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How to identify whether something is in linkage disequilibrium?

How to identify whether something is in linkage disequilibrium?


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If the following loci indicated the presence of an SNP in flu strains, is Locus 2 and Locus 3, which are located 10 bp apart in linkage disequilibrium?

"When alleles and molecular markers are associated with each other at a frequency that is significantly higher than expected by random chance, they are said to exhibit linkage disequilibrium" Brooker's Genetics

Both loci seem to be linked, but how do I determine if it is significant enough to be considered in disequilibrium or not.


As per the definition you gave, you check whether there is a statistical association between the two. If knowing when allele is present at a locus does not affect the probability of finding a given allele at the other locus, then they are independent (there is no association). Otherwise, there is an association and hence the two loci are in linkage disequilirium.

See wikipedia > Linakge disequilibrium for more info.


Q&A: Genetic analysis of quantitative traits

Quantitative, or complex, traits are traits for which phenotypic variation is continuously distributed in natural populations, with population variation often approximating a statistical normal distribution on an appropriate scale. Quantitative traits include aspects of morphology (height, weight) physiology (blood pressure) behavior (aggression) as well as molecular phenotypes (gene expression levels, high- and low-density cholesterol levels).


Linkage disequilibrium

Linkage disequilibrium mapping is something you do in populations: you look at the non-random association of markers, which forms haplotypes (stretches of DNA that have the same markers between individuals). That means that a piece of DNA is co-inherited with a phenotype of interest.

It is linkage disequilibrium (LD), because you can predict the state of one marker if you know the state of the marker next to it (the markers that are used are SNPs). If something is in equilibrium, the distribution would be random.

Linkage is something you do in families (there has not been enough time for chromosomes to be shuffled around to look for LD). Here you look at the co-inheritance of a marker to a phenotype, the closer the two are together, the tighter the linkage between the two will be. If the two are far apart, recombination can reshuffle the physical position of the and linkage is lost.

The resolution of linkage is much lower than LD, so linkage is usually used for rough mapping and LD is used for fine-mapping or candidate-gene studies.

I'm sorry, but I'm a little confused here. Do you mean that when we are studying LD we are actually studying linkage in a population(instead of a family) and across several generations?

u been using wikipedia too much

dpsguy, if u know normal linkage, then u are almost there. state/loci, same meaning. The phenomenom can only analyzed in populations so u have more data to compare with each other, thats all.

LD is not the same as linkage. State and loci also don't mean the same thing. The state of a marker is whether the polymorphism is A or B. A locus is a location on the genome.

For linkage you test markers that are highly polymorphic, so that there is a lot of variation in one family and you can test wether a certain marker co-segregates with you phenotype of interest. Essentially you are looking at the segregation of a whole chromosome, where you use recombination events to narrow down the locus (piece of chromosome) where the marker and the phenotype co-segregate.

For LD you use markers that are very stable, so that you can look at a population level at their distributions. Here you are looking at tiny fragments of chromosomes, you can imagine that huge numbers of recombination events have happened in a population that reshuffled the chromosomes. A random distribution would mean there is an equilibrium. If there is an ancestral piece of DNA that is cosegregated with your phenotype of interest, you have LD. In this analysis you look at haplotypes, a whole series of markers with the same state that are co-segregated.


References

Plenge, R. M., Scolnick, E. M. & Altshuler, D. Validating therapeutic targets through human genetics. Nature Rev. Drug Discov. 12, 581–594 (2013)

Stahl, E. A. et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nature Genet. 42, 508–514 (2010)

Okada, Y. et al. Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population. Nature Genet. 44, 511–516 (2012)

Eyre, S. et al. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nature Genet. 44, 1336–1340 (2012)

Ferreira, R. C. et al. Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases. PLoS Genet. 9, e1003444 (2013)

Westra, H. J. et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nature Genet. 45, 1238–1243 (2013)

Raychaudhuri, S. et al. Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet. 5, e1000534 (2009)

Rossin, E. J. et al. Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology. PLoS Genet. 7, e1001273 (2011)

Segrè, A. V., Groop, L., Mootha, V. K., Daly, M. J. & Altshuler, D. Common inherited variation in mitochondrial genes is not enriched for associations with type 2 diabetes or related glycemic traits. PLoS Genet. 6, e1001058 (2010)

Stahl, E. A. et al. Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis. Nature Genet. 44, 483–489 (2012)

1000 Genomes Project Consortium et al. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012)

Raychaudhuri, S. et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nature Genet. 44, 291–296 (2012)

Trynka, G. et al. Chromatin marks identify critical cell types for fine mapping complex trait variants. Nature Genet. 45, 124–130 (2013)

Parvaneh, N., Casanova, J. L., Notarangelo, L. D. & Conley, M. E. Primary immunodeficiencies: a rapidly evolving story. J. Allergy Clin. Immunol. 131, 314–323 (2013)

Forbes, S. A. et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 39, D945–D950 (2011)

Eppig, J. T., Blake, J. A., Bult, C. J., Kadin, J. A. & Richardson, J. E. The Mouse Genome Database (MGD): comprehensive resource for genetics and genomics of the laboratory mouse. Nucleic Acids Res. 40, D881–D886 (2012)

Knox, C. et al. DrugBank 3.0: a comprehensive resource for ‘omics’ research on drugs. Nucleic Acids Res. 39, D1035–D1041 (2011)

Zhu, F. et al. Therapeutic target database update 2012: a resource for facilitating target-oriented drug discovery. Nucleic Acids Res. 40, D1128–D1136 (2012)

Smolen, J. S. et al. Consensus statement on blocking the effects of interleukin-6 and in particular by interleukin-6 receptor inhibition in rheumatoid arthritis and other inflammatory conditions. Ann. Rheum. Dis. 72, 482–492 (2013)

Nishimoto, N. et al. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod. Rheumatol. 19, 12–19 (2009)

McInnes, I. B. & Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 365, 2205–2219 (2011)

Sekine, C. et al. Successful treatment of animal models of rheumatoid arthritis with small-molecule cyclin-dependent kinase inhibitors. J. Immunol. 180, 1954–1961 (2008)

Sanseau, P. et al. Use of genome-wide association studies for drug repositioning. Nature Biotechnol. 30, 317–320 (2012)

Arnett, F. C. et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31, 315–324 (1988)

Okada, Y. et al. Meta-analysis identifies multiple loci associated with kidney function-related traits in east Asian populations. Nature Genet. 44, 904–909 (2012)

Hindorff, L. A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl Acad. Sci. USA 106, 9362–9367 (2009)

Lage, K. et al. A human phenome-interactome network of protein complexes implicated in genetic disorders. Nature Biotechnol. 25, 309–316 (2007)

Ueda, H. et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506–511 (2003)

Elliott, P. et al. Genetic loci associated with C-reactive protein levels and risk of coronary heart disease. J. Am. Med. Assoc. 302, 37–48 (2009)

Cortes, A. et al. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nature Genet. 45, 730–738 (2013)


Conclusion

In sum, we have described a novel pattern of co-localisation on the same chromosome of genes whose products interact, which cannot obviously be accounted for either by known models for co-ordinate regulation, nor by selection for linkage disequilibrium. The pattern may in part reflect a past history of block duplication. A version of the balance hypothesis is worth considering as underpinning to explain the results.

Tests of this hypothesis should be possible in the future. We should in principle be able, with fuller knowledge of gene order in many mammals, to reconstruct the past history of duplication and gene order re-arrangements that occurred through mammalian history. The model predicts an excess of block duplications in which both ligand and cognate receptor are found, as well as excess in which neither are found, but a dearth of those with one, but not the other. The model also predicts a general weakening of this initial signal with increasing numbers of inter-chromosomal re-arrangements, as the hypothesis proposes only an initial filter of block duplications, not ongoing direct selection to maintain linkage.


Discussion

This paper has introduced an efficient, linear-time forward-backward algorithm to estimate chromosome-wide probabilistic graphical models of fine-scale linkage disequilibrium, and has described a convenient way to display these models. In illustration, the methods have been applied to data obtained from three commercial breeds of pigs using the Illumina Porcine SNP60 BeadChip.

The forward part of the algorithm proceeds by combining a series of overlapping marginal decomposable models of dimension L and overlap length K. This implicitly assumes that the maximum width of the true graph is at most K. The resulting model is then triangulated and backward selection performed. The search space closely resembles that of [15], which samples from decomposable models with a given maximum width, using sliding windows. The difference in approaches lies primarily in the search method: here greedy search to optimize a penalized likelihood criterion is used, whereas in [15] MCMC sampling methods are applied.

The R function used for greedy forward search currently requires that the input data contain no missing values, so it was necessary to impute missing values prior to performing the algorithm, and the BEAGLE software [22] was used for this. This raises the possibility of circularity, or more precisely, that the model selection is influenced by constraints or assumptions implicit in the models used by BEAGLE. But given BEAGLE’s high imputation accuracy with such data it seems unlikely that this plays an important role here.

The algorithm was found to have high accuracy when applied to simulated data sets of the dimensions considered here (Np�), with edgewise false positive and negative rates of around 3%. That it is good at reconstructing the model generating the data is reassuring. Needless to say, the algorithm does not necessarily identify the “true” model, which may not be in the search space. As noted previously, the approach captures short range associations, but not long range ones. Moreover, higher edgewise false negative rates may occur when observed data are used if there are infinitesimal departures from a model that are not detectable at the given sample size, as these are filtered out when data are simulated under a selected model.

A comparison of triangular heatmaps with LD graphs is instructive. The former are compact graphical representations of all pairwise marginal associations for a set of SNPs. They are particularly well-suited to identify LD blocks, which stand out as highlighted triangles. LD graphs supplement heatmaps by showing patterns of association but not their strength. Since they are parametric models they can be put to a number of quantitative uses as described in the background section. At one level, heatmaps and LD graphs convey similar information, since intervals with simple dependence structures tend to appear as series of LD blocks in the heatmap, whereas those with complex structures tend to occur in the inter-block regions and have a more mosaic appearance. But the graphs provide a more incisive characterisation of genetic variation, building on the concept of conditional rather than marginal dependence. In this regard, it may be helpful to regard conditional independence statements as expressing the notion of irrelevance, in the sense that A⊥ ⊥B | C implies that if we know C, information about A is irrelevant for knowledge of B. Thus the graphs say something about connections between specific SNPs, for example about which SNPs are required to predict a specific SNP.

The graphs may also be useful in fine mapping. Genome-wide association studies seek to find the genetic basis of complex traits, typically using single locus methods - that is, by identifying SNPs with strong marginal association with the complex trait. Due to LD, many SNPs in a genomic region may exhibit strong association with the trait, making it hard to identify the causal loci. A way to address this is to assess the effect of a putative causal SNP on the complex trait in a linear model that also includes terms for the two flanking SNPs, in order to adjust for confounding with nearby effects due to LD. This implicitly assumes a simple serial dependence structure between the SNPs, and when the dependence structure is more complex such adjustment might be insufficient, leading to false positives. This may be prevented by including terms for the neighbours of the putative causal SNP, not just for the flanking SNPs. Any SNP is separated from the remaining SNPs by its neighbours, so by the global Markov property it is independent of the remaining SNPs given its neighbours. A similar method has been proposed based on Bayesian networks [38].

Like graphical models, the APFA models that underlie BEAGLE may be represented as graphs that encode a set of conditional independence relations, but in a very different way. In the present context, for example, nodes in APFA graphs represent haplotype clusters rather than SNPs. Where the model classes intersect, APFA graphs are much more complex than the corresponding dependence graphs, and so less amenable to visualization.

A striking feature of the LD graphs for the pig data was that for roughly 80% of the genome, simple serial or near-serial LD patterns were found, but for the remaining 20%, more complex patterns were observed. The regions with the simple serial structure tend to have low haplotype diversity, which is to be expected in livestock breeds with small effective population sizes [39]. Perhaps more unexpected is that roughly 20% of the porcine genome exhibits complex LD patterns, forming islands of relatively high genetic diversity. This information may be useful in an animal breeding context, to identify regions with high genetic variation. It will also be interesting to compare graphs obtained using different SNP densities in a given breed or species to examine whether and how their topologies change with varying marker densities.


Summary

Genetic epidemiology, including twin studies, provides robust evidence that genetic variation in human populations contributes to susceptibility to infectious disease. One of the major limitations of studies that attempt to identify the genes and mechanisms that underlie this susceptibility has been lack of power caused by small sample size. With the development of novel technologies, burgeoning information on the human genome, the HapMap project, and human genetic diversity, we are at the beginning of a new era in the study of the genetics of complex diseases. This review looks afresh at the epidemiological evidence that supports a role for genetics in susceptibility to infectious disease, examines the somewhat limited achievements to date, and discusses current advances in methodology and technology that will potentially lead to translational data in the future.


Lecture 16: Introduction to Linkage Disequilibrium - PowerPoint PPT Presentation

. The fitness of a single locus ripped from its interactive context is about as relevant to real problems of evolutionary genetics . p1 p2 q1 q2 . generation of . &ndash PowerPoint PPT presentation

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presentations for free. Or use it to find and download high-quality how-to PowerPoint ppt presentations with illustrated or animated slides that will teach you how to do something new, also for free. Or use it to upload your own PowerPoint slides so you can share them with your teachers, class, students, bosses, employees, customers, potential investors or the world. Or use it to create really cool photo slideshows - with 2D and 3D transitions, animation, and your choice of music - that you can share with your Facebook friends or Google+ circles. That's all free as well!


Author information

Ying Zhou and Hongxiang Qiu: These authors contributed equally to this work.

Affiliations

Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, Max Planck Independent Research Group on Population Genomics, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

Ying Zhou, Hongxiang Qiu & Shuhua Xu

University of Chinese Academy of Sciences, Beijing, 100049, China

Department of Mathematics, The Chinese University of Hong Kong, Shatin, Hong Kong, China

School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China

Collaborative Innovation Center of Genetics and Development, Shanghai, 200438, China


Basic concepts - linkage disequilibrium

Thinking about it today, I realized there is a "Basic Concept" that I think I should touch upon, and that is linkage disequilibrium (LD). Notice the wiki link? I do that whenever I mention LD because it is such an essential concept for some of the evolutionary ideas which I am interested in, but often not necessarily a transparent or clear one to the lay person.

Its lack of obviousness isn't due to complexity, LD is pretty simple, rather there are particular background ideas which one needs to firmly have in mind before one can easily grasp it. For this reason I've placed an image of a chromosome to the left. LD is not a purely intrachromosomal concept, but, I believe a biophysical model is important in understanding it, so I will use this image for illustrative purposes in the following post. So, you know that the human genome is divided physically into chromosomes, and each chromosome consists of two sister strands of DNA, chromatids. As you see to the left diploid organisms have two copies of a gene, alleles, at each "locus." A locus is obviously an abstract concept, it is basically a synonym for a gene. Assuming we have "gene" under our belts we can now conceive of a strand of DNA which is saturated with various genomic regions, introns, exons, intra and intergenic regions, etc. The details aren't particularly relevant to LD, just remember that locus 1 and locus 2 on the same chromosomal strand are a particular physical distance apart.

Now look at the image to the left. The numerical and letter notation refers to the locus and chromosomal arm position, respectively. Each of the four "slots" represents one of two diploid copies of the gene inherited from one parent. The + & - script represents, for ease of conception, functional and non-functional copies of the gene. Mendel's Laws tell us that the identity of an allele at locus 1 should not give us any information about the identity of the corresponding allele on the same chromatid. In other words, just because on copy "A" locus 1 is - should not tell us whether there is a greater likelihood of locus 2 on copy "A" being + or -.

That is where linkage disequilibrium comes it: LD basically measures the deviation from this expectation of non-association along the genome. As I noted above, though I am using the example on one chromosome, this can apply throughout the genome (my own interest is specifically in physically continguous genomic regions, more on this below). The mathematical calculation of expectation is simple algebra, and I won't reprise the explanation offered in the wikipedia entry for "D." But, I will point to three cases where LD could exist.

1) Consider a circumstance where there is an epistatic interaction between two loci contingent upon the alleles. Imagine a infection which is lethal to individuals with null copies (-) of the alleles above for locus 1 and locus 2 on the same chromatid (imagine that locus 1 & locus 2 enter into cis interactions). This is a case of LD being generated by fitness consequences because of genetic combinations. If the null and functional copies exist at high frequencies (e.g., both start at around 0.5 in generation 1), then you would have a situation where the extant proportion of individuals with genotypes which are shifted toward mixed (+/-) or functional alleles (+/+) along the genome at the loci would be higher than expectation. The presence of one null allele on a given locus can immediately tell you that the other locus does not have a null allele, because that combination is lethal. Of course, over time selection would expunge the variation which generated this LD, as the null alleles would decrease in frequency.

2) Consider a circumstance where two populations, previously separated, come into contact (e.g., an isthmus connects two islands). If the populations exhibit alternative alleles to fixation on several loci, and those loci are on the same chromatid, one can envisage a situation where two alleles on two loci exhibit linkage over many generations. The issue here is that synteny takes time to be broken apart by recombination, so the genetic complexes which had fixed in the parents will carry on and be passed into the subsequent admixed generations until crossing over disrupts the physical association. To give a concrete example, imagine a locus for eye color and hair color. Imagine one population is fixed for "white" for both (100%) and another is fixed for "black" (100%). The first generation would be totally heterozygous intralocus, but, each chromatid with a "white" eye color copy would also have a "white" hair color copy, and vice versa. Over the generations recombination would result in swapping of partners and eventually one would not be able to predict whether the downstream gene was "white" or "black" based on its physical partner, but that would take time.

3) Finally, the one I am most interested in because of its evolutionary historical significance, and that is LD generated by selective sweeps. Imagine a table top that is little used. Over time it builds up a layer of dust which disrupts it smooth symmetry. Now, consider someone sliding a towel over its surface. Across the region that the towel traversed the dust will be swept away and a smooth and clear symmetrical surface will now shine, bordered still by expanses of dust. Over time the smooth region will become obscured by dust once more and fade into the background. The analogy I am making is that the dust is genetic variation, while the sweeping towel is a selection event. If a new mutant allele confers great selective benefits then it can rise in frequency precipitously. If this rise is faster than recombination can destroy genetic associations, other alleles in nearby regions can be "swept" along in a hitchhike. If one imagines a scenario where the likelihood of a "break" along with recombination occurs is equally distributed across the genome (this is not true, but accept it for simplification) then decreasing the distance between two genes along a chromatid decreases the likelihood of a recombination event separating them on any given meiosis. Since a subset of the genome is less diverse than the full genome a selective sweep which favors a coterie of neighboring genes and alleles has a homogenizing effect, generating "long haplotypes," genomic regions cleansed of variation. Of course, this variation eventually reemerges via mutation and recombination, but it takes time.

And so there you have linkage disequilibrium. As you might notice, LD is epiphenomenal. It is a passing fad, but since it erupts periodically it can be an excellent marker for the historically contingent events which are important in evolution.


How to identify whether something is in linkage disequilibrium? - Biology

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07/10/08 05:51 - 75ºF - ID#44920

Linkage Disequilibrium Blocks/Triangles

I just had a zen moment in the interpretation of Linkage Disequilibrium Maps. (Also called LD maps, LD blocks, LD triangles - take your pick.) Turns out I was actually sweating 1st grade stuff!

I found that NO ONE explains this EXTRAORDINARILY SIMPLE thing in their umpteen papers, reviews, tutorials and what-nots. I just want to post this here so that when people google this simple little question, they find an equally simple and straight-forward answer!

This is an example of what a very small section of a Linkage Disequilibrium Map or an LD Map looks like.

Concentrate on the upper part of the map.

The thick blue line represents a strand of a chromosome. The white bars on the blue line of the chromosome are SNPs (Single Nucleotide Polymorphisms) that have been identified and sequenced. This means that we know what initial Nucleotide base has morphed into what final Nucleotide base. (Thus making it a polymorphic locus - or a position on the chromosome that exists in more than one form. The two forms are the intial nucleotide base and the final nucleotide base.)

These SNP locations or loci are labeled in this picture as 1, 2, 3, . and so on. Each of these SNPs has a name that starts with rsXXXXX where XXXXX is some numeric code. Each SNP is represented by a labeled grey triangle below the thick blue line (the chromosome).

The purpose of an LD map is to tell us whether any two given SNPs are INHERITED TOGETHER in an offspring. In other words, we want to know if any two given SNPs are in Linkage Disequilibrium.

An example: Are say, SNP #5 and SNP #9 in linkage disequilibrium? You trace down the column leading from grey triangle #5 or SNP#5 (Name: rs2299433) going toward SNP #9 (rs2237717). Do the same for SNP #9 going toward SNP #5.

The square in which the columns leading from SNP #5 and SNP #9 intersect is the one you should focus on. I have encircled it above. As you can see its a LIGHT RED and has a number, 75. Thus SNP#5 and SNP #9 have a correlation of 0.75 and are in fairly high linkage disequilibrium with each other.

In simple terms, if your square of focus is a deep red, then the two SNPs you are interested in have the highest correlation with each other and have a highest Linkage Disequilibrium. Thus, one of them can easily act as a proxy for another. The lighter the shade of red, the lesser is the correlation between the two SNPs. For example, SNP #5 and SNP #7 have a low correlation (0.32) with each other. Thus, you cannot reliably take SNP #5 and say that it could possibly act as a proxy for SNP #7.

LD Maps also tell us about HAPLOTYPE blocks. See the blocks labeled, "Block 1 (49kb)", "Block 2 (23kb)", "Block 3 (93kb)" . and so on.

These triangles or the blocks of dark red represent SNPs that are all in high linkage disequilibrium with each other and thus are all inherited together. They are also on the same section of the chromosome. These SNPs form a HAPLOTYPE. Every big red triangle or block in the LD map indicates a HAPLOTYPE on the corresponding stretch of the chromosome above. You only need to look at one or maximum a couple SNPs in a haplotype to know about the fate of the entire section of the chromosome that forms a Haplotype. It saves money and time.

The HapMap Consortium project has painstakingly constructed such an LD map for each and every known SNP in the entire human genome. Their LD maps look somewhat like this (using the haploview software: )

Though it is complicated, if you followed the simple tutorial above, you should be able to make sense of even complicated maps such as these. You are most welcome to leave a comment or drop me an email if you need further clarification!

I don't care who is laughing at this ridiculously detailed explanation of a kindergarten concept in genetics and genomics. Personally, I am just EXTREMELY relieved to finally know it well enough to be able to explain it. :)

raddna writes at 12:10:10 03/26/14 - Comment #71500 Awesome explanation. Totally simplified.

tinypliny writes at 09:47:31 07/10/08 - Comment #36909 Wow!! You should totally apply! You'd make an awesome Epidemiologist!! Let me know if I can propel your thoughts a bit more toward Epi. I think (e:boxerboi) is seriously considering Epi as well. The future is in Genetic/Molecular Epi and population studies.

terry writes at 09:21:24 07/10/08 - Comment #36908 More and more I think this may be where I am heading. From chemistry to biology to biochemistry to microbiology to genetic epidemiology. seems logical to me.

tinypliny writes at 08:48:28 07/10/08 - Comment #36900 That's funny, (e:heidi). :)
Thanks for commenting! Just to make it a bit more clear, I think I should add a simplified explanation of why exactly its called Linkage Disequilibrium when two SNPs are inherited together. The first part is easy. The SNPs are linked together on the same chromosome-> hence "Linkage". It's a disequilibrium because if they had not been linked together (or had been independent of each other), the offspring would be as likely to not inherit the two SNPs together as they would be to inherit them together. So there would be a 50/50 chance of getting them together or not getting them together, from the parents. Thus, if you examined a huge number of offspring and looked to see whether they have any two independent/unlinked SNPs, you would find an equilibrium between the condition of inheriting the two SNPs together and the condition of inheriting only one of the SNPs.

A more rigorous and mathematical explanation of the above is called the Hardy-Weinberg Equilibrium/Principle/Law in Genetics. . link.

heidi writes at 07:27:00 07/10/08 - Comment #36894 Wow, Tiny! That's really cool. Not that I'd ever heard of linkage disequilibrium before just now. but learning the word "disequilibrium" alone was worth reading this. :-)

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07/09/08 08:40 - 74ºF - ID#44915

Nifty Research Tools and Software

I found a host of nifty and useful research tools out there that are totally worth sharing multiple times. These might be just the life-savers, organizers and new-idea germinators that graduate students and serious researchers are looking for. Can't guarantee that they would make your life easier though.

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The real question is however, just how many RSS feeds can one read before it turns into an unmanageable information overload and just becomes toxic??

It has a very simple interface that I use to make a checklist of things I need to do everyday. Finishing the tasks on the list actually is very satisfying. I find that the more I use it, the more disciplined I want to be in my reading and work goals. I know I can very well make lists on paper. But if I use an online interface (a) I don't have to worry about losing my lists, (b) I can access and tick off my list from anywhere (Well, almost. Any place that has net access). (c) Save paper! (d) copy out the list if I need to be in a really remote location, or maybe a conference.

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4. Synchronizing Notes, PDF Annotations, Anywhere, Anytime: Note-Taking Software Comparison: If you print out PDFs just because you can't mark them up online/on-screen, there is help! By using some of these FREE note-taking software you can mark and highlight those PDFs on-screen, avoid all that paper clutter and save all those reams of paper (and trees). I currently use Jarnal - a platform-independent, open-source, free Java-based note-taking software ->

Options. Options. So many Options.

tinypliny writes at 11:04:50 07/09/08 - Comment #36879 It's interesting you say that because that very thought is also related in a tangential way to the future of the tissue repository at Roswell. They are planning to set up microarray libraries for all the breast tumour tissue they have in the repository. Microarrays are an indepth analysis of the DNA/RNA (and thus potentially proteins) that a tumour generates. This is called the expression profile of the tumours.

These DNA, RNA and proteins (expression profile) make up the tumour's "signature". Thus, a microarray might be used to recognize a tumour and classify it on the basis of its signature DNA/RNA and proteins (or expression profile). However, tumours have a lot of DNA and produce tons and tons of various RNA sequences (and thus proteins) and their expression profiles can be mind boggling. As we speak, new expression profiles are probably being discovered and characterised.

The problem is not every RNA sequence produced by these tumours can be profiled because of the huge amount of effort and cost involved in building a microarray library that is so detailed as to included every RNA sequence ever discovered. So the researchers now have to pick and choose what DNA/RNA sequences are the most relevant for the classification of the breast tumours and would most likely be used by investigators in their future research. This is necessary to cut down the costs. Also, we have limited amount of tissue and not an endless quantity. Hence, the need for careful consideration.

The dilemma is, research is evolving so rapidly that we cannot possibly know if the profiles that are used to classify tumours today will still be relevant tomorrow. I wonder how we will decide what goes into the microarray library. Would it still be useful, say ten years from now? Would we have wasted all the money to drill for so much information and yet be faced with a lack of information some years down the line? The meeting is next week. The decisions that will be made will be very crucial to the future of tissue-based research at Roswell. And it will all boil down to one question: How much information could we possibly afford today so that it might be helpful tomorrow?

paul writes at 10:19:32 07/09/08 - Comment #36878 I think about this all the time. At work we will be intergrating some blogging technology I am developing into the new intranet. It is hard to tell what happens when there is too much info. Luckily, computers are good at sorting and searching and you don't have to read everything. In my opinion it is better to put too much information in now and find ways to make it usable later than to not collect any info at all.

Permalink: Nifty_Research_Tools_and_Software.html
Words: 477
Location: Buffalo, NY

07/07/08 08:15 - 85ºF - ID#44897

Three Cheers to E:boxerboi

My current inspirational summer hero is (e:boxerboi). He is taking on the formidable MUSSELMAN TRIATHLON CHALLENGE. this weekend!

You could walk by his office and not notice the absolutely cool bloke who works there. But beneath his calm and almost zen-like efficiency lies the makings of a genuine hero! While lesser souls on the third floor show varying degrees of wimpiness and run around in circles, (e:boxerboi) quietly comes by and conquers the world! Like a true hero, he has a magically unceasing and very much hidden stash of some very lethal weapons.

1. Chuckles

2. Blueberries

Don't underestimate the power of these weapons of choice. They are jam-packed with massive undercurrents of overwhelming charm. Needless to say, I have been totally swept away and I hereby appoint him the

Hero of the Extreme 3rd Realm of Planet K

Join me in wishing him all the very best of luck in his mission to conquer the Musselman World not once, not twice but a WHOLE THREE TIMES!!

THREE CHEERS to you, (e:boxerboi). You ROCK.

Permalink: Three_Cheers_to_E_boxerboi.html
Words: 184
Location: Buffalo, NY

07/04/08 12:05 - 69ºF - ID#44858

Subway. Finger-licking Freedom.

I know I am mixing up punch lines and writing a blasphemously laudatory post about a fast-food place, but Subway deserves my respect in so many ways! I am not being paid an obscene amount of money for an ad campaign or miraculously losing bucketloads of adipose tissue by eating here but this chain has rescued me from many a day of hypoglycemia and certainly prevented me from turning cannibalistic. In due recognition of its consistent and gastronomically positive contributions to my life, I am going to do a (e:Drew)-style 10 things I like about Subway here:

1. It's the most healthful food you could eat if you are without access to your kitchen or in a tearing hurry or just poor.

2. If you wisely pick your sandwich (and yes, I do mean the veggie sandwich. I don't care what all you carnivores out there think. The veggie sub rocks your socks off!) you get a very balanced meal.

3. They have a superlative item on their menu that I can easily zone in on (the creatively but wrongly spelled Veggie Delite Sandwich, what else. ). This eliminates my aimless-vacillation-time (AVT). AVT is the eternity that I spend making food decisions while people's heads around me explode with pent-up frustration at my indecision.

4. You get UNLIMITED veggies for a fraction of the money that you might spend for a similarly loaded meal elsewhere in the whole city. I regularly test out if the "unlimited" part of the veggie deal is true and almost invariably the place passes my exacting standards of veggie greed with flying colours. The Chippewa Subway also has BABY SPINACH! 'Nuff said.

5. The bread choices are delicious. And most of them are super healthful. The honey-oat bread is a gustatory dream with its chewy delicious texture and is an awesome boost to your daily fibre intake.

6. If you say the magic (and secret no more) word "double toast", you can get your bread of choice toasted *twice* to a glorious rich golden brown delicious scrunchy heavenly colour. I am running out of elaborate adjectives to describe how perfect the double toasted bread is. Everything tastes about a million times better with a double toast!

7. You could get cheese on your sandwich and not only benefit from all the amazing proteins and calcium, but also make your sub 10x tastier.

8. The wait time between your order and the first morsel reaching your mouth is ridiculously low. Since you can watch your sub being built, it's even shorter and livelier. It's almost sandwich-making-by-proxy calming and fun! You don't have to sit at a table and wonder whether the kitchen ran out of tomatoes and are as a result raising them from the ground or direct a contemplative and lifeless stare at at your companion's hand with the eminent possibility of chewing it off in a demented fit of hunger.

8. The sub arrives and it's time to pay the bill. The price is so reasonable that it blows your mind. After aeons of being overcharged at every single place that is half as comparable to the Subway, you cannot believe that the fabulous piece of divine contentment you hold in your hands only costs $2.49 for a six incher and $5 for a footlong! If you have foupons, the cost is cut by a further .50 to $1.

9. There is no presumption or discrimination at a subway. It's the only place you feel equally at ease chatting up the stressed businessman who has dropped by for a quick bite or the bag-lady from the greyhound station who wants to stretch her last dollar for a substantial lunch. The subway is an oasis of socialism even within a capitalistic framework.

10. You could ask that your sub be loaded up with a truckload of Jalapenos and not have the person serving you give you the look of death or a disgusted stare.

On July 04, 2008, to me, the subway chain represents one of the many facets of freedom that this country lavishes on its residents - citizens or not.

heidi writes at 07:45:23 07/05/08 - Comment #36754 12" veggie delight on italian herb & cheese bread, some of each cheese including the shredded (depends on the sub-maker if I get charged for double cheese), toasted, chipotle sauce, baby spinach ("a little more spinach, please?"), cukes, tomatoes, green peppers, pickles, carrots (at the Mansfield subway, not available at the Walmonster franchise), oregano and shaker cheese. "That's the greenest sub I've ever made," said one sub-maker.

12" means I've got food for later.

metalpeter writes at 01:14:19 07/04/08 - Comment #36720 I'm not sure when the 1st time I ate there was but it was guessing before when Paul said but maybe around then. I myself like there meat but now with their new roast beef have to look to see if it is pink or brown some people like it pink but I don't (insert you're own pink joke here______________________________________________ ) . I like that you can see if everything looks fresh. and they do have pizza also and that isn't bad, my favorite is Buffalo Chicken or even to add Bacon to it. That brings me to my point that everyone thinks subway is healthy and Mcdonald's causes Heart Attacks. That isn't true it is about what you eat. For example once Bacon, Mayo or Cheese gets added or you go for double steak then the health drops. Just like you can go to Mickie D's and get salads like one guy did a drop hundreds of pounds. Since subway did there $5 promo I have gone a lot more. Taste is a very personal thing and so some people might prefer Quiznos but try finding one of those in Buffalo.

paul writes at 12:17:32 07/04/08 - Comment #36718 You should be paid for this, lol. No seriously, when I was younger I loved subway. Escpecially, once they had all those yummy brea choices.

When (e:terry) and I worked at HSBC downtown back in the early 2000s during our "lunch" break there were only two choices. Subway and McGuidos - an irish and italian place. That was really the name. The place has since closed down.

Anyways, we most often ate Subway and I actually got sick of it even thought I loved it. Also their meat is a little weird and over processed - you probably don't experience that.

Permalink: Subway_Finger_licking_Freedom_.html
Words: 669
Location: Buffalo, NY

07/03/08 01:20 - 76ºF - ID#44844

I had a splendid time at the concert yesterday and I am more than convinced that sighting 5 (e:peeps) in one day is the secret recipe to that day's quota of perfect happiness. If the (e:peep) sighting number (EPSN) shoots up to more than 5, the levels of euphoria increase exponentially. I often experience it after (e:) strip parties. I catch myself unconsciously grinning ear to ear for more than 24 hours at a stretch.

The weather was so perfect that the popular song by the Carpenters got stuck in my head. I had to listen to some angry flamenco rough and raw music to erase that ridiculous song. The first (e:peep) sighting was of course (e:imk2) at work. I thought it was weird that she was tip-toeing it into the printer/mail room. I actually checked to see if she was wearing new shoes and had a shoe-bite or something. I learned later that she had been risking her life and limb by going in there. Apparently, a huge wasp was hiding in that room somewhere and the chair of the department had been trying to swat it dead. I am super glad I didn't see it. Who knows what I might have done to (e:imk2) with my tendency to throw extreme drama freak-outs. I saw (e:boxerboi) on the way home and we had a very soul-purging talk about how high-school has an annoying tendency to persist sometimes. :)

I persuaded a couple of my friends to walk to the concert but I omitted to tell them that it was a good half an hour's brisk walk from downtown to Bidwell. We were somewhat dehydrated by the time we reached the concert venue and dashed into Cafe Aroma to get something to drink. A bloke dressed as a huge Target dog entered and in a proper touristy fashion, we got all excited about being clicked with **the target dog**. However, before we could shoot, the target dog made a beeline for the bathroom and was decapitated by his target-mates. It was probably the most disappointing moment of the evening.

We ran into (e:James) at the Bidwell crossing. I was all worked up about missing the photo-op of a lifetime with **the target dog** and all I could remember was (e:James) had been recently promoted to a power position as a deputy commander of something political. That title stuck and I had to struggle not to introduce him as "The deputy commander!". A second title of "James, the terrible (multi-translation poet)!" suggested itself, but I choked that one down as well. Instead, I introduced him to my friends as a "very powerful politician". I could see (e:James) through my peripheral vision looking at me as if I were from planet loony but it was too late! I admit that it was a desperate and poverty-stricken moment for my brain and those are the times I say the weirdest things. So, you all better tell me in advance what you would like to be introduced as! Your profession choices range from God of the Mountains to Ruler of the Land of the Dead. Take your pick.

We finally made it to the frontlines and plonked down on the grass. The Buffalo Philharmonic played some very popular tunes in full regalia.

However, this charming young couple stole a huge chunk of BPO's limelight by waltzing away in abandon in front of the stage. Their dance became more elaborate with every song and my friend and I were half expecting them to break into some crazy whirls and rock and roll dancing.

That didn't happen. At the intermission, I was somewhat bothered by the fact that I could probably never play this cello because it was taller than I was.

A thousand kids invaded the space in front of the stage. The concert was triple the fun just because of these little dancers. :)

However, some stuffed up people were bothered and the primary conductor tried to rein in their exhuberance for a couple songs.

But thankfully, was not very successful. :)

This pretty young artist from Williamsville High School played as part of a scholarship to the BPO. Her oboe solo was pitch perfect and wonderful. I think her whole family was in the audience to cheer her on. It was very sweet.

They had a raffle for this HUGE (and somewhat scary looking) stuffed dog sponsored by Target. No one claimed it for a very long time after the announcement.

I was sorely tempted to go up and lie my way into getting it. It might have made a fabulous chair and totally made up for the missed photo-op with **the target dog***. Much to my disgust, I found that I did have a sneaky little conscience that prompted me not to pull off the smooth con act.

I don't know if kids were losing their balloons or someone was intentionally releasing them every 15 minutes or so. They were so cool to watch in the cloud streaked sky.

The band struck up the chords of the most covered and yet the most perfect song ever recorded in the history of pop - Yesterday. Here's a choir version to give you an idea of how heavenly it sounded.


Your browser does not support inline playing of mp3 files.


The sunset was gorgeous.


On our way back, just as I was telling my friends that it would be so cool if they got to meet (e:drew) and (e:janelle), I walked almost right into (e:drew)! He and (e:Jason) were folding up the chairs. We walked halfway home with them. Enroute, I heard about the heroic story of Roberto Clemente Walker I was told that my lurid suspicion that his plane might have been sabotaged was not really true. Oh well. I guess real life imitates inspiring tragedies rather than spiffy spy movies. The excellent alliterative phrase "mediocre medium" was mentioned in relation to a video game called "Guitar Hero" - I think by (e:Drew).

After (e:Drew) and (e:Jason) turned into Lexington, we ran into none other than (e:fellyconnelly) and the king of (e:) strip, (e:RRRAAALLPPPHII)E! The excitement of finally seeing Ralphie was a like a shot of a crazy drug and my already fried brain could not recall (e:fellyconnelly)'s real name. If you thought (e:James) got a raw deal, hear this. I introduced her as Raphael. Raphael! Holy crackers, I couldn't even think of a modern name. I had to pick something from the 1600s. Don't ask me why!

All of (e:fellyconnelly)'s recent blogging was enacted in real life. My friend and I went down on our knees and cooed all over the little guy. (e:fellyconnelly) rules Ralphie's world. She held out some magic potion and Ralphie stood still for a photograph!

Special thanks to my friends who tolerated my non-stop brainless jabbering and came out with me to enjoy the evening and to all the (e:peeps) who made it even better! It was an awesome official grade 5-EPSN yesterday. :)

james writes at 09:45:41 07/03/08 - Comment #36698 I didn't mean to look at you like you were crazy. I was a little rushed to get a project started and my cohorts were ready to desert me. Feel free to introduce me in the future of "Ruler of the Land of the Dead." It is a very nice title.

And you can still play cello. That was a bass on its side. So cello it up Pliny and we can start a rock band!

drew writes at 11:18:59 07/03/08 - Comment #36677 Just for the record, I am a "mediocre hard," and an "excellent medium" guitar hero.

paul writes at 09:50:31 07/03/08 - Comment #36674 Congratulations - this is your 100th journal.

mrmike writes at 07:36:33 07/03/08 - Comment #36673 Sounds and looks like a thoroughly awesome day :)

Permalink: Yesterday.html
Words: 1208
Location: Buffalo, NY

06/28/08 11:07 - 71ºF - ID#44815

The Genome-Wide Global Dance

Dances bring people together.
So do LD blocks and HapMaps.

An inspirational cross-continent dance video with a number of analogies in genetics that I won't bore you with. :)

fellyconnelly writes at 09:11:05 06/29/08 - Comment #36577 oh man. wouldn't you like to have that guys job? i'm just going to travel to ALL these countries. ANd dance. maaan

jacob writes at 02:37:22 06/29/08 - Comment #36575 I'm astounded. Cute avi.

leetee writes at 11:33:57 06/28/08 - Comment #36571 nice. thanks for posting. :O)

Permalink: The_Genome_Wide_Global_Dance.html
Words: 75
Location: Buffalo, NY
Last Modified: 11/09/11 08:14

06/25/08 10:51 - 68ºF - ID#44781

The TinyPliny Avatarolution

Almost everyone has a story about their avatars - those 125 X 150 pixels of online identification that stay with your readers through the thick and thin of your posts. Since my posts have dropped to the extreme triviality level of picking arguments about comic book fonts and posting pie-charts from arcane web-gadgets that nobody uses, I am under some pressure here. The immediate challenge is to achieve the nadir of triviality and set the bar even lower for the most trivial post on (e:strip). This entry to the "Who-wants-to-be-most-trivial?-I-DO!"-contest is the nausea, triumph, obsession, and nitpickiness-filled story of the evolution of my 18750 pixels. Start holding your breath, the lower boundaries of a tonload of totally unnecessary fluff are about to waft your way.

Anyone who has walked through the Cancer Cell Center (CCC) at Roswell, and has even a fractionally functional olfactory apparatus, can recall the all-pervasive sickly and somewhat homely smell that hangs about in that building. I have heard people make all sort of wild guesses about the source of this smell, ranging from imported transatlantic ducks being slaughtered alive in the building to cell-culture media rotting away to yuck-tastic glory. When your imagination is not up-to-creative-snuff with the almost-hallucinogenic peak of glory that your companions seem to have, you usually have three choices: a) Accept the most entertaining conjecture and hurry away from CCC, b) Make a mental note to not recall the smell while you are eating your lunch and hurry away from CCC and c) Decide in an unhinged moment that you will find out the source of that yucky smell and thrust your already unimaginative mind into the deeper doldrums of absolute, annoying and certain knowledge.

Needless to say, I took the third route. (Now, don't tell me you didn't see this coming!!) Though the exact source of the CCC smell still remains elusive, I do have a fair idea. and also my very own avatar. If you cannot see the relationship between between the last assertion and the rest of the sentence, then I guess you can safely assume that you are sane. (Yeah, breathe slow. You can cancel that shrink appointment today.)

Late last year I took the "Working with the Laboratory Mouse" course in the Animal Lab Facility in the CCC/Library building. It was then that the sickly smell hit me full force. It invaded my senses and took over whatever grey matter I had left, when I got out of the stairwell and headed toward the Animal Lab Facility. At this point, countless crime novelists over centuries might have hastily scribbled, "The realization dawned on her." Since these cool novelists were not around to make their erudite observations, I took on the responsibility of playing up EUREKA moment by shouting, not the eponymous "EUREKA!" but the painfully obvious, "IT'S THE MICE. ". I quite understand why the veterinarian of the facility smiles in sympathy at me even after all these days. I earned the smile in extreme style.

I spent the better part of the practical training sniffing around the facility in what I thought was a discreet and sophisticated manner. But unfortunately, my discreetness was mis-interpreted as an incipient cold and a precautionary mask was thrust into my hands. Being masked put a damper on my detection capabilities and thus the mystery of the exact source of the omnipresent smell remains thus.

I came home, and did what any disappointed graduate student would do - wikisurf. I discovered fascinating details about the life and times of numerous members of the rodent family, hit the wikimedia commons road and fell in love with this magnificent image of the wood mouse.

I resized it and adopted it as my 18-odd-k pixels of online fame. Days passed, and at a party someone remarked that seeing a mouse reminded them of me (actually, they didn't really say this, but my brain came to this euphoric interpretation). My avatar had finally arrived! It was thus time to embellish it with idiosyncratic accessories. I chose a starred neck-tie. As any movie enthusiast would agree, drawing montages are always rolled out to the background of music. My music of choice for the nitpicky tale of avatarolution is the genre better known to the mainstream listeners as rap and to the classicist snobs as poetry.


With ball-point ink and felt-tip pen, I fell to sketching
But captured with a flash, it didn't look so fetching

Under lamplight the eyes were perfectly beady and filled with vice ((e:libertad,41910))
But I had an issue with brightness and I said, "No Dice!"

Tweaked brightness and contrast in PAINT.NET
A software so free that it is not a financial threat

At this point it lacked a certain punch
The oil paint and ink filters gave it the furry scrunch.

But alas, it didn't gel well with (e:strip) so I tinted it red.
However, in the comments background it looked rather dead.

The magic wand and colour inversion came to my rescue
OH NO! I had neglected the neck-tie with the stars askew

Added the sparklies and lightened it up a bit
Behold the 18750 pixels of the TinyPliny image-split.

But those 18750 pixels make it so hard to see
The eye on the right, won't you agree?

Looking out my window I found the perfect antidote
The rich blue of summer skies with a hint of creosote.

'Twas too much of colour and one too many alteration
Got sick of 'em all and opted for a modified third iteration.

james writes at 10:54:39 06/25/08 - Comment #36478 That was awesome. Thank you for sharing.

Permalink: The_TinyPliny_Avatarolution.html
Words: 975
Location: Buffalo, NY

06/23/08 11:48 - 65ºF - ID#44764

The Chaotic Red Musical Pie

Not surprisingly, my daily airplay breaks down into quite a heavy dose of metal of various flavours along with a smattering of other genres:

My "open mind index" that apparently measures how open-minded I am when it comes to music is 102.

To get this silly graph, you need to:

a) have a last.fm profile
b) have played and scrobbled a sizeable chunk of music
c) Go here: and enter your profile name, type in the security code and choose your preferred colour craziness.

And Voila, your musical tastes are neatly broken down into a pie-chart in eleven different colour schemes ranging from tame to frank-epileptic-fit inducing. The epidemiologist in me cannot help but plot a population musical-taste study with such detailed statistics.

Permalink: The_Chaotic_Red_Musical_Pie.html
Words: 132
Location: Buffalo, NY

06/21/08 10:22 - 73ºF - ID#44737

I need to sketch graffiti.

Does Buffalo have an official free-to-all-artists graffiti wall?

Permalink: Oh_how_I_missed_this_.html
Words: 15
Location: Buffalo, NY

06/19/08 04:03 - 62ºF - ID#44721

This question is for the designers and the typographers among you. Why is it that you hate the comic sans font so much? It is the only font that is extremely legible at small sizes, is pleasant to look at and can be read without giving one a headache, and yet there seems to be this almost virulent bunch of people who are hell-bent on eliminating this happy font from the web. Why is that?

I don't find any logic in several of their arguments:
1. It is ugly: How can such a legible font be "ugly". The word "ugly" implies loathsomeness and annoyance - both of which, are far away from your mind when you read text typed in comic sans. It's so darn easy to read it. No effort is required to make out what the alphabets are. It's so eye-friendly.

2. It's inappropriately used in varied contexts: How do you define inappropriate? Who defined what is formal and what is informal? Fonts are not equivalent to clothes, that analogy never works. Is eye-friendliness and ease of reading only meant for kids? What happens to us as adults? Do we intentionally want to ruin our moods and eyesights by being forced to read fonts that don't even have breathing whitespace?

3. It's ill-designed: Again, which font is the "best-designed" according to you? Why is it that only the designers complain ad-nauseum about this beautiful down-to-earth font and the general "lay-public" uniformly love it? Why can't typography be user-friendly instead of being snob-friendly?

I ask you, all you people heading to the Typography convention next month, here in Buffalo. Give me some logical arguments and not snob statements as to why I should not use this font. I sent out two international reports to the scientific community using this font and none of them had any problems with it. I even found a LaTeX version of the comic sans font! Why do you view it as a fly in the typographic ointment? I swear I shall be sneering at you if you say its a "kid font" because being an adult does not mean you punish your eyes!

tinypliny writes at 01:41:18 06/20/08 - Comment #36297 Gee. I stirred the hornet's nest with a comic book font. Hahaha.

Nice points, (e:Jim). (or snobbery, well done. -))I don't think I knew all of that. I just came upon the whole "put the sans back in comic sans" campaign and was pretty needled, considering it does happen to be my favourite font. It doesn't have specific italics and bold versions? That is interesting. So the output pretty much depends on what the recipient's comp can or cannot do. Does it mean that the font has the capacity to look disfigured in some older computers? What font do you usually use for your regular reports etc.? My audience is uniformly above 50 years so all of them are hypermetropic (+3.0D or more) and easily irritable. What would you recommend for such a scenario?

@(e:metalpeter): I love making out what fonts have been used, in random documents. (Even though I am not professional/amateur anything related to web-design or typography). It's just a lot of geeky fun. I also read design blogs, A List Apart and browse the CSS Zen Garden just for the sheer fun of it. (Especially, when I am running short of time on a deadline and feel the massive need to be distracted anyway.)

@(e:Drew): I LIKE the Papyrus font AS WELL!! Talk about being the most average person from the middle of the bell curve. Hehehee.

@(e:Zobar): I think there are some classy and tastefully done websites out there with the Comic Sans Font. (Eg. my own google group. HEHEHE, what did you expect?! And also this site here: . link. ) And holy molly! My next favourite might well be the HIGHWAY FONT. It is interesting that you bring up the point about dyslexia and easy readability. If you read through these guidelines here: . link. you realize that writing and composing documents that are dyslexia-friendly is not really a whole lot different from the guidelines for writing well! And LaTeX rocks. m/ I think people who don't get this and stick to microshit word are just in a huge state of denial - especially when they are composing their 300 page dissertation in word and swearing every couple seconds about some messed-up format.

@(e:Jason): Who knows. Maybe that is why Marvel Comics is as successful as it is. Hehehe.
I agree that I probably should be worrying about my content, but sometimes, it is fun to project your worries to other aspects of your writing so that you can willfully ignore the sheer mediocrity of what you have just composed! What are your favourite fonts?

@(e:felly): Wow. I think that's why I like it. It's not all uniform and looks somewhat imperfect and full of flaws. more human, perhaps.
It's as if you are reading through the text in Comic Sans and almost expect the writer to have crossed out some words at some point, thought through the composition and handed you the finished product, in triumph. Very non-sterile and colourful! It's like falling in love with a scar on your lover's arm/leg and associating happiness and familiarity with it.

@(e:joshua): I need to check this font out. Is it because all the urgent faxes in your office addressed to you are in this font? :)

@(e:jenks): Very subtle indeed. (e:jim)'s made quite a few points that I never even thought about. Maybe we should have our very own Typography Thursdays and also our own Typography convention. Let's pip those suckers at the Hyatt!

jenks writes at 11:18:28 06/20/08 - Comment #36289 wow. that's a lot of passion about fonts.

But jim is right. it's very subtle art. Way more goes into it than most people would ever realize. It's pretty cool, actually.

joshua writes at 09:30:08 06/20/08 - Comment #36281 I hate Lucinda Fax.

fellyconnelly writes at 07:50:57 06/20/08 - Comment #36276 (e:jim), thank you for so eloquently putting all the educated reasons for the inappropriateness of Comic Sans.

When I look at a piece of type that is put together well, my eyes flow through it evenly. Its neat and well organized and there are no odd spaces or gaps or odd curves of a random u sticking out in the middle. Words written in comic sans just stick out wherever it wants. Leaves holes in the middle of words. It just is not a visually appealing text.

I don't think it should be banned, because it does provide a sense of happiness to those who think the world of it. I think anyone who is serious about the visual appearance of their type can see that it just doesn't work well. That is their choice to make though.

jason writes at 07:11:55 06/19/08 - Comment #36262 Haha!

jim writes at 07:02:32 06/19/08 - Comment #36261 My butt cheeks are crushing walnuts as you read this, Jason.

jason writes at 06:57:27 06/19/08 - Comment #36260 Clearly it was meant to be a limited use font. I would never even consider using it in my work. Could you imagine handing a bank a proposal looking like it came out of Marvel Comics? I lol just thinking about it.

What you're stuck on are the practical elements, which are important to you, and ignoring the contextual and aesthetic elements which are important to other people. You have to consider your audience. There are good alternatives.

Tiny, it's just a font, and in the big picture it is about the 12387163128th thing you should care about unless you are a graphic designer, professional or amateur, or simply a fan of typography.

I wouldn't ban it either, and I know some people have their butt cheeks clenched so tight over it they could crush a walnut. I'm not one of those people. As a web developer it is just one of those things you have to be practical about.

zobar writes at 06:49:11 06/19/08 - Comment #36258 For websites, Comic Sans screams 'I am an amateur.' But it's not because of the font itself, but because it's usually surrounded by background images, animated mailbox icons, 'men at work' icons, and even the occasional background sound. For print production, the message is instead 'I don't really care,' 'I only care enough to switch from Times New Roman,' or perhaps 'I want this to be cute but I don't know where to find any other fonts.' But it's not the font so much as where you find it: church bake sales, public libraries, garage sales. It's to the point now where people pay attention to the font rather than the message.

Think about Highway Gothic . link. - it's easy to read, bold, professional, and even kind of interesting. But nobody's going to use it in a corporate newsletter, because of where else it gets used. People will look at your newsletter and go, 'is this the highway font?'

Comic Sans is very easy for dyslexics to read, either on-screen or in print, due to its asymmetry. On-screen, even more legible fonts are widely available [the Lucida series in particular . link. ].

On another note: LaTeX?? Dang man, I used LaTeX in college which was not that long ago, and nobody even knows what that is anymore! I'm all: LaTeX? and they're all condescending like: um no we just type it into Word. Fucking whippersnappers don't know what's good for them.

drew writes at 06:23:21 06/19/08 - Comment #36257 Tiny, I used to like the font, but got tired of it. It has been over-used.

Jim, that was an impassioned and educated response. I never realized a lot of what you pointed out, but sure enough, it's there.

I would like it if there were more readable fonts that were also casual. My current favorite is Trebuchet.

I used to really like Papyrus, but it is WAY overused now.

metalpeter writes at 06:21:11 06/19/08 - Comment #36256 I think Jim does a pretty good job saying why people don't like it. I myself will say I can't see a font and tell what one it is just by how it looks. I do think there is a difference between what is used on a screen and when something is printed. Hey using one of the those handwriting fonts is great if you want to write someone a letter or sign your name, but they can be hard to read and so it goes to the bottom of my list along with anything that makes boxes and lines well expect webdings I think it is that makes pictures (mircosoft word). I think that some fun fonts can be good to use but they have to be used in the right way. Yes fancy is good but if it starts to make things hard to read then it shouldn't be used.

jim writes at 04:32:36 06/19/08 - Comment #36248 There are specific ways that type is designed to be readable - proportionality and spacing, line thicknesses and complementary weights and styles. It's a system which includes bold, italic, display and text alternates. Each individual weight and size of every one of those alternates is carefully sized and re-proportioned to create a coherent and efficient system.

Typography is design, it is a subtle art that aims to be an invisible container for the words which it carries. Design is not 'making things pretty', it's making things work. The best design goes unnoticed. A door handle which you don't have to even think about how to grab onto to open. A website with an easy checkout process. A font which is compact and efficient for reading tiny details on a map, or another that's clear and loud from across a train station.

Comic Sans does not stay out of the way, it intrudes and obscures. And this is why: it is a bad typeface, it is not actually readable compared to other possible font choices due to bad kerning and equally sized downstrokes and horizontals. Every ounce of research into readability speaks to this fact and the need for those distinguishing features.

More reasons: it was not designed as a book face, it's a one-off suitable for only one purpose. The designer of comic sans has said that he did not design it for such a purpose. It has no italic face, no bold face, and no weighting at different point sizes. The computer fakes the italic and bold variants by just slanting or thickening the characters willy-nilly.

There was no thought put into its creation, in terms of use as a text font.

I am biting my tongue here at your accusations of snobbery, but let me just add, to snob it up even some more, that typography is one of the oldest technical skills in the world, dating back to the printing presses of ancient China and middle-ages Europe. It matters. What makes good typography is buried in the tiniest details, but it is those small things that the foundation of the most mighty power of human kind is laid down: the written word.

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