2001) are necessary for normal human iris pigmentation. PubMed Because most human traits have complex genetic origins, wherein the whole is often greater than the sum of its parts, innovative genomics-based study designs and analytical methods for screening genetic data in silico that are respectful of genetic complexity are neededfor example, the multifactorial and/or phase-known components of dominance and epistatic genetic variance. 1996), melanocortin receptor (MC1R; Robbins et al. However, a number of the associations we identified were for SNPs located in other types of genes. Although most TYR-negative OCA patients are completely depigmented, dark-iris albino mice (C44H) and their human type IB oculocutaneous counterparts exhibit a lack of pigment in all tissues except for the iris (Schmidt and Beermann 1994). Other very minor genes are responsible for eye color production, such as agouti signaling protein, but they usually have miniscule effects.5, Finally, two major genes are responsible for eye color: HERC2 and OCA2. Place the PTC paper on your tongue for a few seconds. & WojasPelc, A. Interactions between HERC2, OCA2, and MC1R may influence human pigmentation phenotype. They also have little or no coloration in the iris of the eye, giving their eyes a pale blue or pink appearance. Most of the marginally associated SNPs were found within the pigmentation genes OCA2 (n = 10), TYRP1 (n = 4), AIM (n = 3), MYO5A (n = 2), and DCT (n =, SNPs marginally (independently) associated with iris pigmentation and SNPs associated only within the context of haplotypes and/or diplotypes. (2000). Most of what we have learned about pigmentation since has been derived from molecular genetics studies of rare pigmentation defects in humans and model systems such as mouse and Drosophila. We identified 5 additional genes (ASIP, MC1R, POMC, and SILV) and one additional region (GSTT2-22q11.23) with haplotype and/or diplotypes, but not individual SNP alleles associated with iris colors. Trace your probable genotype from trait 1 through trait 5 until you . We fixed significance levels at 5%, and the alleles of 20 SNPs were found to be associated with specific iris colors, 19 with iris color shades, 19 with blue/brown color comparisons, and 18 using the brown/not brown comparison. 1994). 2) although some associations were found within nonpigmentation genes such as CYP2C8 at 10q23, CYP2C9 at 10q24, CYP1B1 at 2p21, and MAOA at Xp11.3. However, single-gene studies have not provided a sound basis for understanding the complex genetics of human iris color. SNP discovery: We obtained candidate SNPs from the National Center for Biotechnology Information (NCBI) Single Nucleotide Polymorphism Database (dbSNP), which generally provided more candidate SNPs than were possible to genotype. Eye color results from varying degrees of melanin produced in the melanocytes of the iris. Philippe Suarez, Karine Baumer & Diana Hall, Kenneth K. Kidd, Andrew J. Pakstis, William C. Speed, Pirro G. Hysi, Ana M. Valdes, Timothy D. Spector, Kaustubh Adhikari, Javier Mendoza-Revilla, Andrs Ruiz-Linares, Hlne Choquet, Ronald B. Melles, Eric Jorgenson, Frida Lona-Durazo, Marla Mendes, Esteban J. Parra, Mathilde Josserand, Emma Meeussen, Dan Dediu, Journal of Human Genetics It is toward this goal that we have performed the present study. Frudakis, T., Thomas, M., Gaskin, Z., Venkateswarlu, K., Chandra, K. S., Ginjupalli, S. et al. Jannot, A- S., Meziani, R., Bertrand, G., Gerard, B., Descamps, V., Archibaud, A. et al. For example, unlike human hair color (Sturm et al. (2002), although it should be noted that we did not observe this gene association at the level of the SNP as they did; one of the ASIP SNPs that we identified (marker 861, Table 2) is the 8818 G-A SNP transversion that they described to be associated with brown iris colors, but from our study the association was with hazel color at the level of the haplotype. Many of these strains exhibit biologically and medically relevant phenotypes, including pigment dispersion, a common feature of several human ocular diseases. They help with hormone secretion, which affects the pituitary and can lead to dysfunction of the hypothalamus and other protein complexes. 1997). It is inherited or caused by somatic mutations within the cells.2 In addition, it can be caused by the inactivation of particular genes within the cells. Despite the color of the eye, the number of melanocytes does not differ. Iris transillumination: The iris in albinism has little to no pigment to screen out stray light coming into the eye.On slit lamp exam, the examiner may detect speckled or diffuse transillumination defect. Many more genes affect brown and blue more than the other eye colors. However, the results presented herein constitute a good first step toward solving what our results confirm is a very complex genetics problem. .. Rebbeck T R, Kanetsky P A, Walker A H, Holmes R, Halpern A C et al. Aside from these two genes, the genes involved in melanogenesis and other minor genes also contain regions that account for eye color. (2000) with adjusted residuals to compensate for this risk. (1986) and Shriver et al. An individual with this disorder produces little or no pigment in their ocular melanocytes. .. Schioth H B, Phillips S R, Rudzish R, Birch-Machin M A, Wikberg J E et al. To form eumelanin, dopachrome tautomerase, TYR, and TYR-related protein 1 complete the chemical pathway from dopaquinone.3, Although the aforementioned proteins are responsible for the production of melanin, once it has been produced in the melanosomes, other proteins are responsible for melanin maturation. Alternatively, the mechanism for the associations could be LD with phenotypically active loci in nearby pigment genes. From a screen of 754 SNP loci, we have identified 61 that are statistically associated with variable iris pigmentation at one level of intragenic complexity or another. The exact nature and density The distances between these loci associated with iris colors and neighboring pigmentation genes is far greater than the average extent of LD in the genome, and if it is the case that these associations are through LD, it would seem that, again, population structure would need to be invoked as an explanation. Number of times the haplotype was observed in our sample of 851. groups of the world that are of darker average iris color (Frudakis et al. In other words, the distribution of SNPs among the various genes tested was not random. A dark iris pigment (green/brown/black) is dominant over the light pigmentation. For most of the genes, multilocus gene-wise genotype sequences were more strongly associated with iris colors than were haplotypes or SNP alleles. In addition, for 103 of the subjects, iris colors were reported using a number from 1 to 11 as well, where 1 is the darkest brown/black and 11 is the lightest blue, identified using a color placard. During pigment distribution in an infant, a diet low in cysteine or methionine, which it is synthesized from, would likely affect the color of the child's eyes until the amino acid is supplemented. Liu, F., Wollstein, A., Hysi, P. G., Ankra-Badu, G. A., Spector, T. D., Park, D. et al. Supplement Series 1, 544546 (2008). 1993; Valverde et al. For those remaining, only a single round of PCR was performed. .. Ooi C E, Moreira J E, DellAngelica E C, Poy G, Wassarman D A et al. The strongest associations were observed for genes with SNPs that were marginally associated (Table 2) and most of the genes with marginal SNP associations had haplotypes and diplotypes (sometimes referred to as multilocus gene-wise genotypes or diploid pairs of haplotypes) positively (agonist) or negatively (antagonist) associated with at least one iris color (Table 3). Genotypes were subject to several quality controls: two scientists independently pass/fail inspected the calls, requiring an overall UHT signal intensity >1000 for >95% of genotypes and clear signal differential between the averages for each genotype class (i.e., clear genotype clustering in two-dimensional space using the UHT analysis software). In the absence of melanin brown pigment, the iris is blue. Accessibility StatementFor more information contact us atinfo@libretexts.orgor check out our status page at https://status.libretexts.org. lack pigment in skin (recessive) pigmented iris - pigments (dominant) hides blue/gray color of iris back layer ; attached earlobes - free earlobes dominant over attached earlobes ; hitchhiker's thumb - last joint of thumb bends back over 60 degrees . Therefore, single-nucleotide polymorphisms in either of these two genes have a large role in the eye color of an individual. The quantity and quality of melanin in the cytoplasm determines the observed color of the eye. Correspondence to 1997; Box et al. .. J Forensic Sci 55, 315322 (2010). A change in rs1800407 causes a change in the protein, Arg419Gln, and a change from brown to blue eyes. In melanocyte-specific organelles known as melanosomes, two pathways for melanogenesis occur. Slider with three articles shown per slide. These observations suggest that the genetic determinants for pigmentation in the various tissues are distinct and that these determinants have been subject to a common set of systematic and evolutionary forces that have shaped their distribution in world populations. Although such an error is tolerable for identifying sequences marginally associated with iris colors, the use of the sequences described herein for iris color classification would therefore likely require digitally quantified iris colors (which we have begun to accumulate and will present elsewhere). Before screening these genotypes for association with iris colors, we used the 73 nonxenobiotic metabolism AIMs to determine BGA admixture proportions for each sample and we tested for correlation between BGA admixture and iris colors. We focused on human pigmentation and xenobiotic metabolism genes, selected on the basis of their gene identities, not their chromosomal position. It is around 12 . Duffy, D. L., Montgomery, G. W., Chen, W., Zhao, Z., Le, L., James, M. R. et al. PubMed Hum Mol Genet 13, 447461 (2004). Sturm, R., Duffy, D., Zhao, Z., Leite, F., Stark, M., Hayward, N. et al. Although TYR is centrally important for this process, pigmentation in animals is not simply a Mendelian function of TYR or of any other single protein product or gene sequence. This epistatic relationship demonstrates the significance of introns and how a single-base change greatly affects an aspect of the individual. The second parent has a non-mutated HERC2 allele but does not have the coding for brown eyes in the OCA2 gene. Only about half of the 61 SNPs that we identified were associated with iris colors independentlythe others were associated only in the context of haplotypes or diplotypes. Some individuals may express two phenotypesone in each eyeor a complete lack of pigmentation, ocular albinism. Amplification products were subcloned into the pTOPO (Invitrogen, San Diego) sequencing vector and 96 insert-positive colonies were grown for plasmid DNA isolation (the use of 670 individuals for the amplification step reduced the likelihood of an individual contributing more than once to this subset of 96 selected). The remaining SNPs had values and chi-square P values that were not significant on any level of intragenic complexity. Hurst, C. C. On the inheritance of eye colour in man. Within the melanosomes, the tyrosinase (TYR) gene product catalyzes the rate-limiting hydroxylation of tyrosine to 3, 4-dihydroxyphenylanine (DOPA), and the resulting product is oxidized to DOPAquinone to form the precursor for eumelanin synthesis. One leads to eumelanin, a darker pigment (brown-black), and the other to pheomelanin, a light pigment (red-yellow). In Drosophila, iris pigmentation defects have been ascribed to mutations in >85 loci contributing to a variety of cellular processes in melanocytes (Ooi et al. PubMed (1995) and Koppula et al. Phenotypic Effect. We considered all 61 SNPs in Table 2, their haplotypes in Table 3, and their diplotypes (not shown). ISSN 1435-232X (online) Cell Mol Life Sci 62, 18261838 (2005). 5.01 In an experiment designed to study the inheritance of flower color in four-o'clocks, two plants with pink flowers were crossed. The pedigree in the accompanying illustration shows the inheritance of albinism, a homozygous recessive condition resulting in a total lack of pigment. Thank you for visiting nature.com. Refer to TABLE II. CAS brown, hazel) P > p. pp. You are using a browser version with limited support for CSS. .. Frudakis T, Venkateswarlu K, Thomas M J, Gaskin Z, Ginjupalli S et al. genotype - all alleles present in the cell ; phenotype - physical appearance of a trait ; . We thank D. C. Rao, Director of the Division of Biostatistics, Washington University, St. Louis, for help preparing this manuscript; Mark Shriver, Department of Anthropology and Human Genetics at The Pennsylvania State University for his help with the biogeographical ancestry admixture aspect of the project; and Murray Brilliant, professor of Pediatrics and Molecular and Cellular Biology at the University of Arizona for their kind advice and support of our work. ., Oxford University Press is a department of the University of Oxford. Further studies of this region and its sequence revealed that a change in one nucleotide, single-nucleotide polymorphism (SNP), regulates the binding site for the transcription of the OCA2 gene, altering its expression.9 The base changes from a thymine to a cytosine. b) List the possible genotypes for an individual with pigmented iris but lacking a dimpled chin. What is your genotype for this trait? Annals of Hum Genet 73, 160170 (2009). Aside from the fact that many of the SNPs we identified were significant after imposing the Steenland correction for multiple testing, there are three lines of evidence that the SNPs we have identified are not spuriously associated. A few of the genes/regions not harboring a marginally associated SNP had haplotypes and diplotypes positively and/or negatively associated with iris colors (ASIP gene, 1 haplotype; MC1R gene, 2 haplotypes; Tables 2 and 3). For people with brown eyes, some of the cells also have brown pigment in them. In the traditional view of eye color, it was taught that two blue-eyed individuals could only produce blue-eyed offspring. https://doi.org/10.1038/jhg.2010.126, DOI: https://doi.org/10.1038/jhg.2010.126. Even if the OCA2 gene contains the alleles for brown eyes, the SNP in intron 86 of HERC2 will prevent its expression. White, D., Rabago-Smith, M. Genotypephenotype associations and human eye color. 1998), but mouse studies have suggested that 14 genes preferentially affect pigmentation in vertebrates (reviewed in Sturm et al. Digital quantification of human eye color highlights genetic association of three new loci. The sequences for most of these genes vary significantly as a function of population structure (Frudakis et al. As mentioned previously, melanogenesis produces two different types of melanin and requires numerous proteins. In addition, we independently isolated the red hair/blue iris SNP alleles described by Valverde et al. (2002) recently described two OCA2 coding changes associated with darker iris colors. Others genes such as AIM, OCA2, and TYRP1 harbored haplotypes positively associated with brown but negatively associated with blue color (AIM haplotype 2; OCA2 haplotypes 2, 4, 45, 47; TYRP1 haplotype 4; Table 3) while others, such as the MYO5A, OCA2, TYRP1, and CYP2C8 genes located at 10q23, harbored haplotypes positively associated with one color but not negatively associated with any other color (MYO5A haplotype 5 and haplotype 10, OCA2 haplotype 19, TYRP1 haplotype 3, and CYP2C8 haplotype 1; Table 3). Diplotypes explained 15% of the variation, whereas haplotypes explained 13% and SNPs explained only 11% (Table 4) after correcting for the number of variables. Question: In albinism (a recessive disorder), the formation of melanin, a dark skin pigment, are blocked so that albinos have extremely light skin and hair. Eye color is determined by the pattern of brown and red pigment, collagen fibers, and the topography of the iris. Similar to a lack of TYR, other conditions cause ocular albinism. b) Give the genotype of an individual who is homozygous recessive for brown eye color. trends Genet. Department of Chemistry and Biochemistry, Kettering University, Flint, MI, USA, You can also search for this author in Incomplete dominance shows in individuals with lighter shades of brown and hazel. Furthermore, with all genetic expression, aberration also occurs. P is for pigment and dimpled chins (D) are dominant over undimpled chins. The solid figures represent albino individuals. Nature 361, 7276 (1993). Google Scholar. Over 300 SNPs for eye color have been identified on the gene, but classification of their results proved too arduous. In other words, their SNPs were associated with iris colors only within the context of gene haplotypes or diplotypes. The structure behind our results is unlikely to be of a crude (i.e., continental) nature; although two-thirds of our European-American samples were of significant (4%) BGA admixture, few correlations between structure measured on this level and iris colors were observed in this study. Although corrections for multiple testing left most of the SNP-level associations intact, a number of the associations we found did not pass the multiple-testing examination, but nonetheless we present them here to avoid possible type II error; the sequences may be weakly associated with iris colors and possibly relevant within a multiple-gene model for classification (i.e., epistasis). The most common, which the OCA2 gene is named for, is oculocutaneous albinism. Specimens: Specimens for resequencing were obtained from the Coriell Institute in Camden, New Jersey. HERC2/OCA2 rs12913832 and IRF4 rs12203592 influenced both eye colour and the number of iris pigmented lesions. The recessive allele (b) encodes blue eyes. Most of the haplotypes were even more dramatically associated with iris colors in a multiracial sample (data not shown), because many of the SNPs comprising them are good AIMs and variants associated with darker iris colors were enriched in those ancestral, The common haplotypes and diplotypes for the 16 iris color genes discussed in the text. The sequences we have identified constitute a good first step toward developing a classifier model for the inference of iris colors from DNA, and the nature of some of these as markers of population structure might have implications for the design of other complex trait gene-mapping studies. Aside from HERC2 and OCA2, the other genes involved in melanin production have some regions that correlate to other eye colors.5 MC1R contains regions that increase the probability of obtaining green eyes. Abbott C, Jackson I J, Carritt B, Povey S. Akey J M, Wang H, Xiong M, Wu H, Liu W et al. .. Gardner J M, Nakatsu Y, Gondo Y, Lee S, Lyon M F et al. (2001) haplotype reconstruction method. Although this could indicate that the SNPs are in LD with other phenotypically active loci, it may also be a reflection that variability in message transcription and/or turnover may explain part of the variability observed in human iris colors. Hardy-Weinberg equilibrium P value, where a value <0.05 indicates that the alleles are not in equilibrium. We did not confine this higher-order analysis to those genes with marginal SNP associations, but we grouped all of the high-frequency SNPs tested for each gene. Having little effect on eye color, many of them deal primarily with hair and skin pigmentation. To test this, we performed a corrected ANOVA analysis for our data on each of these three levels. In humans, eye color is determined by the amount of light that reflects off the iris, a muscular structure that controls how much light enters the eye. IRIS pigmentation is a complex genetic trait that has long interested geneticists, anthropologists, and the public at large. The two rounds were necessary due to the fact that many of the genes we queried were members of gene families, the SNPs resided in regions of sequence homology, and our genotyping platform required short (100 bp) amplicons. 2000), and adaptin 3B (AP3B) loci (Ooi et al. & Driscoll, D. J. Prader-Willi syndrome. TYR catalyzes the rate-limiting step of melanin biosynthesis and the degree to which human irises are pigmented correlates well with the amplitude of TYR message levels (Lindsey et al. We also acknowledge previous National Science Foundation support under grant numbers 1246120, 1525057, and 1413739. Although cysteine is not an essential amino acid and its deficiency rarely occurs, the lack of it halts the production of pheomelanin. In the population sample, we were also able to examine the correlation between genotype at the W locus and iris color . Before the revelation of the effect of HERC2, rs1800407 in exon nine was thought to be the main factor for eye color. Legal. Gene 277, 4962 (2001). The "P" allele produces the pigment which gives you eye color. .. Shriver M, Parra E, Dios S, Bonilla C, Norton H et al. Science 257, 1121 (1992). 20, 327332 (2004). If you cannot taste anything, you do not possess the dominant allele. 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