The pre-Mendelian, pre-Darwinian world: Shifting relations between genetic and epigenetic mechanisms in early multicellular evolution

The reliable dependence of many features of contemporary organisms on changes in gene content and activity is tied to the processes of Mendelian inheritance and Darwinian evolution. With regard to morphological characters, however, Mendelian inheritance is the exception rather than the rule, and neo-Darwinian mechanisms in any case do not account for the origination (as opposed to the inherited variation) of such characters. It is proposed, therefore, that multicellular organisms passed through a pre-Mendelian, pre-Darwinian phase, whereby cells, genes and gene products constituted complex systems with context-dependent, self-organizing morphogenetic capabilities. An example is provided of a plausible ’core’ mechanism for the development of the vertebrate limb that is both inherently pattern forming and morphogenetically plastic. It is suggested that most complex multicellular structures originated from such systems. The notion that genes are privileged determinants of biological characters can only be sustained by neglecting questions of evolutionary origination and the evolution of developmental mechanisms.     

THE EVOLUTION OF MATERNAL CHARACTERS

We develop quantitative-genetic models for the evolution of multiple traits under maternal inheritance, in which traits are transmitted through non-Mendelian as well as Mendelian mechanisms, and maternal selection, in which the fitness of offspring depends on their mother's phenotype as well as their own. Maternal inheritance results in time lags in the evolutionary response to selection. These cause a population to evolve for an indefinite number of generations after selection ceases and make the rate and direction of evolution change even when the strength of selection and parameters of inheritance remain constant. The rate and direction of evolution depend on the inheritance of traits that are not under selection, unlike under classical Mendelian inheritance. The models confirm earlier findings that the response to selection can be larger or smaller than what is possible with simple Mendelian inheritance, and even in a direction opposite to what selection favors. Maternal selection, in which a mother's phenotype influences her offspring's fitness, is frequency-dependent and can cause a population to evolve maladaptively away from a fitness peak, regardless of whether traits are transmitted by Mendelian or maternal inheritance. Maternal selection differs from other forms of selection in that its force depends not only on the fitness function but also on the phenotypic resemblance of parents and offspring.     

Making biology count: integrating mathematics into the teaching of inheritance

In this paper, I explore how seamless embedding of four mathematical concepts: counting, ratio, distribution, and statistical significance, into a unit on inheritance enables students to gain a deeper insight into biological phenomena than a qualitative only approach achieves. The topic of Mendelian inheritance is used to illustrate this proposal. An introductory activity is presented that separates the specialized genetics vocabulary from the inheritance process, allowing the initial mathematical relationship to be developed and subsequently followed by the language requirements.     

Using Mendelian Inheritance To Improve High-Throughput SNP Discovery

Restriction site-associated DNA sequencing or genotyping-by-sequencing (GBS) approaches allow for rapid and cost-effective discovery and genotyping of thousands of single-nucleotide polymorphisms (SNPs) in multiple individuals. However, rigorous quality control practices are needed to avoid high levels of error and bias with these reduced representation methods. We developed a formal statistical framework for filtering spurious loci, using Mendelian inheritance patterns in nuclear families, that accommodates variable-quality genotype calls and missing data—both rampant issues with GBS data—and for identifying sex-linked SNPs. Simulations predict excellent performance of both the Mendelian filter and the sex-linkage assignment under a variety of conditions. We further evaluate our method by applying it to real GBS data and validating a subset of high-quality SNPs. These results demonstrate that our metric of Mendelian inheritance is a powerful quality filter for GBS loci that is complementary to standard coverage and Hardy–Weinberg filters. The described method, implemented in the software MendelChecker, will improve quality control during SNP discovery in nonmodel as well as model organisms.     

Selection response in traits with maternal inheritance

Maternal inheritance is the non-Mendelian transmission of traits from mothers to their offspring. Despite its presence in virtually all organisms, acting through a variety of mechanisms, the evolutionary consequences of maternal inheritance are not well understood. Here we review and extend a model of the inheritance and evolution of multiple quantitative characters with complex pathways of maternal effects. Extensions of the earlier model include common family environmental effects not associated with maternal phenotype, sexual dimorphism, and paternal effects (non-Mendelian influence of the father on offspring traits). We find that, in contrast to simple Mendelian inheritance, maternal inheritance produces qualitatively different evolutionary dynamics for two reasons: (1) the response to selection on a set of characters depends not only on their additive genetic variances and covariances, but also on maternal characters that influence them, and (2) time lags in the response to selection create a form of evolutionary momentum. These results have important implications for evolution in natural populations and practical applications in the economic improvement of domesticated species. We derive selection indices that maximize either the economic improvement in a single generation of artificial selection or the asymptotic rate of improvement in long-term selection programmes, based on individual merit or a combination of individual and family merit. Numerical examples show that accounting for maternal inheritance can lead to considerable increases in the efficiency of artificial selection.     

Genome scans for transmission ratio distortion regions in mice

Transmission ratio distortion (TRD) is the departure from the expected genotypic frequencies under Mendelian inheritance. This departure can be due to multiple physiological mechanisms during gametogenesis, fertilization, fetal and embryonic development, and early neonatal life. Although a few TRD loci have been reported in mouse, inheritance patterns have never been evaluated for TRD. In this article, we developed a Bayesian binomial model accounting for additive and dominant deviation TRD mechanisms. Moreover, this model was used to perform genome-wide scans for TRD quantitative trait loci (QTL) on six F2 mouse crosses involving between 296 and 541 mice and between 72 and 1854 genetic markers. Statistical significance of each model was checked at each genetic marker with Bayes factors. Genome scans revealed overdominance TRD QTL located in mouse chromosomes 1, 2, 12, 13, and 14 and additive TRD QTL in mouse chromosomes 2, 3, and 15, although these results did not replicate across mouse crosses. This research contributes new statistical tools for the analysis of specific genetic patterns involved in TRD in F2 populations, our results suggesting a relevant incidence of TRD phenomena in mouse with important implications for both statistical analyses and biological research.     

Science and representation: the case of genetic maps

At the beginning of the 20th century, the main objective of Mendelian hybridization was, through controlled crosses, to attain the expression of desired "factors", for example in crop improvement. Because of these aims, Mendel's principles were adopted faster among agronomists than academic sectors. The change from the Mendelian conception of factors to the first genetic maps consisted in looking at genes not as abstract and functional entities like in Mendelian studies, but to visualise them as dots on a line, as dots on a map in classical genetics. What genes could do wasn't any more the core interest; their localization on a map was privileged. This new conception was followed by a new way to study, interpret and represent the inheritance phenomena, also, a new way to conduct experiments different from Mendelian hybridization. The construction of the first genetic maps and their representations were a successful means to study, explain and represent different inheritance issues and was a new way in which genetic studies could be done. At the beginning, these maps were hypothetical representations that facilitated the handling of empirical data as well as the classification of mutants. Later on, the culture of mapping strongly contributed to the understanding of the mechanics of chromosomes and the hereditary transmission.     

Inheritance of the general shell color in the scallop Argopecten purpuratus (Bivalvia: Pectinidae)

Although some external coloration and pigmentation patterns in molluscan shells may be attributable to environmental factors, most variation in these phenotypic characters depends on uncomplicated genetic mechanisms. Genetic research on inheritance of color variations in the north-Chilean scallop (Argopecten purpuratus) has now been expanded to analyze color segregation in juvenile scallops produced under controlled conditions employing self- and cross-fertilization. Calculations from the results were used for comparison with different numerical models based on Mendelian inheritance, and results were also obtained on the inheritance of a dorsoventral white line often observed on the left (upper) valve in this species. The results confirmed the hereditary basis for color variation in the shell of this scallop, suggesting a simple, dominant model of epistasis to explain the distribution of the different color variants observed (purple, brown, orange, yellow, and white). The presence of the white line may be controlled by a recessive allele with simple Mendelian traits on a locus distinct from those that control color variation.     

Darwin’s contributions to genetics

Darwin’s contributions to evolutionary biology are well known, but his contributions to genetics are much less known. His main contribution was the collection of a tremendous amount of genetic data, and an attempt to provide a theoretical framework for its interpretation. Darwin clearly described almost all genetic phenomena of fundamental importance, such as prepotency (Mendelian inheritance), bud variation (mutation), heterosis, reversion (atavism), graft hybridization (Michurinian inheritance), sex-limited inheritance, the direct action of the male element on the female (xenia and telegony), the effect of use and disuse, the inheritance of acquired characters (Lamarckian inheritance), and many other observations pertaining to variation, heredity and development. To explain all these observations, Darwin formulated a developmental theory of heredity — Pangenesis — which not only greatly influenced many subsequent theories, but also is supported by recent evidence.     

Integration and inheritance of transgenes in crop plants and trees

Transgene integration and inheritance have been investigated in a number of crop plants and few tree species. Transgene integration is predominantly a random process, whether mediated by Agrobacterium or particle bombardment. Depending on the genomic position of the integrated transgene and structure of the integration site as well as copy number of the transgene in the genome, its expression may be stable or variable. Therefore, integration patterns would affect the mode of transgene inheritance in plants, regardless of the method of gene transfer. So far, both Mendelian and non-Mendelian inheritance of transgenes has been reported across several generations (T1–T3) of crop plants. In few tree species (apple, poplar, plum, and American chestnut), mostly Mendelian inheritance of the transgenes has been observed in the T1 or BC1 generations. However, detailed studies in the transgenic papaya trees showed Mendelian segregation of the transgene in the T1 generation but non-Mendelian inheritance in the T2 generation. Variation in transgene inheritance was also detected in transgenic apple and plum trees. Long generation cycles in many economically important tree species preclude investigation of inheritance of transgenes in the tree progeny. Production of early flowering trees, either by genetic modification or by environmental modulation, would facilitate the study of transgene inheritance across generations of transgenic trees. In order to overcome problems of randomness of transgene integration, targeted transgene insertions by homologous or site-specific recombination or by designer recombinases or nucleases offer prospects for stable integration of transgenes in predetermined locations in the plant genome. And perhaps, that might provide a platform for stable expression and Mendelian inheritance of transgenes in plants.     

A unified approach to the evolutionary consequences of genetic and nongenetic inheritance

Inheritance-the influence of ancestors on the phenotypes of their descendants-translates natural selection into evolutionary change. For the past century, inheritance has been conceptualized almost exclusively as the transmission of DNA sequence variation from parents to offspring in accordance with Mendelian rules, but advances in cell and developmental biology have now revealed a rich array of inheritance mechanisms. This empirical evidence calls for a unified conception of inheritance that combines genetic and nongenetic mechanisms and encompasses the known range of transgenerational effects, including the transmission of genetic and epigenetic variation, the transmission of plastic phenotypes (acquired traits), and the effects of parental environment and genotype on offspring phenotype. We propose a unified theoretical framework based on the Price equation that can be used to model evolution under an expanded inheritance concept that combines the effects of genetic and nongenetic inheritance. To illustrate the utility and generality of this framework, we show how it can be applied to a variety of scenarios, including nontransmissible environmental noise, maternal effects, indirect genetic effects, transgenerational epigenetic inheritance, RNA-mediated inheritance, and cultural inheritance.     

Rethinking heredity, again

The refutation of 'soft' inheritance and establishment of Mendelian genetics as the exclusive model of heredity is widely portrayed as an iconic success story of scientific progress. Yet, we are witnessing a re-emergence of debate on the role of soft inheritance in heredity and evolution. I argue that this reversal reflects not only the weight of new evidence but also an important conceptual change. I show that the concept of soft inheritance rejected by 20th-century genetics differs fundamentally from the current concept of 'nongenetic inheritance'. Moreover, whereas it has long been assumed that heredity is mediated by a single, universal mechanism, a pluralistic model of heredity is now emerging, based on a recognition of multiple, parallel mechanisms of inheritance.     

Three epigenetic information channels and their different roles in evolution

There is increasing evidence for epigenetically mediated transgenerational inheritance across taxa. However, the evolutionary implications of such alternative mechanisms of inheritance remain unclear. Herein, we show that epigenetic mechanisms can serve two fundamentally different functions in transgenerational inheritance: (i) selection-based effects, which carry adaptive information in virtue of selection over many generations of reliable transmission; and (ii) detection-based effects, which are a transgenerational form of adaptive phenotypic plasticity. The two functions interact differently with a third form of epigenetic information transmission, namely information about cell state transmitted for somatic cell heredity in multicellular organisms. Selection-based epigenetic information is more likely to conflict with somatic cell inheritance than is detection-based epigenetic information. Consequently, the evolutionary implications of epigenetic mechanisms are different for unicellular and multicellular organisms, which underscores the conceptual and empirical importance of distinguishing between these two different forms of transgenerational epigenetic effect.     

Inheritance of allozymes in Atlantic herring (Clupea harengus harengus)

Progeny from single pair crosses of Atlantic herring were examined to determine the heritability of genetic variation at seven polymorphic allozyme loci. Mendelian inheritance of codominant autosomal alleles was established for IDH-2, LDH-1, LDH-2, ME-2, PGM-1, and PGI-2. This demonstration of Mendelian inheritance is essential for accurate interpretation of allozymic variation among natural populations of this pelagic species.     

A population of wheat and tritordeum transformants showing a high degree of marker gene stability and heritability

The stability and heritability of three marker genes was investigated in a population of twelve independent transgenic cereal lines (six wheat and six tritordeum). Integration patterns, inheritance of structural transgenes and inheritance of expression were analysed in the T₀ and T₁ generations for all 12 lines. Transmission and expression were analysed in the T₂ generation for 9 lines and in the T₃ generation for the six wheat lines. Inheritance of integration patterns was highly stable, and transmission of the transgenes and inheritance of their expression followed Mendelian ratios in the majority of lines. A gradual reduction in uidA expression was observed over three generations, which was not accompanied by a similar reduction in bar expression. Some unexpected phenomena associated with transgene inheritance were also observed and are discussed. Received: 9 February 1999 / Accepted: 11 February 1999     

Genomic imprinting: a case of inherited hematocrit, radiosensitivity, and antioxidant status in human being, as well as weight of newborn mammals

Epigenetic hypothesis of dynamic genomic parental imprinting, explaining the mechanisms of formation and inheritance of quantitative characters in multicellular organisms, is proposed. Method for analyzing the compliance of quantitative characters of organisms with the hypothesis of dynamic genomic parental imprinting is developed. Examples of human characters and characters of other mammals inherited in accordance with the proposed model are given. It is concluded that the hypothesis can be used for studying ontogeny and explaining the mechanisms of inheritance of the morphoses providing the stability and evolution of species. Possible ways of further experimental verification of the hypothesis and areas of its practical application are discussed.     

Epigenetic inheritance,prions and evolution

The field of epigenetics has grown explosively in the past two decades or so. As currently defined, epigenetics deals with heritable, metastable and usually reversible changes that do not involve alterations in DNA sequence, but alter the way that information encoded in DNA is utilized. The bulk of current research in epigenetics concerns itself with mitotically inherited epigenetic processes underlying development or responses to environmental cues (as well as the role of mis-regulation or dys-regulation of such processes in disease and ageing), i.e., epigenetic changes occurring within individuals. However, a steadily growing body of evidence indicates that epigenetic changes may also sometimes be transmitted from parents to progeny, meiotically in sexually reproducing organisms or mitotically in asexually reproducing ones. Such transgenerational epigenetic inheritance (TEI) raises obvious questions about a possible evolutionary role for epigenetic ‘Lamarckian’ mechanisms in evolution, particularly when epigenetic modifications are induced by environmental cues. In this review I attempt a brief overview of the periodically reviewed and debated ‘classical’ TEI phenomena and their possible implications for evolution. The review then focusses on a less-discussed, unique kind of protein-only epigenetic inheritance mediated by prions. Much remains to be learnt about the mechanisms, persistence and effects of TEI. The jury is still out on their evolutionary significance and how these phenomena should be incorporated into evolutionary theory, but the growing weight of evidence indicates that likely evolutionary roles for these processes need to be seriously explored.     

Complex segregation analysis of nonsyndromic cleft lip and palate.

This study was undertaken to examine the inheritance pattern of nonsyndromic cleft lip with or without cleft palate (CL/P). Complex segregation analysis using the unified model as in POINTER and the regressive model as in REGD programs were applied to analyze a midwestern U.S. Caucasian population of 79 families ascertained through a proband with CL/F. In REGD, the dominant or codominant Mendelian major locus models of inheritance were the most parsimonious fit. In POINTER, besides the Mendelian major locus model, the multifactorial threshold (MF/T) model and the mixed model were also consistent with the observed data. However, the high heritability parameter of .93 (SD .063) in the MF/T model suggests that any random exogenous factors are unlikely to be the underlying mechanisms, and the mixed model indicates that this high heritability is accounted for by a major dominant locus component. These findings indicate that the best explanation for the etiology of CL/P in this study population is a putative major locus associated with markedly decreased penetrance. Molecular studies may provide further insight into the genetic mechanism underlying CL/P.     

Non-Mendelian inheritance of paralogs of 2 cytoskeletal genes in the ciliate Chilodonella uncinata

Recognition of the role of non-Mendelian inheritance is on the rise, particularly as epigenetic phenomena are shown to shape the transformation of genomes into phenotypes. Ciliates provide a model system in which to explore the role of epigenetics because ciliates have both a germ line (micronuclear) and somatic (macronuclear) genome within every cell. In the ciliate Chilodonella uncinata, the macronucleus is extensively fragmented such that many genes end up on their own chromosomes. Hence, it is possible to track the fate of unlinked genes within macronuclei of C. uncinata. Here we demonstrate that the pattern of inheritance in isolates of C. uncinata is complex and involves both Mendelian transmission between micronuclei and macronuclei and epigenetic phenomena. The macronuclei from 2 isolates of C. uncinata and their progeny share identical rDNA loci and 2 identical beta-tubulin paralogs, yet have different actin paralogs and some beta-tubulin paralogs that are not shared. We propose a model in which all the divergent paralogs are present in the ciliate micronuclei. Under this model, different paralogs are retained in developing macronuclei following conjugation. We further speculate that an epigenetic mechanism, such as RNA interference, is involved in selective retention of specific paralogs within lines. This system allows the exploration of epigenetic phenomena that shape somatic genomes and provides parallels to studies of the development of somatic nuclei within animals.     

The inheritance of organelle genes and genomes: patterns and mechanisms.

Unlike nuclear genes and genomes, the inheritance of organelle genes and genomes does not follow Mendel's laws. In this mini-review, I summarize recent research progress on the patterns and mechanisms of the inheritance of organelle genes and genomes. While most sexual eukaryotes show uniparental inheritance of organelle genes and genomes in some progeny at least part of the time, increasing evidence indicates that strictly uniparental inheritance is rare and that organelle inheritance patterns are very diverse and complex. In contrast with the predominance of uniparental inheritance in multicellular organisms, organelle genes in eukaryotic microorganisms, such as protists, algae, and fungi, typically show a greater diversity of inheritance patterns, with sex-determining loci playing significant roles. The diverse patterns of inheritance are matched by the rich variety of potential mechanisms. Indeed, many factors, both deterministic and stochastic, can influence observed patterns of organelle inheritance. Interestingly, in multicellular organisms, progeny from interspecific crosses seem to exhibit more frequent paternal leakage and biparental organelle genome inheritance than those from intraspecific crosses. The recent observation of a sex-determining gene in the basidiomycete yeast Cryptococcus neoformans, which controls mitochondrial DNA inheritance, has opened up potentially exciting research opportunities for identifying specific molecular genetic pathways that control organelle inheritance, as well as for testing evolutionary hypotheses regarding the prevalence of uniparental inheritance of organelle genes and genomes.