy number in 3,723 individuals from 85 populations, revealing that Indigenous Peruvian Andean populations possess the ...
[106]
The Impact of Human Salivary Amylase Gene Copy Number and ...
AMY1 duplications are believed to have undergone positive selection following the Neolithic Revolution—the transition to an agricultural lifestyle that resulted ...2. Materials And Methods · 2.7. Bioinformatics And... · 3. Results<|separator|>
[107]
Systems genetics uncovers associations among host amylase locus ...
Apr 21, 2025 · We found salivary (Amy1) amylase gene expression level and pancreatic (Amy2) amylase gene copy number were associated with gut microbiome. Both ...
[108]
The Influence of CCL3L1 Gene-Containing Segmental Duplications ...
Possession of a CCL3L1 copy number lower than the population average is associated with markedly enhanced HIV/acquired immunodeficiency syndrome (AIDS) ...
[109]
Dosage-dependent phenotypes in models of 16p11.2 lesions found ...
Recurrent copy number variations (CNVs) of human 16p11.2 have been associated with a variety of developmental/neurocognitive syndromes.
[110]
The 16p11.2 locus modulates brain structures common to autism ...
Nov 25, 2014 · We find a correlation between gene dosage and alterations in brain structure with diametrically opposite changes in both global and local brain volumes.Missing: variable expressivity
[111]
Accurate long-read sequencing identified GBA1 as major risk factor ...
Nov 23, 2023 · ... copy number variants ... Association of GBA mutations and the E326K polymorphism with motor and cognitive progression in Parkinson disease.