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PubMed2004

Enhanced stem cell survival in familial adenomatous polyposis.

Individuals with heterozygous germline adenomatous polyposis coli (APC) mutations or familial adenomatous polyposis (FAP) are born with normal appearing colons but later develop hundreds to thousands of polyps. Tumor progression apparently starts after somatic loss of the normal APC allele, but germline APC mutations may potentially alter niche stem cell survival through dominant-negative interactions or haploinsufficiency. Although morphologically occult, altered stem cell turnover or clonal evolution rates may be detected by measuring the diversity of crypt sequences, with greater diversity expected with longer lived stem cell lineages. Methylation pattern diversity (numbers of unique patterns per crypt) was higher in normal appearing crypts from four of five FAP colons compared to six non-FAP colons and one attenuated FAP colon. Simulations indicate higher FAP crypt diversity is consistent with slower clonal evolution from enhanced stem cell survival, either through increased stem cell numbers or decreased stem cell lineage extinction, which is predicted to increase progression rates to cancer. Enhanced stem cell survival was associated with APC mutations that remove some but not all catenin-binding repeats. Therefore, some APC mutations may be common in colorectal cancers because they confer occult pretumor "caretaker" and "gatekeeper" defects. FAP crypts accumulate more alterations from slower stem cell clonal evolution rather than increased error rates. In non-FAP crypts, enhanced stem cell survival conferred by somatic heterozygous APC mutations would favor fixation through occult clonal niche expansions. Heterozygous APC mutations may change stem cell survival during colorectal pretumor progression.

Adenomatous Polyposis Coli↗
PubMed2025

Evolutionary fingerprints of epithelial-to-mesenchymal transition.

Mesenchymal plasticity has been extensively described in advanced epithelial cancers; however, its functional role in malignant progression is controversial1-5. The function of epithelial-to-mesenchymal transition (EMT) and cell plasticity in tumour heterogeneity and clonal evolution is poorly understood. Here we clarify the contribution of EMT to malignant progression in pancreatic cancer. We used somatic mosaic genome engineering technologies to trace and ablate malignant mesenchymal lineages along the EMT continuum. The experimental evidence clarifies the essential contribution of mesenchymal lineages to pancreatic cancer evolution. Spatial genomic analysis, single-cell transcriptomic and epigenomic profiling of EMT clarifies its contribution to the emergence of genomic instability, including events of chromothripsis. Genetic ablation of mesenchymal lineages robustly abolished these mutational processes and evolutionary patterns, as confirmed by cross-species analysis of pancreatic and other human solid tumours. Mechanistically, we identified that malignant cells with mesenchymal features display increased chromatin accessibility, particularly in the pericentromeric and centromeric regions, in turn resulting in delayed mitosis and catastrophic cell division. Thus, EMT favours the emergence of genomic-unstable, highly fit tumour cells, which strongly supports the concept of cell-state-restricted patterns of evolution, whereby cancer cell speciation is propagated to progeny within restricted functional compartments. Restraining the evolutionary routes through ablation of clones capable of mesenchymal plasticity, and extinction of the derived lineages, halts the malignant potential of one of the most aggressive forms of human cancer.

Animals↗
PubMed1996

The imprint of somatic hypermutation on the repertoire of human germline V genes.

In the human immune system, antibodies with high affinities for antigen are created in two stages. A diverse primary repertoire of antibody structures is produced by the combinatorial rearrangement of germline V gene segments and antibodies are selected from this repertoire by binding to the antigen. Their affinities are then improved by somatic hypermutation and further rounds of selection. We have dissected the sequence diversity created at each stage in response to a wide range of antigens. In the primary repertoire, diversity is focused at the centre of the binding site. With somatic hypermutation, diversity spreads to regions at the periphery of the binding site that are highly conserved in the primary repertoire. We propose that evolution has favoured this complementarity as an efficient strategy for searching sequence space and that the germline V gene families evolved to exploit the diversity created by somatic hypermutation.

Antibody Diversity↗
PubMed1990

Neurobiological aspects of the pelvic floor muscles involved in defecation.

Neurobiological aspects of the organization of pelvic floor musculature are reviewed. Evolutionary considerations on the origin of these muscles indicate that they develop with specific attachments and function, i.e., do not derive from preexisting muscles such as the ones from the tail. Anatomically, pelvic floor muscles can be divided into 1) true sphincters and related muscles and 2) muscles which flank the visceral outlets. While in quadrupedal mammals the EAS behaves as a fast twitch muscle, in man this muscle has slow twitch characteristics. Like some epaxial muscles the EAS has a strong connectivity with its surrounding skin. In further analogy with some epaxial muscle the EAS, although endowed with muscle spindles, is devoid of the phasic, monosynaptic component of the stretch reflex. Onuf's nucleus which innervates pelvic floor muscles receives an important group of suprasegmental afferents including, probably, direct corticospinal fibers. Pelvic floor muscles play a fundamental role in signaling arrival of feces to the perineum. While sphincteric activity is important for continence, other mechanisms such as the anorectal angle and anal cushions are also of relevance. Although emphasis has been put on motor factors, fecal incontinence can also result from impairments in sensory mechanisms of the anorectal system. In diseases like amyotrophic lateral sclerosis, Werdnig Hoffman's and others there is selective sparing of neuropathology in Onuf's nucleus. In contrast, the nucleus is affected in some autonomic visceromotor neuronal disorders, e.g., Shy Drager syndrome, Fabry's disease. It has been suggested that Onuf's nucleus occupies an intermediate position between visceral and somatic nuclei.

Animals↗
PubMed2003

Sexual antagonism and X inactivation--the SAXI hypothesis.

X inactivation has evolved in the soma of mammalian females so that both sexes have the same ratio of X:autosomal gene expression. The X chromosome in the germ cells of XY males is also precociously inactivated for reasons that remain unclear. Unlike X inactivation in the soma, this germline X inactivation is not restricted to mammals but has evolved independently in several animal phyla. Thus, germline X inactivation might have been the precursor of somatic X inactivation in mammals. We now propose a hypothesis for the evolution of germline X inactivation. The hypothesis predicts a redistribution of late spermatogenic genes from the X chromosome to the autosomes, leading eventually to germline X inactivation as the X chromosome becomes 'demasculinized'. Sexual antagonism could be the mechanism driving this redistribution. Recent expression and genetic studies in mammals, nematodes and Drosophila support this hypothesis, and expression data on taxa that have not evolved germline X inactivation, such as birds and butterflies, should shed further light on it.

Aneuploidy↗
PubMed2002

Specialized DNA polymerases, cellular survival, and the genesis of mutations.

Cell death caused by arrested replication of damaged or structurally altered DNA can be avoided in prokaryotic and eukaryotic cells by multiple DNA polymerases that are specialized to bypass DNA damage. Some of these polymerases perform such translesion DNA synthesis of specific types of damage with high genetic fidelity. However, they exhibit greatly reduced fidelity when they operate on undamaged DNA or on DNA with lesions that are (apparently) not cognate substrates. The low fidelity of some of these specialized polymerases when copying undamaged DNA may be physiologically functional, including generating immunoglobulin diversity.

Animals↗
PubMed1979

Evolution of multiple genome mutations during long-term persistent infection by vesicular stomatitis virus.

Persistent infection of BHK21 cells was established with cloned vesicular somatitis virus plus purified Dl particles and maintained in vitro for over 5 years. After 1 year of persistence, the infectious virus RNA genome had evolved several oligonucleotide map changes, and numerous changes had accumulated by 3.5 years. Additional evolution occurred by the fourth year and continued until the fifth year. In contrast, repeated passage of virus in acute infections of several cell types in vitro or in vivo did not lead to detectable oligonucleotide map changes. The short Dl particle originally used to co-infect with infectious virus in establishing persistent infection has been displaced by an ever present and constantly changing population of other Dl particles of differing sizes and radically differing oligonucleotide maps. We conclude that the genomes of both infectious VSV and its Dl particles undergo continuous evolutionary change during years of persistence. In the infectious virus, these changes involve hundreds of mutations which are usually expressed as poorly replicating, temperature-sensitive, small plaque mutants. These are stable mutants which do not revert to wild-type when passaged repeatedly in acute infections at 37 or 33 degrees C. It appears that the sequestered intracellular environment of persistently infected cells favors rapid and continuous virus evolution.

Animals↗
PubMed1998

Dual enigma of somatic hypermutation of immunoglobulin variable genes: targeting and mechanism.

The immunoglobulin loci are uniquely unstable regions of the genome which undergo as much mutation and selection in a matter of days as a species can undergo in generations of evolution. We have studied the mutational pattern and targeting of this unusual hypermutation process over the past 16 years. The pattern of somatic mutations in rearranged variable (V) genes differs from the pattern of meiotic mutations, indicating that a different mechanism generates hypermutation than generates spontaneous mutation. Hypermutations begin on the 5' end of rearranged V genes downstream of the transcription initiation site and continue through the V exon and into the 3'-flanking region before tapering off. Mutations are located randomly throughout the DNA sequence and exhibit strand bias. The targeting of mutations to the region in and around the rearranged V gene appears to require interactions between the promoter and downstream intronic DNA sequences. The same mechanism that initiates hypermutation around V genes may also produce double-strand breaks that catalyze homologous recombination between rearranged V genes on two chromosomal alleles. With this data we have built a model of hypermutation which predicts that V-region DNA is destabilized at the nuclear matrix during transcription and undergoes strand breaks.

Animals↗
PubMed1986

Reflections on the evolution of the regulation of spermatogenesis.

We have developed the concept that mechanisms evolved very early for the modulation of spermatogenesis in response to changes in the external environment, and that these ancient control mechanisms were retained during subsequent evolution. In nearly all animals, the regulation of germinal cell development is postulated to be mediated through the control of gonadal somatic cell functions, associated with the creation and maintenance of an optimal milieu within the spermary of seminiferous tubule in which gametogenesis takes place. In primitive organisms, a small number of stages intervenes between environmental stimuli and subsequent alteration of gonadal somatic cell functions. In contrast, in more complex organisms, the number of intervening stages is greatly amplified and modulated via neuroendocrine mechanisms involving receptors, transducers, and various sorts of relays and messengers. The evolution of these neural and endocrine controls appears to have occurred in lock-step with the evolution of increasing layers of complexity of regulators of spermatogenesis. This is not unduly surprising, since the requirement to have functionally fertile male and female partners of the same species together at the same time and place would require considerable integration of behavioral and recognition mechanisms during courtship and mating. The nature of these neural mechanisms is likely to prove no less complex than that of mechanisms in the gonad required for successful gamatogenesis. The neuroendocrine regulation of spermatogenesis in starfish and in chordates is postulated to act in a manner completely homologous to the ways in which external environmental stimuli influence spermatogenesis in more primitive organisms. In both sets of cases, the gonadal somatic cells (nurse cells) are the ultimate targets which mediate the effective turning on or turning off of spermatogenesis. The hormone-responsive nurse cells are postulated to achieve this simply by creating a microenvironment in the vicinity of germinal cells which permits the expression of program required for development, or by failing to do so. In mammals, Sertoli cells and peritubular cells, only when optimally stimulated by hormones and paracine factors, are thought to form a functional unit which provides this necessary microenvironment. In less complex organisms, other nurse cell arrangements exist to nourish the syncytia of developing germ cells with the mixture of nutrients, salts, etc. required for a gametogenesis to take place in a protected milieu.

Animals↗
PubMed2004

Primitive immune systems: are your ways my ways?

Although vertebrate immune systems have been commonly conceived as exquisitely developed to combat pervasiveness by pathogens, they are not infallible. The enigmatic expression of histocompatibility in vertebrates, the manifestation of natural chimerism, autoimmunity, malignancy, and other puzzling outcomes hint that immunity did not arise in evolution to fight infections and that this capacity is a late evolutionary appendage, owing its appearance to the redeployment of a system developed for other reasons. Allorecognition in the colonial tunicate Botryllus schlosseri serves here as a platform for a contending paradigm, advocating that immunity has developed as a surveillance machinery against and for purging of nascent selfish cells (stemmed from a kin organism or from transformed cells within the organism of origin). Defense against pathogens (always representing xenogeneic aliens) appeared later, revealing the multiplicity of newly developed phenomena. Allorecognition events characteristic of the Botryllus primitive immune system, such as fusion versus rejection, the morphological resorption with its expressed hierarchy, and the somatic/germ-cell parasitic outcomes, provide clues to the evolutionary basis of allorecognition. Recent work on Botryllus immunity that highlights the cost of littering individuality by somatic variants/allogeneic cells is discussed.

Animals↗
PubMed1979

Genetic and evolutionary aspects of aging.

Four questions of fundamental importance to gerontology are considered. 1) The number of genes involved in aging--in the case of man, an analysis of the phenotypes of relevant spontaneous mutants indicates that aging is highly polygenic. 2) General categories of genes--regulator genes may be more relevant than structural genes: a) three aneuploid disorders, Down's, Turner's and Klinefelter's syndromes, ranked among the top 10 candidates as "segmental progeroid syndromes" when compared with 162 single gene disorders of relevance to the pathobiology of aging; b) the rates at which maximum life spans have been increasing, especially among hominids, have probably been too rapid to be accounted for by changes in the amino acid sequences of proteins; c) a preliminary analysis of the variance of maximum life spans among a few orders of mammals is suggestive of a linear correlation with the indexes of rates of chromosomal evolution, as estimated by Bush et al. (Proc. Natl. Acad. Sci. USA 74: 3942-3946, 1977). 3) Nature of gene action--although there are reasons for invoking genes that modulate the rates of accumulation of somatic mutations, differential regulation of development is likely to be a major setting for gene action. 4) New approaches to formal genetic analysis of aging--advances in experimental embryology and somatic cell genetics offer such opportunities.

Aged↗
PubMed2001

A comparative analysis of the immunological evolution of antibody 28B4.

In an effort to gain greater insight into the evolution of the redox active, catalytic antibody 28B4, the germline genes used by the mouse to generate this antibody were cloned and expressed, and the X-ray crystal structures of the unliganded and hapten-bound germline Fab of antibody 28B4 were determined. Comparison with the previously determined structures of the unliganded and hapten-bound affinity-matured Fab [Hsieh-Wilson, L. C., Schultz, P. G., and Stevens, R. C. (1996) Proc. Natl. Acad. Sci. U.S.A. 93, 5363] shows that the germline antibody binds the p-nitrophenyl ring of hapten 3 in an orientation significantly different from that seen in the affinity-matured antibody, whereas the phosphonate moiety is bound in a similar mode by both antibodies. The affinity-matured antibody 28B4 has more electrostatic and hydrophobic interactions with hapten 3 than the germline antibody and binds the hapten in a lock-and-key fashion. In contrast, significant conformational changes occur in the loops of CDR H3 and CDR L1 upon hapten binding to the germline antibody, consistent with the notion of structural plasticity in the germline antibody-combining site [Wedemayer, G. J., Patten, P. A., Wang, L. H., Schultz, P. G., and Stevens, R. C. (1997) Science 276, 1665]. The structural differences are reflected in the differential binding affinities of the germline Fab (K(d) = 25 microM) and 28B4 Fab (K(d) = 37 nM) to hapten 3. Nine replacement mutations were found to accumulate in the affinity-matured antibody 28B4 compared to its germline precursor. The effects of each mutation on the binding affinity of the antibody to hapten 3 were characterized in detail in the contexts of both the germline and the affinity-matured antibodies. One of the mutations, Asp95(H)Trp, leads to a change in the orientation of the bound hapten, and its presence is a prerequisite for other somatic mutations to enhance the binding affinity of the germline antibody for hapten 3. Thus, the germline antibody of 28B4 acquired functionally important mutations in a stepwise manner, which fits into a multicycle mutation, affinity selection, and clonal expansion model for germline antibody evolution. Two other antibodies, 20-1 and NZA6, with very different antigen specificities were found to be highly homologous to the germline antibody of 28B4, consistent with the notion that certain germline variable-region gene combinations can give rise to polyspecific hapten binding sites [Romesberg, F. E., Spiller, B., Schultz, P. G., and Stevens, R. C. (1998) Science 279, 1929]. The ultimate specificity of the polyspecific germline antibody appears to be defined by CDR H3 variability and subsequent somatic mutation. Insights into the evolution of antibody-combining sites provided by this and other structural studies are discussed.

Amino Acid Sequence↗
PubMed2005

Evolution of class switch recombination function in fish activation-induced cytidine deaminase, AID.

Following activation of mammalian B cells, class switch recombination (CSR) and somatic hypermutation (SHM) of the Ig heavy chain (IgH) gene can improve the functions of the expressed antibodies. Activation-induced cytidine deaminase (AID) is the only known B cell-specific protein required for inducing CSR and SHM in mammals. Lower vertebrates have an AID homologue, and there is some evidence of SHM in vivo. However there is no evidence of CSR in the cartilaginous or bony fishes, and this may be due in part to a lack of cis-elements in the IgH gene that are the normal targets of AID-mediated recombination. We have tested whether bony fish (zebrafish and catfish) AID can mediate CSR and SHM in mammalian cells. As expected, ectopic expression of fish AID in mouse fibroblasts resulted in mutations in an introduced SHM reporter gene, indicating that fish AID can mediate SHM. Unexpectedly, expression of fish AID in mouse AID-/- B cells induced surface IgG expression as well as switched transcripts from Ig gene loci, clearly indicating that the fish AID protein can mediate CSR, at least in mouse cells. These results suggest that the AID protein acquired the ability to mediate CSR before the IgH locus evolved the additional exon clusters and switch regions that are the targets of recombination. We discuss how pleiotropic functions of specific domains within the AID protein may have facilitated the early evolution of CSR in lower vertebrates.

Animals↗
PubMed1990

Structure and evolution of mammalian VH families.

Antibodies are encoded by a limited number of germline gene segments that undergo somatic diversification through rearrangement and mutation. Because these mutation processes are efficient, it is widely believed that there is little environmental selection pressure for the maintenance of specific antibody gene sequences. We have performed pairwise comparisons of known germline (as opposed to somatically generated) antibody VH elements with the hope of identifying conserved structural features common to sets of VH gene segments. These studies reveal that VH families arose prior to the mammalian radiation and have since been conserved, that this conservation appears to reflect selection at the level of protein sequence, and that the conserved regions are discretely localized on a solvent-exposed face of the heavy chain, at some distance from the antibody combining site. A family-specific region was also identified within the recombinase recognition sequences. Our results provide a context for theories that address the physiological significance of variations in VH family utilization during the development of the immune repertoire.

Animals↗
PubMed2000

mtDNA tandem repeats in domestic dogs and wolves: mutation mechanism studied by analysis of the sequence of imperfect repeats.

The mitochondrial (mt) DNA control region (CR) of dogs and wolves contains an array of imperfect 10 bp tandem repeats. This region was studied for 14 domestic dogs representing the four major phylogenetic groups of nonrepetitive CR and for 5 wolves. Three repeat types were found among these individuals, distributed so that different sequences of the repeat types were formed in different molecules. This enabled a detailed study of the arrays and of the mutation events that they undergo. Extensive heteroplasmy was observed in all individuals; 85 different array types were found in one individual, and the total number of types was estimated at 384. Among unrelated individuals, no identical molecules were found, indicating a high rate of evolution of the region. By performing a pedigree analysis, array types which had been inherited from mother to offspring and array types which were the result of somatic mutations, respectively, could be identified, showing that about 20% of the molecules within an individual had somatic mutations. By direct pairwise comparison of the mutated and the original array types, the physiognomy of the inserted or deleted elements (indels) and the approximate positions of the mutations could be determined. All mutations could be explained by replication slippage or point mutations. The majority of the indels were 1-5 repeats long, but deletions of up to 17 repeats were found. Mutations were found in all parts of the arrays, but at a higher frequency in the 5' end. Furthermore, the inherited array types within the mother-offspring pair were aligned and compared so that germ line mutations could be studied. The pattern of the germ line mutations was approximately the same as that of the somatic mutations.

Animals↗
PubMed2000

Evolution, stress, and longevity.

The disposable soma theory suggests that longevity is determined through the setting of longevity assurance mechanisms so as to provide an optimal compromise between investments in somatic maintenance (including stress resistance) and in reproduction. A corollary is that species with low extrinsic mortality are predicted to invest relatively more effort in maintenance, resulting in slower intrinsic ageing, than species with high extrinsic mortality. We tested this prediction in a comparative study of stress resistance in primary skin fibroblasts and confirmed that cells from long-lived species are indeed more resistant to a variant of stressors. A widely studied example of within-species variation in lifespan is the rodent calorie restriction model. Food-restricted animals show elevations in a range of stress response mechanisms, and it has been suggested that this is an outcome of natural selection for life history plasticity. We have developed a theoretical model for dynamic optimisation of the allocation of effort to maintenance and reproduction in response to fluctuations in food availability. The model supports the suggestion that the response to calorie restriction may be an evolutionary adaptation, raising interesting questions about the hierarchy of genetic control of multiple stress response systems. The model identifies ecological factors likely to support such an adaptation that may be relevant in considering the likely relevance of a similar response to calorie restriction in other species. Comparative and theoretical studies support the role of somatic maintenance and stress response systems in controlling the rate of ageing.

Animals↗
PubMed2004

The CDKN2A database: Integrating allelic variants with evolution, structure, function, and disease association.

In this report, we introduce the CDKN2A Database, an online database of germline and somatic variants of the CDKN2A tumor suppressor gene recorded in human disease through the year 2002, annotated with evolutionary, structural, and functional information. The CDKN2A Database improves upon existing resources by: 1) including both somatic mutations and germline variants, thereby adding the perspective of somatic cell carcinogenesis to that of hereditary cancer predisposition; 2) including information that assists with the interpretation of allelic variants, such as other primary data (sequences, structures, alignments, functional measurements, and literature references) and annotations (extensive text, figures, and a tree-based phylogenetic classification); and 3) providing the information in a format that allows a user to either download the database or to easily manipulate it online. We describe the database structure, content, current uses, and potential implications (http://biodesktop.uvm.edu/perl/p16).

Alleles↗