Two years and a new 365 project. Day 1: Epigenetics.

So it has been two years to the day since I defended my dissertation (see pics below, appreciatively provided by Share and Enjoy). I have somehow managed to survive and the shell shocked look of a recent post Ph.D. has somewhat dimminishe since then, although my nutritional intake hasn't changed much - still consists of coffee and hefty dosages of water and my profile still isn't that great.

So in celebration (and procrastination), I thought it would be an interesting idea to start a new 365 project (one that I may actually be able to finish). Also, it will result in blog post 1000 for me. This project will look at a science article or science news item every day for a year. We are inundated with science news (some good, most bad), so I will seek to sift through it and find something of interest, at least to me but feel free to send suggestions. To start things off, I'm going to start with a post on epigenetics. This is somewhat appropos as a post on epigenetics was one of my first, and is still relevant if not even more important today.

My main argument is that from an anthropological/evolutionary perspective we need to get away from the idea of a direct impact between genotype = phenotype for complex traits. This does occur such as with sickle cell but these are rare. My interest primarily lies with complex traits. These compex traits are a mixture of the biology and the environment and there is a whole lot of biology that occurs after transcription (you know the part where DNA is made to messenger RNA). Geneticists tend to ignore the environment for the most part, but like politicians and social security, one day we will have to deal with it (more on another post in the future (how is that for foreshadowing and an inner join)). However ignoring the environment, once the mRNA passes through the nucleus boundary a whole bunch of stuff can happen and does to it. This is largely where epigenetics comes into play. Epigenetic changes can occur from DNA Methylation, microRNAs, histone modification, etc.  This may result in a modified protein, which is part of a biological pathway that then turn impacts an endophenoytpe that effects the trait of interest. Anywhere along this path from gene to phenotype something can intersect and influence a complex trait making discovery of genes something of well a complexity - but that is what makes them interesting.

So it is therefore nice that PLoS in celebration of Ph.Diversary has listed a number of article over the last year that deal with epigentics in 2010. Here is a list of these articles, including two excellent primers.

• Epigenetic Epidemiology of Common Complex Disease: Prospects for Prediction, Prevention, and Treatment. CL Relton, G Davey Smith (Research in Translation)

• Centromeres Convert but Don’t Cross PB Talbert, S Henikoff (Primer)

• Genomic Responses to Abnormal Gene Dosage: The X Chromosome Improved on a Common Strategy X Deng, CM Disteche (Primer)

• Spatial Epigenetic Control of Mono- and Bistable Gene Expression JZ Kelemen, P Ratna, S Scherrer, A Becskei

• Widespread Gene Conversion in Centromere Cores J Shi, SE Wolf, JM Burke, GG Presting, J Ross-Ibarra, RK Dawe

• Expression in Aneuploid Drosophila S2 Cells Y Zhang, JH Malone, SK Powell, V Periwal, E Spana, DM MacAlpine, B Oliver

• 2-D Structure of the A Region of Xist RNA and Its Implication for PRC2 Association S Maenner, M Blaud, L Fouillen, A Savoye, V Marchand, A Dubois, S Sanglier-Cianférani, A Van Dorsselaer, P Clerc, P Avner, A Visvikis, C Branlant

• Poised Transcription Factories Prime Silent uPA Gene Prior to Activation C Ferrai, SQ Xie, P Luraghi, D Munari, F Ramirez, MR Branco, A Pombo, MP Crippa

• Computational Analysis of Whole-Genome Differential Allelic Expression Data in Human JR Wagner, B Ge, D Pokholok, KL Gunderson, T Pastinen, M Blanchette

• Altering a Histone H3K4 Methylation Pathway in Glomerular Podocytes Promotes a Chronic Disease Phenotype GR Dressler, G Lefevre , S Patel , D Kim , L Tessarollo

• The IG-DMR and the MEG3-DMR at Human Chromosome 14q32.2: Hierarchical Interaction and Distinct Functional Properties as Imprinting Control Centers M Kagami, MJ O’Sullivan, AJ Green, Y Watabe, O Arisaka, N Masawa, K Matsuoka, M Fukami, K Matsubara, F Kato, AC Ferguson-Smith, T Ogata

• siRNA-Mediated Methylation of Arabidopsis Telomeres J Vrbsky, S Akimcheva, JM Watson, TL Turner, L Daxinger, B Vyskot, W Aufsatz, K Riha

• Initial Genomics of the Human Nucleolus A Németh, A Conesa, J Santoyo-Lopez, I Medina, D Montaner, B Péterfia, I Solovei, T Cremer, J Dopazo, G Längst

• Nuclear Pore Proteins Nup153 and Megator Define Transcriptionally Active Regions in the Drosophila Genome JM Vaquerizas, R Suyama, J Kind, K Miura, NM Luscombe, A Akhtar

• Maternal Ethanol Consumption Alters the Epigenotype and the Phenotype of Offspring in a Mouse Model N Kaminen-Ahola, A Ahola, M Maga, K-A Mallitt, P Fahey, TC Cox, E Whitelaw, S Chong

• Epigenetic Analysis of KSHV Latent and Lytic Genome Z Toth, DT Maglinte, SH Lee, H-R Lee, L-Y Wong, KF Brulois, S Lee, JD Buckley, PW Laird, VE Marquez, JU Jung

• The Epigenetic Landscape of Latent Kaposi Sarcoma-Associated Herpesvirus Genomes T Günther, A Grundhoff

• A New Nuclear Function of the Entamoeba histolytica Glycolytic Enzyme Enolase: The Metabolic Regulation of Cytosine-5 Methyltransferase 2 (Dnmt2) Activity A Tovy, R Siman Tov, R Gaentzsch, M Helm, S Ankri

• Epigenetic Variation in Mangrove Plants Occurring in Contrasting Natural Environment CF Lira-Medeiros, C Parisod, RA Fernandes, CS Mata, MA Cardoso, PCG Ferreira

• Hepatocellular Carcinoma Displays Distinct DNA Methylation Signatures with Potential as Clinical PredictorsH Hernandez-Vargas, M-P Lambert, F Le Calvez-Kelm, G Gouysse, S McKay-Chopin, SV Tavtigian, J-Y Scoazec, Z Herceg

• Whole Methylome Analysis by Ultra-Deep Sequencing Using Two-Base Encoding CA Bormann Chung, VL Boyd, KJ McKernan, Y Fu, C Monighetti, HE Peckham, M Barker

• Role for DNA Methylation in the Regulation of miR-200c and miR-141 Expression in Normal and Cancer Cells L Vrba, TJ Jensen, JC Garbe, RL Heimark, AE Cress, S Dickinson, MR Stampfer, BW Futscher

• Differential DNA Methylation Correlates with Differential Expression of Angiogenic Factors in Human Heart Failure M Movassagh, M-K Choy, M Goddard, MR Bennett, TA Down, RS-Y Foo

Talking Points Thursday - Putting the Complex back in Complex Diseases

So each Thursday, I thought I would blog about some current talk in genetic or anthropology or the combination of them both. As I blogged about the Havasupai Indians and the finalization of their case against Arizona State University, I thought genetics would be more appropro this week.

There is a recent article being disected on the blogoverse (or at least the one I frequent) that rehashes the argument (which is now getting old) regarding common vs. rare variants in GWAS studies. Other people have done a much better job of disecting this article and this post is incredibly informative. My argument is that everyone knows GWAS works to an extent but that it is still not identifying the missing heritabilty or the lack of variation described by significant SNPs. This is however because these SNPs represent only a small portion of the whole interaction occuring between genes that are involved in pathways. The genome is part of a biological system that is intergrated and inherently complex.

The basic idea regarding complex disease genetics is that the phenotypes involved are "complex"! This means that they are made of several genes that interact to create a protein and that they are also affected by the environment. A problem with candidate gene studies is that focus on variation within a single gene, without regard to the other genes or the biological pathways involved. So when a GWAS reports a gene to be involved in a complex disease it is only the tip of the iceberg. I'm not going to argue that GWAS is not informative, but it is an explatory statistical method. The idea proposed in the Mckellan and King article that the SNPs are not functional identfied in GWAS, totally misinterpets the method. The idea of GWAS is to identify regions of the genome that may be involved in a phenotype at higher resolution. GWAS works on the basis of linkage disequilbrium and provides 1 centimorgan region around where association occurs. This is ten-fold increase over linkage studies based on STRs. Besides, there are certain genes we know are involved in complex disease genetics because experimental work has been conducted on them in mice, rabbits, E. coli, etc., like hepatic lipase with HDL-C and variants with this gene show up in GWAS studies.

An alternative approach is to intergrate gene expression data and SNP data in order to identify the biological pathway involved in your trait of intrest. A recent paper in the American Journal of Human Genetics entitled "Integrating Pathway Analysis and Genetics of Gene Expression for Genome-Wide Studies" does a good job of describing this along with a certain type of methodology involved. One of the current problems associated with the joint type of analysis is that there is no set methodology and so different people analyze this in different ways. This paper represents a good start at this and may help in better identfying genetic variants that are impacting protein expression, which are then altering biological pathways that lead to chronic diseases. This is what will lead to a better understanding of the complexity of diseases, not denser chip set.