Viruses and bacteria could be the missing piece in the missing heritability puzzle

© EEG

I've discussed the issue of the missing heritability before: in layman words, same mutations shared across people don't lead to the same phenotype. This is particularly true for diseases. Many whole genome studies have looked at possible associations between DNA mutations and diseases, but, alas, the mutations that have been found generally explain only 10% of the cases. This suggests that there's a lot more to who and what we are than genes alone, and that complex interactions between DNA, RNA and proteins come to play. If you've been following the blog for a while you know that I love to talk about epigenetics (so much so that \begin{plug} I wrote a detective thriller based on epigenetics \end{plug}): I do believe a good portion of the missing heritability puzzle relies on epigenetics, which studies the mechanisms that turn our genes "on" and "off". These mechanisms are not coded in our genes, yet they can be carried on for 2-4 generations.

There are other factors, besides epigenetics and complicated genetic interactions, that could explain the missing heritability. Bacteria and viruses for example could be playing a fundamental role. In a recent post I discussed a study that points at the gut bacteria as responsible for the inheritance of a propensity towards an obese phenotype rather than a lean one. Another example is Crohn Disease: there are some specific mutations that make an individual prone to the disease, yet not everyone with those mutations manifest the symptoms. A 2010 study [1] on a mouse model found that in the presence of the mutation, the disease manifested only after infection with a particular strain of MNV (murine norovirus), the mouse variant of norovirus, a family of viruses that cause viral gastroenteritis. So, rather than the mutation alone, it's an interaction between genetic predisposition and viral infection that seems to cause Crohn Disease.

In a recent study published in PNAS [2], Edwards et al. proposed an yeast model to study the interaction between chromosomal mutations and non-chromosomal elements. In the yeast case, the non-chromosomal elements were:

"... the presence or absence of the yeast killer dsRNA virus and the other was varying mitochondria among two backgrounds with distinct differences in their genome sequence. The two mitochondrial genomes we selected show considerable variation, with about two to three SNPs per kilobase between them and 10 times as many insertions and deletions per kilobase between them as found in the chromosomal genome [2]."

The researchers induced chromosomal changes in different strains of yeast expecting their phenotype to change accordingly: they examined 17 single gene deletions that induced growth defects, expecting to observe much smaller populations. It turns out that this didn't work as a "switch". In other words, the belief "you turn on the green eye gene, you get green eyes" (which, sadly, is a very common misconception that people have about genes) is a myth. Yeast bacteria don't have green eyes, of course, but the researchers saw that despite changing certain genes, they were still getting a broad spectrum of growth phenotypes. Despite having the induced mutations, whether the yeast colonies did or didn't grow depended on the presence or absence of the dsRNA virus and the variation in mitochondrial genes. With their experiment, Edwards et al. showed that

"the heritability of a trait can depend on nonlinear interactions between chromosomal and nonchromosomal information that is transmitted from generation to generation. The nonchromosomal information can interact with the various chromosomal alleles at a locus to modify phenotype significantly. [...] Our results show that the nonchromosomal contribution to heritability can be large and, in some cases, can completely mask the effect of a chromosomal mutation [2]."

[1] Cadwell K, Patel KK, Maloney NS, Liu TC, Ng AC, Storer CE, Head RD, Xavier R, Stappenbeck TS, & Virgin HW (2010). Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine. Cell, 141 (7), 1135-45 PMID: 20602997

[2] Edwards, M., Symbor-Nagrabska, A., Dollard, L., Gifford, D., & Fink, G. (2014). Interactions between chromosomal and nonchromosomal elements reveal missing heritability Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1407126111

Angelina no longer has them. Does that mean I should get rid of them too?

We love them and yet we hate them. They get censored, augmented, reduced, replaced, covered, exposed. They get grilled, occasionally, but those are not the ones I'm talking about. We want to see them and yet we pretend we don't. We criticize them and yet we forget what they are made for, the most beautiful thing of all: nourish a new life.

Yes, I'm talking about breasts.

Angelina Jolie's breasts have been extensively discussed this week, more now that they are reportedly gone than when they were around. Sort of ironic, if you thin about it. Angelina did the unthinkable: she had both her healthy breasts removed to prevent cancer. In a second phase of her preventive plan, she will have her ovaries removed, too. The tabloids will no longer be able to speculate on her possible new pregnancies, but they will have plenty to discuss on and around her missing body parts.

Somehow the news left me a little puzzled, unable to share the views of those who praised Angelina for her bravery. Yes, it takes guts to do what she did. At the same time, the huge resonance she's been given seems blown out of proportion. Just another Hollywood thing. It reminds me of back when our mothers were told that formula was way better than breast milk. Are we facing a new era where silicon is better than milk ducts? Are they trying to convince us that fake is healthier than real? Well, of course it is. It's fake!

So, before we go around demonizing breasts and invoking chopping off body parts in the name of longevity, I wanted to get some facts straight.

First of all, I read over and over again, "Angelina Jolie carries the gene BRCA1 ..." Turns out, we all carry the gene. What makes us different is that there are distinct copies of this gene across individuals, and some copies (but not all) do raise the risk of breast and ovarian cancer.

BRCA1 and BRCA2 are part of the so called tumor suppressor genes, genes that code for proteins that are in charge of repairing damaged DNA. Our cells undergo numerous cellular divisions during our lifespan, and every cell division carries a certain chance of damaging the DNA. Though rare, mutations can be introduced, which can either be lethal or create a cancerous cell. Tumor suppressor proteins make a first attempt to repair the damaged DNA. If the DNA cannot be repaired, they promote apoptosis, or cell death. Another example of tumor suppressor gene is TP53, which encodes the protein p53.

The first link between BRCA1 and breast cancer was discovered in 1990 by Hall et al. [1]. BRCA1 and BRCA2 are expressed mostly in breast tissue. Some mutations in these genes cause them to code proteins that are not fully functional. When this happens, a cell with damaged DNA has a higher chance to escape the "screening" and start dividing instead of undergoing apoptosis. Because BRCA1 and BRCA2 are expressed mostly in the breast tissue, by removing the breast tissue one gets rid of the majority of cells expressing the defective genes, which in turns significantly lowers the chance of developing breast cancer.

While hundreds of mutations/variations in the BRCA1 and BRCA2 genes have been found, not all are linked to breast cancer, and the ones that are don't increase the risk in the same amount. Furthermore, the majority of breast cancers are not linked to mutations in these two genes. In other words, having the mutations raises the risk, but not having them does not lower it.

So, let's get some numbers straight. According to the American Cancer Society about 15% of women diagnosed with breast cancer have a family member diagnosed with it. That leaves the majority of breast cancers unrelated to family history:

"About 85% of breast cancers occur in women who have no family history of breast cancer. These occur due to genetic mutations that happen as a result of the aging process and life in general, rather than inherited mutations."

It's a puzzle I've discussed before, the missing herediatbility. On the one hand we know genes play a large role in cancer and we spend all this research money into looking for genetic causes. Yet, the vast majority of cancers are non-hereditary.

While women with certain mutations in either the BRCA1 or BRCA2 genes have up to 80% (the exact chance varies depending on the type of mutation they carry) increased risk of developing breast cancer, only between 5% and 10% of breast cancers are linked to deleterious mutations in the BRCA1 or BRCA2 genes. So, yes, get tested. But chances are, your copy of BRCA1 and BRCA2 are fine.

So, what makes BRCA1 and bRCA2 so scary?

The American Cancer Society reports that approximately 60% of women with one of the harmful mutations in BRCA1 or BRCA2 develop breast cancer during their lifetime, versus the 12% of women in the general population. Remember, though: these genes are not the only ones playing a role in cancer. Things like epistasis with other loci in the genome can deeply affect such risks and, unfortunately, we still don't know enough to quantify them. High levels of IGF-1, the insulin-like growth factor have also been linked to breast cancer. So while having those mutations raises the risk, it does not mean that the individual will develop breast cancer for sure as other factors are still unknown. Careful considerations should be made before making a drastic choice like Angelina's. These considerations should also include risks associated to a double mastectomy (infection, necrosis, etc.) and reconstruction surgery, neither one free of complications. I'm somehow reluctant to consider implants healthier than normal breasts, whether or not those breasts were expressing faulty genes.

What about those 85% of breast cancers that are not linked to BRCA1 or BRCA2 mutations? Can we do anything to prevent those?

When you look at the global population, the most common risk factors for breast cancer are not the mutations in BRCA1 and BRCA2, rather, as Bernstein reports in a 2009 review [2]:

"The most consistently acknowledged risk factors for breast cancer other than gender and race/ethnicity are age, family history of breast cancer, early menarche, late age at first birth, nulliparity, late age at menopause, high postmenopausal weight or substantial weight gain as an adult, exposure to high levels of ionizing radiation and a history of benign proliferative breast disease [2]."

All these risk factors point at one common etiology, ovarian hormones (estradiol and progesterone), because they

"promote cellular proliferation in the breast, providing greater opportunity for the accumulation of random errors, which may lead to tumor development [2]."

Body weight and exercise can be linked to different levels of estradiol in the blood (high body weight is associated with higher levels, exercise is associated with lower levels), hence their correlation to breast cancer risk. Some studies found up to 40% reduction in risk in women who exercised in particular in their adolescence. Of all risk factors, these two, body weight and exercise, are the ones we can actually take control over and actively lower our risk of developing breast cancer. A diet rich in antioxidants may lower the risk of DNA damage during cellular division.

Things we have less control over is the woman's age at the first pregnancy. One of my grad school professors used to say, "Having a baby as a teen may ruin your life, but it sure lowers your risk of developing breast cancer later in life." The risk keeps lowering for every additional pregnancy, though not as significantly as with the first one.

What's not clear is the extent to which breastfeeding can lower the risk of breast cancer, as the American Cancer Society reports:

"Research suggests that breastfeeding has only a slight effect on breast cancer risk and that effect is only among women who have breastfed for a long time. They also concluded that breastfeeding seems to be more protective against the most aggressive types of breast cancer, including tumors in women with mutations in the BRCA1 gene, basal-like cancers, hormone-receptor negative, and possibly triple negative tumors."

And while we do the things that we can to lower our risks, I am hopeful that one day gene therapy will be perfected to the point that it will offer a better options than what, in gross terms, amounts to amputation.

Thoughts?

[1] Hall, J., Lee, M., Newman, B., Morrow, J., Anderson, L., Huey, B., & King, M. (1990). Linkage of early-onset familial breast cancer to chromosome 17q21 Science, 250 (4988), 1684-1689 DOI: 10.1126/science.2270482

[2] Bernstein, L. (2008). Identifying population-based approaches to lower breast cancer risk Oncogene, 27 DOI: 10.1038/onc.2009.348

Stress-induced epigenetic changes last up to four generations in mice

One of the most intriguing aspects of epigenetics is its ability to confer transgenerational changes. General belief used to be that inheritance pertained exclusively to DNA, and that what did not affect DNA could not be inherited. Epigenetics encompasses all molecular "processes that regulate genome activity independent of DNA sequence [1]." It has revolutionized the way we view heritability: epigenetic changes do not alter the DNA sequence, only the way genes are expressed. And yet environmental exposures and chronic stress, two factors that can indeed change gene expression patterns, have been shown to induce epigenetic transgenerational inheritance. In other words, you could have inherited some epigenetic switch from your parents, even though the epigenetic switch was caused by some exposure your parents experienced, not you!

In order for this to happen, the epigenetic modification has to be incorporated into the germ line.

In a recent PNAS paper [1], Crews et al. showed the

"epigenetic transgenerational inheritance of a behavioral phenotype induced by an environmental toxicant (a fungicide) and transmitted through the germ line, involving a permanent alteration in the sperm epigenome (i.e., DNA methylation)."

Crews et al. looked at the effects of chronic restraint stress in young male mice. Because social status also influences the way individuals react to stress, with dominant individuals usually being able to cope better than subordinate ones, they housed the experimental mice together with different mixes of social structures. The "stress" was the exposure of a gestational female to a fungicide (vinclozolin), which disrupts endocrine activity. The effects were changes in the brain and behavior and, eventually, the early onset of disease. These were still observed over four generations later.

"We find that this ancestral exposure promotes weight gain and, as such, provides pivotal empirical evidence that exposure to an endocrine disruptor in generations past results in substantial weight gain in the descendants."

In the study, the authors refer the exposure of the mother as "ancestral exposure" to indicate that it wasn't a direct exposure on the individuals under study.

In particular, the researchers observed that the changes in body weight were correlated with lower secretions of corticosterone and higher testosterone circulating levels. The researchers performed other tests in order to measure the sociability of the fungicide exposed animals versus the non-(ancestrally)-exposed ones under stressful circumstances. In both stressful and non-stressful circumstances, the animals ancestrally exposed to the fungicide showed higher levels of anxiety.

Finally, Crews et al. performed gene networks analyses in order to evaluate changes in gene expression between the two mice groups. They looked in several brain regions, including subregions of the hippocampus and the primary and secondary motor cortex. Interestingly, the most altered pathway was the olfactory one.

"An olfactory receptor promoter has been shown to have an epigenetic transgenerational alteration in sperm. [...] Why should genes involved in olfaction be expressed in areas of the brain not involved with olfaction and taste? Olfactory and vomeronasal receptors as a group are among the most rapidly evolving of all genes and have been linked to higher processing centers in the brain as well as to behavior."

[1] David Crewsa, Ross Gillettea, Samuel V. Scarpinoa, Mohan Manikkamb, Marina I. Savenkovab, and Michael K. Skinner (2012). Epigenetic transgenerational inheritance of altered stress responses PNAS DOI: 10.1073/pnas.1118514109

Do rare variants hold the missing answers?

Most DNA is identical across subjects. However, some genes are polymorphic, which means different alleles of the same gene are present across individuals. Since we all have two copies of each gene, individuals who carry two identical copies are called homozygous, and those who carry different copies are called heterozygous. Typically, one allele is most common in the population, the "wild type," and the other ones, present at lower frequencies, are called "mutants." Single-base differences are called single nucleotide polymorphism, or SNP (pronounced "snip"), and, on average, they occur about every thousand base pairs.

For the past 20 years, genetic research has focused on finding associations between SNPs and major diseases like cancer, Alzheimer, diabetes, etc. Back when I was doing this type of research, from 2004 until 2006, we used to exclude SNPs whose minor allele frequency (MAF) was lower than 0.5% in a given ethnic group. The logic was that it was too rare to make any significant contribution. Back then we were sampling a few hundred people and we simply didn't have enough statistical power to detect an effect when the frequency was that low.

A note from the statistician: SNP association studies ask the question, "Does mutant allele X raise the risk to develop disease Y"? As it happens with all statistical tests, the answer comes with a p-value, and the p-value represents the probability of observing the given data distribution by chance. P-values of 0.05 or lower are "good" because they mean that the chance of the association not being real but simply due to chance is low (less than 5%). On the other hand, we could make the opposite mistake: we could have missed something real. A measure of the probability of not missing a true association is given by the "power" of the test. In general, the larger the dataset, the higher the power of the test; however, the smaller the effect one is trying to detect, the lower the power. Therefore, if a rare variant does affect the risk of a certain disease, a very large dataset is needed in order to have enough power to detect the association.

In less than ten years sequencing technology has improved steadily and genotyping costs have decreased, allowing researchers to genotype many more people. Furthermore, though SNP association studies have been very informative, they still haven't answered the question of the missing heritability: a large portion of hereditary traits (including diseases) are not explained by known associations.

Bottom line: this has shifted the interest back to the "rare" variants, SNPs whose MAF is less than 0.5%.

"Rare and low frequency (MAF between 0.5%-1%) variants have been hypothesized to explain a substantial fraction of the heritability of common, complex diseases. [...] Common variants explain only a modest fraction of the heritability of most traits [1]."

Tennessen et al. sequenced 15,585 human protein-coding genes from over 2,000 individuals of either European or African ancestry, and identified more than 500,000 single nucleotide variants, 86% of which were rare.

"This excess of rare functional variants is due to the combined effects of explosive, recent accelerated population growth and weak purifying selection. Furthermore, we show that large sample sizes will be required to associate rare variants with complex traits."

In the last few thousand years populations have experienced a rapid growth that had likely gone undetected in previous studies due to small sample sizes. Most rare variants (58%) found by Tennessen et al. were population specific and nonsynonimous, meaning that they yielded different amino acids. Surprisingly, this study found that "the vast majority of protein-coding variation is evolutionarily recent, rare, and enriched for deleterious alleles. Thus, rare variation likely makes an important contribution to human phenotypic variation and disease susceptibility."

In the next couple of years we will see more and more studies looking at associations between rare variants and diseases using 454 and deep sequencing technology. Many more rare variants will be discovered and the question will be to find the meaningful ones that rise above the background noise.

[1] Tennessen, J., Bigham, A., O'Connor, T., Fu, W., Kenny, E., Gravel, S., McGee, S., Do, R., Liu, X., Jun, G., Kang, H., Jordan, D., Leal, S., Gabriel, S., Rieder, M., Abecasis, G., Altshuler, D., Nickerson, D., Boerwinkle, E., Sunyaev, S., Bustamante, C., Bamshad, M., Akey, J., , ., , ., & , . (2012). Evolution and Functional Impact of Rare Coding Variation from Deep Sequencing of Human Exomes Science DOI: 10.1126/science.1219240

Genome, epigenome, mutations, epimutations... rethinking inheritance

I just learned a new word: epimutation. Genetic mutations occur in the DNA, while epimutations describe the transcriptional silencing of a gene that is normally active.

What's intriguing about epimutations is that even though they do not change the DNA, these changes can be transmitted from one cell to its daughter cells, a process called epigenetic somatic inheritance. There's another level of inheritance, which happens when such epigenetic changes are passed on from one generation of individuals to the next. This is a very intriguing concept because, since epigenetic changes don't affect the DNA, it is a non-Mendelian type of inheritance. Also, this type of inheritance is non-obvious because of a caveat called epigenetic reprogramming: all epigenetic marks are generally erased during gametogenesis and early embryogenesis so that the cells that will make a new individual can start afresh. If you think about it, it makes perfect sense: embryonic stem cells have the "potential" to become any kind of cell line and hence they have to start from an epigenetic "clean slate." So, in order for epigenetic inheritance to occur, an epimutation must escape epigenetic reprogramming.

"If the entire genome were reprogrammed in the germline it would be impossible for epigenetic modifications to be inherited. However there are epigenetic markers that can escape both incidences of reprogramming resulting in epigenetic modifications that persist in the somatic cells of the individual [1]."

In [1], Migicovsky and Kovalchuk review the different mechanisms by which epigenetic inheritance could arise: for example, you know how in all cells DNA is wound around proteins called histones? Well, it turns out that in sperm chromatin the majority of DNA is actually bound by "protamines," another kind of proteins that replace histones during spermatogenesis. However, a small percentage of histones are still retained in mature sperm and these histones could be responsible for epigenetic inheritance. In addition, there is methylation- and histone-mediated inheritance, which alter the gene expression patterns, and, finally, certain RNAs could be inherited through the germlines, again, making non-DNA changes inheritable.

Epigenetic inheritance has been documented in the case of MLH1, a gene located on chromosome 3. Individuals carrying a germline epimutation in this gene only have one functional copy of the gene and are at a higher risk of developing non-polyposis colorectal cancer:

"Studies have indicated that such inheritance is possible, with one family showing maternal transmission of the epimutation to the son, although the mutation was erased in his spermatozoa. In this case, the MLH1 epimutation that caused a predisposition to HNPCC in the mother was also present in the son, indicating he also had an increased risk of cancer. However, in her other children the epimutation was shown to revert to its normal state, indicating that the mutation was erased during reprogramming. These results indicated that germline transmission of an epigenetic state that confers disease susceptibility such as in the case of hypermethylation of MLH1 is possible. Overall, studies thus far have indicated that although epimutations are usually erased in the germline, they may be retained at a low frequency."

[1] Migicovsky, Z., & Kovalchuk, I. (2011). Epigenetic Memory in Mammals Frontiers in Genetics, 2 DOI: 10.3389/fgene.2011.00028

Missing heritability: the humble opinion of a mathematician

Tomorrow, February 3, is Eric Lander's birthday, the director of the Broad Institute (the well-known MIT/Harvard genomic research center), and the first author of the historic 2001 Nature paper that marked the completion of the Human Genome Project [1]. I heard him once speak at USC and without ever getting technical he managed to engage the whole audience and share his passion for genetics. As you know, I've been honoring famous geneticists by discussing one of their papers on their birthday and today I'm facing a conundrum. You see, the natural choice would be to pick the latest PNAS paper titled "The mystery of genetic heritability" [2]. I want to talk about this paper and at the same time I don't want to talk about this paper.

I'm not a geneticist. I'm a computational biologist, which means my background is mostly analytical, not biological. I used to work on SNP associations and cancer epidemiology and now I work on HIV. I am NOT one of the players in this game. Hence, what does my opinion count when it comes to a highly debated paper as this one?

The thing is, this paper resonates with me. It makes a great point about a mathematical model that's been "assumed" for years now in the world of genetics. Often people don't get mathematical models. They don't get that mathematical models are tools, not the truth. Hence when one says "I present this model," you get two possible reactions: those who have seen data concordant with your model will smile and happily welcome your model. Those who instead have seen the opposite will boo you and challenge you. Problem is, models are neither right or wrong. Models are tools. Do they help describe what we see? Fine, we keep the model. When they don't, we go back to the data and try to understand which of our assumptions failed. We use the model to discern the situations that meet the assumptions stated in the model from those that don't. Models help us shape our thinking, not the data! For example, evolution is a model, too. Go tell that to creationists and followers of intelligent design. They can challenge evolution as much as they want, but until they hand me a model that explains the genetic diversity we observe today better than evolution does, I will stick with evolution.

Back to the PNAS paper. It's a hot topic right now, and I'm kind of late discussing this particular paper in the blogosphere. Razib Khan discussed it here, Luke Jostins here and here, and I'm sure many others whom I don't know have talked about it too.

So, what is the missing heritability? Since I've already defined it in an earlier post of mine, for the time being, let me just quote Razib Khan:

"The issue is basically that there are traits where patterns of inheritance within the population strongly imply that most of the variation is due to genes, but attempts to ascertain which specific genetic variants are responsible for this variation have failed to yield much. For example, with height you have a trait which is ~80-90 percent heritable in Western populations, which means that the substantial majority of the population wide variation is attributable to genes. But geneticists feel very lucky if they detect a variant which can account for 1 percent of the variance."

The implications of this are clear: we want to find risk alleles to predict common diseases, but given the missing heritability, we can't predict common diseases.

Is this surprising?

Given the reactions I saw on the internet, apparently it is. People claim we still haven't found all variants and that's where the missing heritability's hiding. Maybe. However, after reading so much about epigenetics, RNA editing, and epistasis, allow me to be skeptical. Traits (proteins, diseases, etc.) are not genes. The path from genes to traits is long and convoluted.

So, what's Lander's point in this PNAS paper? Something I've also previously discussed: epistasis, or the way genes interact together. We're missing heritability because we think of risks as additive, but additivity doesn't count for interactions. If you take into account interactions between genes, the total heritability is much smaller than anticipated and hence the percentage of what the variants are explaining (all together) much larger.

"Quantitative geneticists have long known that genetic interactions can affect heritability calculations. However, human genetic studies of missing heritability have paid little attention to the potential impact of genetic interactions."

Now here's the beauty of this paper. They do not deny the additive risk model. They extend it:

"We thus introduce the limiting pathway (LP) model, in which a trait depends on the rate-limiting value of k inputs, each of which is a strictly additive trait that depends on a set of variants (that may be common or rare). When k = 1, the LP model is simply a standard additive trait. For k > 1, we show that LP(k) traits can have substantial phantom heritability."

Again, mathematician thinking here, but that's exactly what models are for: some traits may very well be additive. However, the model does not fit all the data we observe it. Hence we need a better model, one that encompasses the old one and at the same time goes beyond it. Gene-gene interactions need not explain all missing heritability. But since they've been observed, we need to account for them in those situations where they may be real.

"The potential magnitude of phantom heritability can be illustrated by considering Crohn's disease, for which GWAS have so far identified 71 risk associated loci (13). Under the usual assumption that the disease arises from a strictly additive genetic architecture, these loci explain only 21.5% of the estimated heritability. However, if Crohn's disease instead follows an LP(3) model, the phantom heritability is 62.8%, thus genetic interactions could account for 80% of the currently missing heritability."

"In short, genetic interactions may greatly inflate the apparent heritability without being readily detectable by standard methods. Thus, current estimates of missing heritability are not meaningful, because they ignore genetic interactions."

"The results show that mistakenly assuming that a trait is additive can seriously distort inferences about missing heritability. From a biological standpoint, there is no a priori reason to expect that traits should be additive. Biology is filled with nonlinearity: The saturation of enzymes with substrate concentration and receptors with ligand concentration yields sigmoid response curves; cooperative binding of proteins gives rise to sharp transitions; the outputs of pathways are constrained by rate-limiting inputs; and genetic networks exhibit bistable states."

Mother Nature did not create mathematics. We created mathematics to describe Mother Nature. We start with a simple model and build up on it. The data is always the reality check, we should never forget that.

[1] Lander, E., Linton, L., Birren, B., Nusbaum, C., Zody, M., Baldwin, J., Devon, K., Dewar, K., Doyle, M., FitzHugh, W., Funke, R., Gage, D., Harris, K., et al. (2001). Initial sequencing and analysis of the human genome Nature, 409 (6822), 860-921 DOI: 10.1038/35057062

[2] Zuk, O., Hechter, E., Sunyaev, S., & Lander, E. (2012). The mystery of missing heritability: Genetic interactions create phantom heritability Proceedings of the National Academy of Sciences, 109 (4), 1193-1198 DOI: 10.1073/pnas.1119675109

The case of "junk DNA" and why it shouldn't be called junk: Epigenetics.

(This is part 3 of 4 in a series dedicated to "junk DNA". Links to the previous parts: Part 1, and Part 2.)

Last year I was diagnosed with thyroid disease. Despite feeling pretty crappy, I found the phenomenon extremely fascinating. Okay, I'll admit, I found it fascinating after my doc told me worst case scenario they'd remove the thyroid and I'd be as good as new (minus the thyroid, that is). Here's what happened: somehow, my immune system decided that my thyroid was some kind of foreign object that did not belong, and it started producing antibodies to destroy it. And I mean literally destroy it: left untreated, the antibodies will keep attacking the thyroid until it's gone.

How the immune systems knows "self" from "non-self" (and hence attacks foreign objects but, under normal conditions, not its own cells) is a fascinating topic and worth a post in itself (and I promise it'll come, just give me a few more weeks!).

For now, though, I want to focus on this: thyroid disease is a purely genetic disease. So, if it was encoded in my DNA, why did I end up getting it last year instead of having it since birth?

Epigenetics  holds the answer to my question (for the veterans in the field, please see my note below).

There was a nice article in the Time magazine a few months ago that described the concept really well: if you compare our body to a computer, genetics is the hardware and epigenetics is the software. Or, to use another analogy that my friend and fellow scientist/writer Ian Tregillis coined, if the genome is a four-note musical score, then the epigenome is the musician who interprets and executes the music.

"Epigenetics" is an umbrella term that encompasses all processes that regulate gene expression. In other words, what decides which genes are "turned on" and which are "turned off."

Think of en encrypted message. You don't know the meaning of the message until I give you the key. Depending on what key I give you, the message may change dramatically. DNA is the encrypted message. In order to "read" the message, i.e. the instructions on how to make proteins, we need a system capable of "translating" the message. It's a very delicate and complex system. And while our DNA is exactly the same in every cell of our body, the epigenetics is different.

Well, that's kind of obvious, isn't it? Think about it: how does a brain cell know to behave like a brain cell, and a skin cell to behave like a skin cell? After all, they have the same DNA. What differentiates them is the epigenetic processes that translate the DNA in each type of cell. The brain cell will have "brain genes" activated, and the skin cell will have the "skin genes" activated, while the others will be turned off.

So far so good. Still, how do you explain genetic diseases like diabetes showing up in adults rather than from birth? They are indeed encoded in the individual's DNA, but in a very subtle way. Mutations that sit there, waiting to go off. Waiting for the right change in the epigenetic process that will suddenly activate them.

Yes, that's exactly what happens: our DNA stays the same throughout our lifetime, but the way we express the genes can and does in fact change. Environmental stress is one of the major reasons affecting these changes [1]. Example: drought can cause certain plants to switch on pseudogenes regulating their capability of survival with less water [2]. The availability of food can induce analogous epigenetic changes in animals. Studies have shown that a pregnant woman's diet can activate pseudogenes not only on the baby, but the changes are actually inherited by the baby's babies as well [3]. Even though these are not genetic changes, hence they do not alter the DNA, still, they are in fact inheritable and it takes a few generations for the switches in gene expression to wear off [4].

So, think about it: (1) DNA doesn't quite dictate who or what we are. And (2) good ol' Lamarck was not so far from the truth after all, was he?

Back to my original question: thyroid disease was indeed "encoded" in my genome, but it was an epigenetic change in the way my genes were expressed that one day set my immune system off to an anti-thyroid mission.

What does this have to do with junk DNA?

Well, remember what junk DNA really is: it's non-coding DNA. Genes that are "turned off." But wait, we just learned that "turned off" or "turned off" is something that can change during one's lifespan. So, what we call "junk DNA" is something dynamical, something that when we look again tomorrow may have suddenly become functional because of the way DNA gets translated.

More and more studies are finding a link between cancer and mutations that sit in pseudogenes (non-functional genes that are part of the so-called junk DNA). At first this was quite surprising. If these genes aren't translated, how can they affect our body? Well, it turns out they are indeed expressed in cancer patients, giving origin to the term oncogene. In other words, the mutation is there, and it's not until an epigenetic change occurs and the pseudogene gets activated, that the disease takes off.

So, don't call non-coding DNA junk.

We need to study this part of our DNA, because it holds important information about our health. It also holds the key to our survival as a species by allowing us to adapt and change as the environment around us changes. And, finally, it holds our evolutionary history: we carry our ancestors, from viruses to bacteria to monkeys in our DNA.

Technical note: I am using the term "epigenetics" in a broad way, to include any of the following scenarios: post-replication DNA changes; post-transcription RNA changes; and, finally, changes in protein translation. The association between thyroid disease and epigenetics is purely my own, but an analogous conclusion has been reached for similar autoimmune disorders, where the immune systems fails to recognize self from non-self -- see this paper.   

REFERENCES:
[1] Inheritance of Stress-Induced, ATF-2-Dependent Epigenetic Change. Ki-Hyeon Seong, Dong Li, Hideyuki Shimizu, Ryoichi Nakamura, Shunsuke Ishii. Cell - 24 June 2011 (Vol. 145, Issue 7, pp. 1049-1061)

[2] Epigenetics in the extreme: prions and the inheritance of environmentally acquired traits. Halfmann R, and Lindquist S. Science. 2010 Oct 29;330(6004):629-32.

[3] Epigenomic disruption: the effects of early developmental exposures. Bernal AJ, Jirtle RL. Birth Defects Res A Clin Mol Teratol. 2010 Oct;88(10):938-44.

[4] Transgenerational Epigenetic Inheritance: Prevalence, Mechanisms, and Implications for the Study of Heredity and Evolution. Eva Jablonka and Gal Raz, The Quarterly Review of Biology. Vol. 84, No. 2 (June 2009), pp. 131-176

Picture: Rock. Canon 40D, focal length 85mm, exposure time 1/100.