Review article on epigenetic inheritance

From the paper:

Incorporating epigenetic inheritance into evolutionary theory extends the scope of evolutionary thinking and leads to notions of heredity and evolution that incorporate development. Dobzhansky's definition of evolution as “a change in the genetic composition of populations” (1937, p.11) appears to be too narrow because it does not incorporate all sources of heritable variations. Both evolution and heredity need to be redefined. Jablonka and Lamb (2007a,b,c) suggested that evolution should be redefined as the set of processes that lead to changes in the nature and frequency of heritable types in a population, and heredity as the developmental reconstruction processes that link ancestors and descendants and lead to similarity between them. These deliberately broad redefinitions allow evolutionary possibilities denied by the “Modern Synthesis” version of evolutionary theory, which states that variations are blind, are genetic (nucleic acid‐based), and that saltational events do not significantly contribute to evolutionary change (Mayr 1982). The epigenetic perspective challenges all these assumptions, and it seems that a new extended theory, informed by developmental studies and epigenetic inheritance, and incorporating Darwinian, Lamarckian, and saltational frameworks, is going to replace the Modern Synthesis version of evolution (Jablonka and Lamb 2005, 2007c). We believe, therefore, that the impact of epigenetics and epigenetic inheritance on evolutionary theory and the philosophy of biology will be profound.

Some related posts:

• Epigenetics via twin studies
• Maternal inheritance and male reproductive fitness
• Epigenetic effects of slavery in African Americans (?)
• The eclipse of the gene

The Quarterly Review of Biology, June 2009, vol. 84, no. 2, DOI: 10.1086/598822

TRANSGENERATIONAL EPIGENETIC INHERITANCE: PREVALENCE, MECHANISMS, AND IMPLICATIONS FOR THE STUDY OF HEREDITY AND EVOLUTION

Eva Jablonka, Gal Raz

Abstract

This review describes new developments in the study of transgenerational epigenetic inheritance, a component of epigenetics. We start by examining the basic concepts of the field and the mechanisms that underlie epigenetic inheritance. We present a comprehensive review of transgenerational cellular epigenetic inheritance among different taxa in the form of a table, and discuss the data contained therein. The analysis of these data shows that epigenetic inheritance is ubiquitous and suggests lines of research that go beyond present approaches to the subject. We conclude by exploring some of the consequences of epigenetic inheritance for the study of evolution, while also pointing to the importance of recognizing and understanding epigenetic inheritance for practical and theoretical issues in biology.

Link

Epigenetics via twin studies

Coverage elsewhere:

Epigenetics reveals unexpected, and some identical, results
Inherited traits may explain differences in 'identical' twins

Related: In search of the Hidden Heritability

Nature Genetics doi: 10.1038/ng.286

DNA methylation profiles in monozygotic and dizygotic twins

Zachary A Kaminsky et al.

Abstract

Twin studies have provided the basis for genetic and epidemiological studies in human complex traits. As epigenetic factors can contribute to phenotypic outcomes, we conducted a DNA methylation analysis in white blood cells (WBC), buccal epithelial cells and gut biopsies of 114 monozygotic (MZ) twins as well as WBC and buccal epithelial cells of 80 dizygotic (DZ) twins using 12K CpG island microarrays. Here we provide the first annotation of epigenetic metastability of 6,000 unique genomic regions in MZ twins. An intraclass correlation (ICC)-based comparison of matched MZ and DZ twins showed significantly higher epigenetic difference in buccal cells of DZ co-twins (P = 1.2 10^-294). Although such higher epigenetic discordance in DZ twins can result from DNA sequence differences, our in silico SNP analyses and animal studies favor the hypothesis that it is due to epigenomic differences in the zygotes, suggesting that molecular mechanisms of heritability may not be limited to DNA sequence differences.

Link

In search of the Hidden Heritability

Nature has a very interesting high level survey of the problem of the "hidden heritability". While many traits such as height, autism, or schizophrenia are known to be significantly heritable, recent genome scans with high-density microarray chips, that look at hundreds of thousands of DNA polymorphisms, have failed to produce any significant results.

So, if these traits are in our genes, how come we can't find them there?

The article does a great job at identifying the possible ways to find the "hidden heritability". Here they are, in my own words:

1. Look at more DNA spots

There is a long way between the million or so DNA bases covered by current microarray chips and the whole human genome. Because of linkage disequilibrium, i.e., DNA's propensity to be cut and inherited in large chunks, and not small pieces, you can often tell the value of a marker by looking at nearby markers. But, still, you don't really know until you look. So, denser microarrays, or even whole genome sequences may uncover some of the hidden heritability.

2. Look at more people

Associations between traits and genes are established by statistics. To find a weak association, or an association between a not-so-common variant and the trait in question, you need a large sample. So, if the hidden heredity is hidden away in markers that are beyond your statistical power, you can simply increase this power: sample more people.

3. Look at copy-number variations (CNVs)

Any two individuals don't just have single-letter differences, but also structural changes, where an individual may have more or fewer copies of entire chunks of DNA. So, by looking at single nucleotides you are examining one source of human variation, but missing another chunk of it that may as important.

3. Study gene-gene interactions

Genes form complex networks of interaction. If you flip a SNP from C to T, you don't always get the same effect on the phenotype. This flip may increase, decrease, or leave unaffected, your risk for a disease, depending on what other genes you have. This epistatic interaction of genes makes it difficult to detect associations. It's a lot easier to study the individual effects of 2N alleles at N genes than it is to study the effects of 2^N possible combinations.

4. Don't trust heritability estimates

What if inherited conditions thought to be genetic aren't really genetic, because of epigenetic modifications of gene expression, or shared environments (e.g., in the womb) that aren't accounted for?

5. Don't trust diagnoses of conditions

If you want to find a correlation between a gene G and a trait T, you'd better be sure what T actually is. If it's a whole set of different behaviors, conveniently bundled into a condition T (such as schizophrenia), then you're in trouble, since each of these conditions may have its own causative agent. Many major diseases may be caused by more than one underlying condition, with a different genetic background. So, if you are seeking to find the common thread between people with trait T, you might not find it because there is no common thread!

My guess is that the bulk of the missing heritability is to be found in three sources:

1. Epistasis. Humans are makeshift accidents of evolution, and not well-engineered machines where the effects of individual components have been designed to work well in isolation, shielding other components from their effects. Most things in the human body affects most other things, either directly or indirectly. There are, of course, some master switches which do have individual pronounced effects (e.g., giving you lactose tolerance or breast cancer), but these are the exception. Normal variation is due to how well-put together the individual is, and not so much in the individual components.
2. Gene-Environment interactions. Just as the effect of genes depends on the joint presence of other genes (epistasis), so it depends on the presence of particular environmental influences. Imagine an allele that shows zero association with a particular trait. Does this mean that it has no influence on that trait? No, since zero association is perfectly compatible with even a huge influence, provided that a positive influence under one type of genomic or environmental background is balanced by a negative influence under another.
3. Very low frequency (family) alleles. Natural selection faces a constant battle against the continuing re-emergence of less-than-optimal alleles. Children are almost certainly on average genetically worse than their parents, since parents have survived and reproduced, while children's ability to do so is yet to be tested (*) While human variation is -in part- due to long-lived alleles that have braved the generations, quite a lot of it is due to recent alleles that arose in families, and have not had the time to spread to many bodies. It is these extremely rare family alleles and allele combinations that population studies can't quite capture.
   

Read the original story at Nature: Personal genomes: The case of the missing heritability.

Some related posts on the limits of genome-wide association studies: on intelligence, on height and body mass index, and on CNVs.

(*) Incidentally, this is why the population replacement rate is more than 2 children per woman.

Maternal inheritance and male reproductive fitness

Humans get roughly half their genes from each parent, but mothers affect their offspring in additional ways. First, there is mtDNA which is inherited only from one's mother. Second, there is epigenetic inheritance via mothers' eggs, which covers all their non-genetic qualities of these cells which grow up (post-fertilization) to become humans.

If a maternally inherited trait reduces the genetic fitness of a woman, then it will be under negative selection, and will be weeded out. If, on the other hand, it reduces the genetic fitness of a man, then it will not be affected at all: this reduction in fitness has no evolutionary effect since maternally inherited traits (e.g., mtDNA) are doomed in male bodies anyway.

Not surprisingly, such traits have been implicated in male sperm quality conditions, with e.g., specific haplogroups leading to reduced sperm count or mobility.

Sexual selection theory suggests that humans pick their mates because of their "good genes" (see other recent post). But this raises this issue: if males with good genes are selected for in each generation, then how come is a great reproductive skew maintained in the human species: why do some men produce many offspring while many produce none or a few? And, why do women often "cheat" on their mates, having children with others than their official mates.

Maternal inheritance explains this paradox: male reproductive variation due to the Y-chromosome or the autosomes can be shaped by evolution to produce males with good (well-adapted) genes, but maternally inherited factors cannot.

UPDATE: Interestingly, this may solve the paradox of non-inheritance of male attractiveness. While sexy parents have sexy daughters, apparently they don't tend to have especially attractive sons. This may be due to male-expressed maternally inherited traits. Such traits don't make their mothers' attractive (they are male expressed), and they are not inherited from their fathers.



Genetica. 2008 Sep;134(1):45-54.

Maternal inheritance, epigenetics and the evolution of polyandry

Zeh JA, Zeh DW.

Abstract

Growing evidence indicates that females actively engage in polyandry either to avoid genetic incompatibility or to bias paternity in favor of genetically superior males. Despite empirical support for the intrinsic male quality hypothesis, the maintenance of variation in male fitness remains a conundrum for traditional "good genes" models of sexual selection. Here, we discuss two mechanisms of non-Mendelian inheritance, maternal inheritance of mitochondria and epigenetic regulation of gene expression, which may explain the persistence of variation in male fitness traits important in post-copulatory sexual selection. The inability of males to transmit mitochondria precludes any direct evolutionary response to selection on mitochondrial mutations that reduce or enhance male fitness. Consequently, mitochondrial-based variation in sperm traits is likely to persist, even in the face of intense sperm competition. Indeed, mitochondrial nucleotide substitutions, deletions and insertions are now known to be a primary cause of low sperm count and poor sperm motility in humans. Paradoxically, in the field of sexual selection, female-limited response to selection has been largely overlooked. Similarly, the contribution of epigenetics (e.g., DNA methylation, histone modifications and non-coding RNAs) to heritable variation in male fitness has received little attention from evolutionary theorists. Unlike DNA sequence based variation, epigenetic variation can be strongly influenced by environmental and stochastic effects experienced during the lifetime of an individual. Remarkably, in some cases, acquired epigenetic changes can be stably transmitted to offspring. A recent study indicates that sperm exhibit particularly high levels of epigenetic variation both within and between individuals. We suggest that such epigenetic variation may have important implications for post-copulatory sexual selection and may account for recent findings linking sperm competitive ability to offspring fitness.

Link

Epigenetic effects of slavery in African Americans (?)

I can't say I buy the thesis of these two papers, namely that inherited epigenetic effects from the days of slavery are responsible for birth-weight and cardiovascular disease (CVD) disparities between whites and blacks in the US.

Does anyone know of any studies of birth weight or CVD in biracial children with a white vs. a black mother, with otherwise similar admixture proportions? An expectation of this theory is that the former should have a higher birth weight.

American Journal of Human Biology doi: 10.1002/ajhb.20824

Low birth weight of contemporary African Americans: An intergenerational effect of slavery?

Grazyna Jasienska

Abstract

The average birth weight in the contemporary African-American population is about 250 g lower than the average birth weight of European Americans. Differences in genetic and socioeconomic factors present between these two groups can explain only part of birth weight variation. I propose a hypothesis that the low birth weight of contemporary African Americans not only results from the difference in present exposure to lifestyle factors known to affect fetal development but also from conditions experienced during the period of slavery. Slaves had poor nutritional status during all stages of life because of the inadequate dietary intake accompanied by high energetic costs of physical work and infectious diseases. The concept of fetal programming suggests that physiology and metabolism including growth and fat accumulation of the developing fetus, and, thus its birth weight, depend on intergenerational signal of environmental quality passed through generations of matrilinear ancestors. I suggest that several generations that have passed since the abolition of slavery in the United States (1865) has not been enough to obliterate the impact of slavery on the current biological and health condition of the African-American population.

Link

American Journal of Human Biology doi: 10.1002/ajhb.20822

Epigenetics and the embodiment of race: Developmental origins of US racial disparities in cardiovascular health

Christopher W. Kuzawa, Elizabeth Sweet

Abstract

The relative contribution of genetic and environmental influences to the US black-white disparity in cardiovascular disease (CVD) is hotly debated within the public health, anthropology, and medical communities. In this article, we review evidence for developmental and epigenetic pathways linking early life environments with CVD, and critically evaluate their possible role in the origins of these racial health disparities. African Americans not only suffer from a disproportionate burden of CVD relative to whites, but also have higher rates of the perinatal health disparities now known to be the antecedents of these conditions. There is extensive evidence for a social origin to prematurity and low birth weight in African Americans, reflecting pathways such as the effects of discrimination on maternal stress physiology. In light of the inverse relationship between birth weight and adult CVD, there is now a strong rationale to consider developmental and epigenetic mechanisms as links between early life environmental factors like maternal stress during pregnancy and adult race-based health disparities in diseases like hypertension, diabetes, stroke, and coronary heart disease. The model outlined here builds upon social constructivist perspectives to highlight an important set of mechanisms by which social influences can become embodied, having durable and even transgenerational influences on the most pressing US health disparities. We conclude that environmentally responsive phenotypic plasticity, in combination with the better-studied acute and chronic effects of social-environmental exposures, provides a more parsimonious explanation than genetics for the persistence of CVD disparities between members of socially imposed racial categories.

Link

The eclipse of the gene

CURRENT ANTHROPOLOGY Volume 46, Number S5, December 2005

Eclipse of the Gene and the Return of Divination

by Margaret Lock

Research in the field of epigenetics challenges the assumption on which the molecular genetics of the past 50 years has been based, namely, genetic determinism. This paper reviews the social science literature that considers the social effects of the application of molecular genetics and genetic testing in connection with Mendelian conditions. It is argued that anthropologists must now go farther and respond to the challenge posed by current moves toward the implementation of genetic profiling and testing for susceptibility genes. Following a discussion of ontological problems associated with molecular genetics raised by philosophers and biologists who subscribe to epigenetics, current knowledge about molecular and population genetics of late-onset Alzheimer's disease and cross-cultural findings about the epidemiology of this disease are introduced. These findings illustrate the provisional nature of these bodies of knowledge and the complexity associated with susceptibility genes, which makes estimations of probabilities of individual risk unrealistic. A controlled clinical trial is discussed in which first-degree relatives of Alzheimer's disease patients are genotyped for risk for late-onset Alzheimer's disease. In conclusion, the social implications of testing for susceptibility genes are discussed, with comments about the role that anthropologists might play in future research.

Link