Genetic Complexity Research Articles

Potential Involvements of Cilia-Centrosomal Genes in Primary Congenital Glaucoma.

Primary congenital glaucoma (PCG) occurs in children due to developmental abnormalities in the trabecular meshwork and anterior chamber angle. Previous studies have implicated rare variants in CYP1B1, LTBP2, and TEK and their interactions with MYOC, FOXC1, and PRSS56 in the genetic complexity and clinical heterogeneity of PCG. Given that some of the gene-encoded proteins are localized in the centrosomes (MYOC) and perform ciliary functions (TEK), we explored the involvement of a core centrosomal protein, CEP164, which is responsible for ocular development and regulation of intraocular pressure. Deep sequencing of CEP164 in a PCG cohort devoid of homozygous mutations in candidate genes (n = 298) and controls (n = 1757) revealed CEP164 rare pathogenic variants in 16 cases (5.36%). Co-occurrences of heterozygous alleles of CEP164 with other genes were seen in four cases (1.34%), and a physical interaction was noted for CEP164 and CYP1B1 in HEK293 cells. Cases of co-harboring alleles of the CEP164 and other genes had a poor prognosis compared with those with a single copy of the CEP164 allele. We also screened INPP5E, which synergistically interacts with CEP164, and observed a lower frequency of pathogenic variants (0.67%). Our data suggest the potential involvements of CEP164 and INPP5E and the yet unexplored cilia-centrosomal functions in PCG pathogenesis.

Convergent evolution in Afrotheria and non-afrotherians demonstrates high evolvability of the mammalian inner ear

Evolutionary convergence in distantly related species is among the most convincing evidence of adaptive evolution. The mammalian ear, responsible for balance and hearing, is not only characterised by its spectacular evolutionary incorporation of several bones of the jaw, it also varies considerably in shape across modern mammals. Using a multivariate approach, we show that in Afrotheria, a monophyletic clade with morphologically and ecologically highly disparate species, inner ear shape has evolved similar adaptations as in non-afrotherian mammals. We identify four eco-morphological trait combinations that underlie this convergence. The high evolvability of the mammalian ear is surprising: Nowhere else in the skeleton are different functional units so close together; it includes the smallest bones of the skeleton, encapsulated within the densest bone. We suggest that this evolvability is a direct consequence of the increased genetic and developmental complexity of the mammalian ear compared to other vertebrates.

Onco-Ontogeny of Squamous Cell Cancer of the First Pharyngeal Arch Derivatives.

Head and neck squamous cell carcinoma (H&NSCC) is an anatomic, biological, and genetic complex disease. It involves more than 1000 genes implied in its oncogenesis; for this review, we limit our search and description to the genes implied in the onco-ontogeny of the derivates from the first pharyngeal arch during embryo development. They can be grouped as transcription factors and signaling molecules (that act as growth factors that bind to receptors). Finally, we propose the term embryo-oncogenesis to refer to the activation, reactivation, and use of the genes involved in the embryo's development during the oncogenesis or malignant tumor invasion and metastasis events as part of an onco-ontogenic inverse process.

MOLECULAR SURVEILLANCE OF GONOCOCCAL CIPROFLOXACIN SUSCEPTIBILITY/RESISTANCE IN BULGARIA, 2022-2023

Background: The emergence and spread of antimicrobial resistance in Neisseria gonorrhoeae is a significant public health issue, with Euro-GASP conducting surveillance across the EU-EEA. The advent of molecular diagnostics for N. gonorrhoeae may possibly limit the surveillance data because it is dependent on gonococcal culture for phenotypic susceptibility testing. Ideally, molecular diagnostics should combine identification and resistance detection but the complexity of gonococcal molecular genetics of resistance is a major barrier for test development. Currently, resistance prediction in N. gonorrhoeae is accurate only for fluoroquinolones and there are commercial kits available on the market that allow antimicrobial resistance surveillance and individualized treatment. The study examined Bulgaria's gonococcal fluoroquinolone resistance rate for 2022-2023 by molecular methods and compared it with previous years and EU-EEA trends. Methods: The commercial ResistancePlus® GC assay was used to predict ciprofloxacin susceptibility/resistance in 66 Neisseria gonorrhoeae-positive DNA samples from patients, diagnosed in 2022-2023. Results: The identified fluoroquinolone resistance rate in 2022-2023 was 68.2%. The majority of the cases were males in the age group 20-29 (50.8%), the most common mode of transmission was MSM (77%) and 17% of the cases with known HIV status were positive. Conclusion: This study found a higher than before fluoroquinolone resistance rate (68.2%) in Bulgaria, following the trend in Europe. In the EU-EEA, ciprofloxacin resistance increased to 65.9% in 2022. Molecular testing for predicting susceptibility/resistance is suitable for effective antimicrobial resistance surveillance and individualized treatment decisions.

PSV-19 Uncovering breed-origin allele effects and their role in thermotolerance through genome-wide association study in Brangus cattle

Abstract In subtropical and tropical environments, beef cattle production faces significant challenges due to heat stress, affecting animal welfare and productivity. To mitigate these effects, producers have turned to crossbreeding and the development of composite breeds like Brangus, which combine the desirable carcass and meat quality traits of European taurine cattle with the thermotolerance of Indicine breeds. However, the genetic underpinnings of thermotolerance in these composite populations are not well understood, owing to the complex nature of measuring related traits and the genetic intricacies arising from crosses of distinct populations. This study aims to identify key quantitative trait loci (QTL) related to thermotolerance, employing an approach that integrates genetic markers alongside the marker’s breed of origin of alleles (BOA) in Brangus heifers. Data were collected on histological sweat gland area (SWA), hair length (HL), and thermal stress slope as a measure of the increase in body temperature from a low to a high temperature-humidity index (TSS), from 2,233 Brangus heifers genotyped with the 250K functional chip. BOA was determined using LAMP-LD software, using Angus and Brahman cattle from the University of Florida’s multibreed Angus-Brahman project as a reference population. We conducted a genome-wide association study (GWAS) incorporating BOA-specific effects, revealing several genes with BOA-specific effects. Notably, the CGGBP1 gene exhibited a significant effect on TSS only when alleles originated from Brahman. Conversely, the PLK1 gene was significant for TSS when alleles originated from Angus. Both CGGBP1 and PLK1 interact with heat shock proteins during heat stress, these findings reveal different genetic mechanisms for controlling internal body temperature. For HL, a significant Brahman-specific effect was found near the PRLR gene, which is known as the gene controlling the SLICK hair phenotype in Criollo cattle. For SWA, an Angus-specific significant association was found with the PDE4D gene. PDE4D interacts with the cAMP pathway which regulates sweat gland growth and sweat production. These findings underline the genetic complexity of thermotolerance in composite cattle and the crucial role of BOA in identifying key QTL. The study offers novel insights into the genetic mechanisms of thermotolerance, providing a foundation for breeding strategies aimed at improving heat resilience in cattle in subtropical and tropical environments.

Pregnancy Planning and Genetic Testing: Exploring Advantages, and Challenges.

Pregnancy planning and genetic testing (PPGT) has emerged as a tool in reproductive healthcare, offering parents-to-be insight in their risks of having a child with a genetic disorder. This paper reviews the advantages, drawbacks and challenges associated with PPGT, providing some practical guidance for health care professionals. Advantages include identification of genetic risks, a possibility to informed reproductive decision-making, and the potential to reduce the parents-to-be risk for an affected child. Challenges and drawbacks include provision of service, ethical considerations, genetic counselling complexities, and the need to increase public and professional awareness by comprehensive education and accessibility. Practical guidance involves considerations for selecting appropriate candidates, counselling strategies, and how to integrate PPGT into existing healthcare frameworks. By addressing these factors, PPGT can offer an increased reproductive informed choice for the individual and the couple reducing the burden of disease in the family.

Clinical and Genetic Insights into Desbuquois Dysplasia: Review of 111 Case Reports.

Skeletal disorders encompass a wide array of conditions, many of which are associated with short stature. Among these, Desbuquois dysplasia is a rare but severe condition characterized by profound dwarfism, distinct facial features, joint hypermobility with multiple dislocations, and unique vertebral and metaphyseal anomalies. Desbuquois dysplasia is inherited in an autosomal recessive manner, with both the DBQD1 (MIM 251450) and DBQD2 (MIM 615777) forms resulting from biallelic mutations. Specifically, DBQD1 is associated with homozygous or compound heterozygous mutations in the CANT1 gene, while DBQD2 can result from mutations in either the CANT1 or XYLT1 genes. This review synthesizes the findings of 111 published case reports, including 54 cases of DBQD1, 39 cases of DBQD2, and 14 cases of the Kim variant (DDKV). Patients in this cohort had a median birth weight of 2505 g, a median length of 40 cm, and a median occipitofrontal circumference of 33 cm. The review highlights the phenotypic variations across Desbuquois dysplasia subtypes, particularly in facial characteristics, joint dislocations, and bone deformities. Genetic analyses revealed a considerable diversity in mutations, with over 35% of cases involving missense mutations, primarily affecting the CANT1 gene. Additionally, approximately 60% of patients had a history of parental consanguinity, indicating a potential genetic predisposition in certain populations. The identified mutations included deletions, insertions, and nucleotide substitutions, many of which resulted in premature stop codons and the production of truncated, likely nonfunctional proteins. These findings underscore the genetic and clinical complexity of Desbuquois dysplasia, highlighting the importance of early diagnosis and the potential for personalized therapeutic approaches. Continued research is essential to uncover the underlying mechanisms of this disorder and improve outcomes for affected individuals through targeted treatments.

Taxonomic and functional characterization of biofilms from a photovoltaic panel reveals high genetic and metabolic complexity of the communities.

Biofilms are complex microbial cell aggregates that attach to different surfaces in nature, industrial environments, or hospital settings. In photovoltaic panels (PVs), biofilms are related to significant energy conversion losses. In this study, our aim was to characterize the communities of microorganisms and the genes involved in biofilm formation. In this study, biofilm samples collected from a PV system installed in southeastern Brazil were analyzed through shotgun metagenomics, and the microbial communities and genes involved in biofilm formation were investigated. A total of 2030 different genera were identified in the samples, many of which were classified as extremophiles or producers of exopolysaccharides. Bacteria prevailed in the samples (89%), mainly the genera Mucilaginibacter, Microbacterium, Pedobacter, Massilia, and Hymenobacter. The functional annotation revealed >12 000 genes related to biofilm formation and stress response. Genes involved in the iron transport and synthesis of c-di-GMP and c-AMP second messengers were abundant in the samples. The pathways related to these components play a crucial role in biofilm formation and could be promising targets for preventing biofilm formation in the PV. In addition, Raman spectroscopy analysis indicated the presence of hematite, goethite, and ferrite, consistent with the mineralogical composition of the regional soil and metal-resistant bacteria. Taken together, our findings reveal that PV biofilms are a promising source of microorganisms of industrial interest and genes of central importance in regulating biofilm formation and persistence.

Whole-exome sequencing uncovers the genetic complexity of bicuspid aortic valve in families with early-onset complications

Bicuspid aortic valve (BAV) is the most common congenital heart lesion with an estimated population prevalence of 1%. We hypothesize that specific gene variants predispose to early-onset complications of BAV (EBAV). We analyzed whole-exome sequences (WESs) to identify rare coding variants that contribute to BAV disease in 215 EBAV-affected families. Predicted damaging variants in candidate genes with moderate or strong supportive evidence to cause developmental cardiac phenotypes were present in 107 EBAV-affected families (50% of total), including genes that cause BAV (9%) or heritable thoracic aortic disease (HTAD, 19%). After appropriate filtration, we also identified 129 variants in 54 candidate genes that are associated with autosomal-dominant congenital heart phenotypes, including recurrent deleterious variation of FBN2, MYH6, channelopathy genes, and type 1 and 5 collagen genes. These findings confirm our hypothesis that unique rare genetic variants drive early-onset presentations of BAV disease.

A tradeoff between bacteriophage resistance and bacterial motility is mediated by the Rcs phosphorelay in Escherichia coli.

Across the tree of life, pleiotropy is thought to constrain adaptation through evolutionary tradeoffs. However, few examples of pleiotropy exist that are well explained at the genetic level, especially for pleiotropy that is mediated by multiple genes. Here, we describe a set of pleiotropic mutations that mediate two key fitness components in bacteria: parasite resistance and motility. We subjected Escherichia coli to strong selection by phage U136B to obtain 27 independent mucoid mutants. Mucoidy is a phenotype that results from excess exopolysaccharide and can act as a barrier against viral infection but can also interfere with other cellular functions. We quantified the mutants' phage resistance using efficiency of plaquing assays and swimming motility using swim agar plates, and we sequenced the complete genomes of all mutants to identify mucoid-causing mutations. Increased phage resistance co-occurred with decreased motility. This relationship was mediated by highly parallel (27/27) mutations to the Rcs phosphorelay pathway, which senses membrane stress to regulate exopolysaccharide production. Together, these results provide an empirical example of a pleiotropic relationship between two traits with intermediate genetic complexity.

A Heuristic Approach to Analysis of the Genetic Susceptibility Profile in Patients Affected by Airway Allergies.

Allergic respiratory diseases such as asthma might be considered multifactorial diseases, having a complex pathogenesis that involves environmental factors and the activation of a large set of immune response pathways and mechanisms. In addition, variations in genetic background seem to play a central role. The method developed for the analysis of the complexities, as association rule mining, nowadays may be applied to different research areas including genetic and biological complexities such as atopic airway diseases to identify complex genetic or biological markers and enlighten new diagnostic and therapeutic targets. A total of 308 allergic patients and 205 controls were typed for 13 single nucleotide polymorphisms (SNPs) of cytokine and receptors genes involved in type 1 and type 2 inflammatory response (IL-4 rs2243250 C/T, IL-4R rs1801275A/G, IL-6 rs1800795 G/C, IL-10 rs1800872 A/C and rs1800896 A/G, IL-10RB rs2834167A/G, IL-13 rs1800925 C/T, IL-18 rs187238G/C, IFNγ rs 24030561A/T and IFNγR2 rs2834213G/A), the rs2228137C/T of CD23 receptor gene and rs577912C/T and rs564481C/T of Klotho genes, using KASPar SNP genotyping method. Clinical and laboratory data of patients were analyzed by formal statistic tools and by a data-mining technique-market basket analysis-selecting a minimum threshold of 90% of rule confidence. Formal statistical analyses show that IL-6 rs1800795GG, IL-10RB rs2834167G positive genotypes, IL-13 rs1800925CC, CD23 rs2228137TT Klotho rs564481TT, might be risk factors for allergy. Applying the association rule methodology, we identify 10 genotype combination patterns associated with susceptibility to allergies. Together these data necessitate being confirmed in further studies, indicating that the heuristic approach might be a straightforward and useful tool to find predictive and diagnostic molecular patterns that might be also considered potential therapeutic targets in allergy.

New insights shed light on the enigma of genetic diversity and species complexity.

New insights shed light on the enigma of genetic diversity and species complexity.

Quantitative evaluation and genome-wide association studies of chrysanthemum flower color

Chrysanthemum, one of the economically most important and highly favored ornamental crops, exhibits a wide range of flower colors that are pivotal in determining its aesthetic value and market demand. However, probably due to the high genetic complexity of flower color traits, the progress in the dissection of genetic architecture and identification of quantitative trait nucleotides (QTNs) or candidate genes moves rather slowly. In this study, we systematically assessed the genetic variation of flower color phenotypes by integrating multiple color systems (RHSCC, CIELAB, and RGB) and four principal floral pigments (anthocyanins, chlorophylls, carotenoids, and flavonoids) in a diverse collection of 141 chrysanthemums. The results showed that the flower color traits exhibited a wide range of variations, with coefficients of variation (CV) varying from 26.00 % to 203.52 %. Among the 66 pairs of flower color traits, 48 exhibited highly significant correlations at p < 0.01 or p < 0.05 levels. Moreover, eight exponential regression models were established for predicting anthocyanin and carotenoid contents. Based on the 370,562 high-quality SNPs, genome-wide association studies (GWAS) revealed 36 QTNs significantly associated with flower color phenotype traits and 109 QTNs for pigment content traits. By integrating the functional annotation and expression profiles, a total of 809 candidate genes surrounding the QTNs were initially filtered out. The candidate genes encompassed multiple transcription factor families related to flavonoid metabolism pathways, including MYB, bHLH, WD40, NAC, and AP2/ERF transcription factors, as well as cytochrome P450-type enzyme genes. The current findings contribute to the accurate assessment of flower colors and provide valuable resources for the molecular breeding and functional analysis of flower color in chrysanthemums.

Decomposition of phenotypic heterogeneity in autism reveals distinct and coherent genetic programs.

Unraveling the phenotypic and genetic complexity of autism is extremely challenging yet critical for understanding the biology, inheritance, trajectory, and clinical manifestations of the many forms of the condition. Here, we leveraged broad phenotypic data from a large cohort with matched genetics to characterize classes of autism and their patterns of core, associated, and co-occurring traits, ultimately demonstrating that phenotypic patterns are associated with distinct genetic and molecular programs. We used a generative mixture modeling approach to identify robust, clinically-relevant classes of autism which we validate and replicate in a large independent cohort. We link the phenotypic findings to distinct patterns of de novo and inherited variation which emerge from the deconvolution of these genetic signals, and demonstrate that class-specific common variant scores strongly align with clinical outcomes. We further provide insights into the distinct biological pathways and processes disrupted by the sets of mutations in each class. Remarkably, we discover class-specific differences in the developmental timing of genes that are dysregulated, and these temporal patterns correspond to clinical milestone and outcome differences between the classes. These analyses embrace the phenotypic complexity of children with autism, unraveling genetic and molecular programs underlying their heterogeneity and suggesting specific biological dysregulation patterns and mechanistic hypotheses.

The genetic complexity of familial hypercholesterolaemia: Whole genome sequencing analysis in 100,000 genome project

The genetic complexity of familial hypercholesterolaemia: Whole genome sequencing analysis in 100,000 genome project

Genomic insights into prenatal diagnosis of congenital heart defects: value of CNV-seq and WES in clinical practice.

This study aimed to assess the efficiency of CNV-seq and WES in detecting genetic cause of congenital heart disease (CHDs) in prenatal diagnoses and to compare CNV detection rate between isolated and non-isolated CHD cases. We conducted a retrospective study of 118 Chinese fetuses diagnosed with CHD by prenatal ultrasound. Participants underwent CNV-seq and, if necessary, WES to detect chromosomal and single nucleotide variations. The overall detection rate for pathogenic or likely pathogenic chromosomal abnormalities was 16.9%, including 7.6% aneuploidies and 9.3% pathogenic/likely pathogenic copy number variations (CNVs), predominantly 22q11.2 deletion syndrome (54.4%). The sensitivity and specificity of CNV-Seq for detecting P/Lp CNVs were 95% and 100%, respectively. CNV-Seq offered a 6.7% improvement in detecting chromosomal abnormalities over karyotyping. WES further identified significant single nucleotide and small indel variations contributing to CHD in genes such as TMEM67, PLD1, ANKRD11, and PNKP, enhancing diagnostic yield by 14.8% in cases negative for CNVs. Non-isolated CHD cases exhibited higher rates of detectable chromosomal abnormalities compared to isolated cases (32.4% vs. 9.9%, p = 0.005), underlining the genetic complexity of these conditions. The combined use of CNV-seq and WES provides a comprehensive approach to prenatal genetic testing for CHDs, unveiling significant genetic cause that could impact clinical management and parental decision-making. This study supports the integration of these advanced genomic technologies in routine prenatal diagnostics to increase detection diagnostic yields of causal genetic variants associated with CHDs.

3D chromatin-based variant-to-gene maps across 57 human cell types reveal the cellular and genetic architecture of autoimmune disease susceptibility.

A portion of the genetic basis for many common autoimmune disorders has been uncovered by genome-wide association studies (GWAS), but GWAS do not reveal causal variants, effector genes, or the cell types impacted by disease-associated variation. We have generated 3D genomic datasets consisting of promoter-focused Capture-C, Hi-C, ATAC-seq, and RNA-seq and integrated these data with GWAS of 16 autoimmune traits to physically map disease-associated variants to the effector genes they likely regulate in 57 human cell types. These 3D maps of gene cis-regulatory architecture are highly powered to identify the cell types most likely impacted by disease-associated genetic variation compared to 1D genomic features, and tend to implicate different effector genes than eQTL approaches in the same cell types. Most of the variants implicated by these cis-regulatory architectures are highly trait-specific, but nearly half of the target genes connected to these variants are shared across multiple autoimmune disorders in multiple cell types, suggesting a high level of genetic diversity and complexity among autoimmune diseases that nonetheless converge at the level of target gene and cell type. Substantial effector gene sharing led to the common enrichment of similar biological networks across disease and cell types. However, trait-specific pathways representing potential areas for disease-specific intervention were identified. To test this, we pharmacologically validated squalene synthase, a cholesterol biosynthetic enzyme encoded by the FDFT1 gene implicated by our approach in MS and SLE, as a novel immunomodulatory drug target controlling inflammatory cytokine production by human T cells. These data represent a comprehensive resource for basic discovery of gene cis-regulatory mechanisms, and the analyses reported reveal mechanisms by which autoimmune-associated variants act to regulate gene expression, function, and pathology across multiple, distinct tissues and cell types.

Patterns of persistence: Genetic and behavioral population complexity of winter flounder amid population declines.

Winter flounder Pseudopleuronectes americanus (Walbaum 1792) are a coastal flatfish species of economic and cultural importance that have dwindled to <15, % of their historic abundance in the southern New England/Mid-Atlantic region of the United States, with evidence indicating near-extirpation of certain local populations. This species exhibits intricate behaviors in spawning and migration that contribute to population complexity and resilience. These behaviors encompass full or partial philopatry to natal estuaries, the generation of multiple pulses of larval delivery, and partial migration. The patterns of genetic diversity within and among estuaries and cohorts presented here carry important implications in understanding the susceptibility to demographic shocks, even if the full extent of genetic diversity within and among winter flounder stocks on the US East Coast remains unresolved. Our findings reveal connectivity between estuaries in Long Island, New York, suggesting the potential for genetic rescue of depleted subpopulations. Family reconstruction and relatedness analysis indicate that split cohorts and migration contingents are not the result of genetically distinct lineages. We found no evidence for genetic structure separating these groups, and in some instances, we were able to detect closely related individuals that belonged to different migratory contingents or cohorts. Characterizing the spatial and behavioral organization of this species at the population level is crucial for comprehending its potential for recovery, not only in terms of biomass but also in reinstating the complex population structure that supports resilience. The search for generality in winter flounder spawning and migration behavior remains elusive, but perhaps the lack of generalities within this species is what has allowed it to persist in the face of decades of environmental and anthropogenic stressors.

Genetic complexity of killer-cell immunoglobulin-like receptor genes in human pangenome assemblies.

The killer-cell immunoglobulin-like receptor (KIR) gene complex, a highly polymorphic region of the human genome that encodes proteins involved in immune responses, poses strong challenges in genotyping owing to its remarkable genetic diversity and structural intricacy. Accurate analysis of KIR alleles, including their structural variations, is crucial for understanding their roles in various immune responses. Leveraging the high-quality genome assemblies from the Human Pangenome Reference Consortium (HPRC), we present a novel bioinformatic tool, the structural KIR annoTator (SKIRT), to investigate gene diversity and facilitate precise KIR allele analysis. In 47 HPRC-phased assemblies, SKIRT identifies a recurrent novel KIR2DS4/3DL1 fusion gene in the paternal haplotype of HG02630 and maternal haplotype of NA19240. Additionally, SKIRT accurately identifies eight structural variants and 15 novel nonsynonymous alleles, all of which are independently validated using short-read data or quantitative polymerase chain reaction. Our study has discovered a total of 570 novel alleles, among which eight haplotypes harbor at least one KIR gene duplication, six haplotypes have lost at least one framework gene, and 75 out of 94 haplotypes (79.8%) carry at least five novel alleles, thus confirming KIR genetic diversity. These findings are pivotal in providing insights into KIR gene diversity and serve as a solid foundation for understanding the functional consequences of KIR structural variations. High-resolution genome assemblies offer unprecedented opportunities to explore polymorphic regions that are challenging to investigate using short-read sequencing methods. The SKIRT pipeline emerges as a highly efficient tool, enabling the comprehensive detection of the complete spectrum of KIR alleles within human genome assemblies.

Zebrafish: unraveling genetic complexity through duplicated genes.

The zebrafish is an invaluable model organism for genetic, developmental, and disease research. Although its high conservation with humans is often cited as justification for its use, the zebrafish harbors oft-ignored genetic characteristics that may provide unique insights into gene structure and function. Zebrafish, along with other teleost fish, underwent an additional round of whole genome duplication after their split from tetrapods-resulting in an abundance of duplicated genes when compared to other vertebrates. These duplicated genes have evolved in distinct ways over the ensuing 350 million years. Thus, each gene within a duplicated gene pair has nuanced differences that create a unique identity. By investigating both members of the gene pair together, we can elucidate the mechanisms that underly protein structure and function and drive the complex interplay within biological systems, such as signal transduction cascades, genetic regulatory networks, and evolution of tissue and organ function. It is crucial to leverage such studies to explore these molecular dynamics, which could have far-reaching implications for both basic science and therapeutic development. Here, we will review the role of gene duplications and the existing models for gene divergence and retention following these events. We will also highlight examples within each of these models where studies comparing duplicated genes in the zebrafish have yielded key insights into protein structure, function, and regulation.