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Algorithms to reconstruct past indels: The deletion-only parsimony problem.

Ancestral sequence reconstruction is an important task in bioinformatics, with applications ranging from protein engineering to the study of genome evolution. When sequences can only undergo substitutions, optimal reconstructions can be efficiently computed using well-known algorithms. However, accounting for indels in ancestral reconstructions is much harder. First, for biologically-relevant problem formulations, no polynomial-time exact algorithms are available. Second, multiple reconstructions are often equally parsimonious or likely, making it crucial to correctly display uncertainty in the results. Here, we consider a parsimony approach where only deletions are allowed, while addressing the aforementioned limitations. First, we describe an exact algorithm to obtain all the optimal solutions. The algorithm runs in polynomial time if only one solution is sought. Second, we show that all possible optimal reconstructions for a fixed node can be represented using a graph computable in polynomial time. While previous studies have proposed graph-based representations of ancestral reconstructions, this result is the first to offer a solid mathematical justification for this approach. Finally we provide arguments for the relevance of the deletion-only case for the general case.

Algorithms

The simplest treatment alternative: the law of parsimony applied to choosing appropriate instructional control and errorless-learning procedures for the difficult-to-teach child.

A method for choosing effective teaching procedures for difficult-to-teach children is proposed. Assessment of child responses during teaching that involves gradually increasing environmental support in the learning setting is the basis for choice. The levels of environmental support in which child responses are assessed are (1) trial-and-error procedures; (2) increased environmental support involving analyses of reinforcement systems, incompatible responses, and prerequisite skills, as well as the most effective use of instructional control; and (3) errorless-learning procedures. Effects of instructions upon learning are discussed in terms of instructional detail and pacing, as well as with respect to the role of instructions in feedback and progressively delayed cue procedures. Stimulus shaping and stimulus fading are discussed in terms of the effectiveness of each for teaching children who have difficulty learning with more traditional procedures. The importance of the incorporation of criterion-related cues when utilizing stimulus shaping or fading is emphasized. It is proposed that an assessment of child responses should be made with respect to the three general levels of environmental support, as well as from sublevels within these, in order to choose the simplest but still effective alternative procedure for teaching difficult-to-teach children.

Child

Parsimony in designing a drug use survey: a methodology study.

This paper makes a special study of how one question in an index frequently has as much relationship to students involvement in drug use as the entire additional index developed from may questions. If one or two questions can cover an attitudinal area as well as many, this has significant implications for future surveying. Frequently, researchers want to develop much longer questionnaires than can be easily administered, and therefore have to leave out some crucial areas of interest. It was found that in each of the following attitudinal areas--family, school, friends, taking risks, and opinions about drugs--one item in each area had as much relationship to drug use as the entire indiex built on many items.

Adolescent

On investigating the statistical properties of the populous path algorithm by computer simulation. Counterconclusions to those of Tateno and Nei.

Goodman et al.'s (1974) populous path algorithm for estimating hidden mutational change in protein evolution is designed to be used as an adjunct to the maximum parsimony method. When the algorithm is so used, the augmented maximum parsimony distances, far from being overestimates, are underestimates of the actual number of nucleotide substitutions which occur in Tateno and Nei's (1978) computer simulation by the Poisson process model, even when the simulation is carried out at two and a half times the sequence density. Although underestimates, our evidence shows that they are nevertheless more accurate than estimates obtained by a Poisson correction. In the maximum parsimony reconstruction, there is a bias towards overrepresenting the number of shared nucleotide identities between adjacent ancestral and descendant nodal sequences with the bias being stronger in those portions of the evolutionary tree sparser in sequence data. Because of this particular property of maximum parsimony reconstructed sequences, the conclusions of Tateno and Nei concerning the statistical properties of the populous path algorithm are invalid. We conclude that estimates of protein evolutionary rates by the maximum parsimony--populous path approach will become more accurate rather than less as larger numbers of closely related species are included in the analysis.

Biological Evolution

Criteria for optimising phylogenetic trees and the problem of determining the root of a tree.

The process of determining the optimal phylogenetic tree from amino acid sequences or comparable data is divided into six stages. Particular attention is given both to the criteria that are used when testing for the optimal tree and the problem of determining the position of the original ancestor. Four types of criteria for evaluating the optimal tree are considered: 1. parsimony (fewest total changes), 2. path lengths from an ancestor to existing species, 3. subtracting the difference between each pair of species as measured on the tree and as compared directly with the data ("excess differences"), 4. Moore Residual Coefficient. These criteria are examined on a set of test data and some of the reasons for the differences among them are discussed. For example, the "average percent standard deviation" weights excess differences unequally in inverse proportion to the square of the observed differences. The Moore Residual Coefficient and the "excess differences" will not necessarily give a value of zero when there are no duplicated changes unless there can only be two states for each character (i.e. binary data). The path length and difference criteria (as well as the Moore Residual Coefficient) give unequal weighting to the individual branches of the tree by counting some branches more times than others. Particularly because of this some criteria will reject trees that are equally parsimonious and the criteria are said to be invalid. However the criterion of parsimony is insensitive in that it can give the same value for several basic networks and it does not specify the position of the original ancestor, the root of the tree. The importance is emphasised of stating a model and examining its predictions before a criterion is chosen to select the best network. The number of rooted trees that can be derived from a basic network (or unrooted tree) is described in relation to how detailed a description of the original ancestor is required. Four methods are described for determining the position of the root of the tree or original ancestor. Each method depends upon some additional information to that used in constructing the basic network and the method chosen will depend on this additional knowledge.

Animals

A measure of the denseness of a phylogenetic network.

The concept of phylogenetic denseness bears critically on the accuracy of evolutionary pathways inferred from experimentally sequenced proteins isolated from extant species. In this paper I develop an objective measure, rho, of denseness to supplement previous intuitive concepts and which permits one to use this concept in comparing the quality of different evolutionary reconstructions. This measure is used to examine several published phylogenetic trees: insulin, alpha-hemoglobin, beta-hemoglobin, myoglobin, cytochrome c, and the parvalbumin family. The paper emphasizes 1) the importance of denseness in accurately estimating the number of nucleotide replacements which separate homologous sequences when this estimation is made by the method of parsimony, 2) the value of this concept in assessing the quality of those estimates, and 3) the use of this concept as a biologically practical heuristic method for identifying poorly studied regions in a phylogenetic tree, whether or not the tree was obtained by the parsimony method.

Biological Evolution

Psychoanalysis, "focal psychotherapy," and the nature of the therapeutic influence.

It has traditionally been asserted that the nature of the therapeutic influence in psychoanalysis is qualitatively different from that in "psychotherapy." This thesis is considered untendable. Analysis of a case history by Balint, Ornstein, and Balint shows evidence that therapeutic change can be conceptualized more parsimoniously along lines other than those traditionally preferred. The therapist establishes himself as a good parent or authority figure vis-a-vis the patient, and within that context mediates important lessons in nonneurotic constructive living. Given strong motivation to seek change, the patient is won over to a point of view different from the one that has, in essential respects, guided his life in the past, and he has to make these teachings his own. Analytic therapy is an education for optimal personal freedom in the context of social living.

Adult

Evidence for organicity in concrete vs. overinclusive thought-disordered schizophrenics.

Matched 20 overinclusive schizophrenics, 13 schizophrenics with a concrete thought disorder, defined in terms of performance errors on a conceptual ability test, and 11 brain-damaged patients on age, education, vocabulary proficiency, severity of illness and length of hospitalization. Ss then were given the Combined Test Battery for Organicity. No differences were found between the overinclusive and concrete schizophrenics on any measure of organicity. The Organic Test Battery had poor concurrent validity in distinguishing between brain-damaged and schizophrenic patients. Schizophrenics with a concrete thought disorder have a relatively rare condition that continues to defy explanation, though on the basis of past research an organic involvement seems to be the most parsimonious explanation.

Adult

Genetic and environmental determinants of periodontal disease.

Reanalysis of data on periodontal disease in 241 families [Chung et al, 1977b], based on an extended and more satisfactory path model [Rao et al, 1979], failed to detect significant heritability, and concluded in favor of cultural inheritance only, without maternal effects or intergenerational differences. The most parsimonious hypothesis yields a relative variance component of 0.338 +/- 0.024 due to indexed environment for both children and adults, the remainder (1.0--0.338 = 0.662) being due to residual nongenetic factors.

Culture

The discriminative efficiency of the Bayley Scales of Infant Development.

This study was designed to determine the discriminative efficiency of the Bayley Mental and Motor Scales for classifying infants as neurologically suspicious and neurologically normal. The two groups employed in the study were formed on the basis of the results from comprehensive neurological examinations performed at ages 1 and 7. Three discriminant function analyses were conducted, one for each scale separately and a third incorporating both scales using a stepwise procedure. Efficiency was measured in terms of number of correct and incorrect classifications, false positive and false negative errors, and validity coefficients. Comparisons among the analyses were examined by means of relative discrimination power and incremental validity. The findings suggested that the Motor Scale provides the most accurate identification of infants with suspected neurological impairments. A statistically significant likelihood discriminant function derived from both scales yielded some additional discriminative power. The law of parsimony, however, dictated the use of the single Motor Scale.

Child

Absence of "cheese effect" during deprenyl therapy: some recent studies.

Although the selective monoamine oxidase (MAO) B inhibitor, (-)deprenyl, has been shown to be free from the "cheese effect" in man after tyramine challenge, the reason for this is far from clear: it may well be independent of the selective inhibitory action of the drug, for during chronic administration there is some evidence to suggest that both A and B forms of the enzyme are equally inhibited. By-passing the putative MAO A gut barrier in the pig (chosen because it possesses MAO B alone in all other tissues) by intravenous tyramine administration into the deprenyl-pretreated animal failed to provoke a pressor response, despite substantial MAO inhibition. Conversely, clorgyline (MAO A inhibitor) pretreatment, which resulted in minimal MAO inhibition, produced a profound hypertensive response, resembling that observed with the non-MAO-inhibiting drug, isoniazid. The most parsimonious explanation for these findings may be that two separate but closely associated pharmacological effects are normally found with "orthodox" MAO inhibitors, enzyme inhibition proper and facilitation of noradrenaline release from its binding sites during tyramine challenge.

Amphetamines

Evolutionary diversification of structure and function in the family of intracellular calcium-binding proteins.

The maximum parsimony method was used to reconstruct the genealogical history of the family of intracellular calcium-binding proteins represented by six major present-day lineages, three of which--calcium dependent modulator protein, heart and skeletal muscle troponin Cs, and alkali light chains of myosin--were found to share a closer kinship with one another than with the other lineages. Similarly, parvalbumins and regulatory light chains of myosin were depicted as more closely related, whereas the branch of intestinal calcium-binding protein proved to have the most distant separation. The computer-generated amino acid sequence for the common ancestor of these six lineages described a four domain protein in which each domain of approximately 40 amino acid residues had a mid-region. 12 residue segment that bound calcium and had properties most resembling those of the calcium dependent modulator protein. It could then be deduced that parvalbumins evolved by deletion of domain I, inactivation of calcium-binding properties in domain II, and acquisition of increased affinity for Ca++ and Mg++ in domains III and IV. Regulatory light chains of myosin lost the cation binding property from three domains, retaining it in I, whereas alkali light chains of myosin lost this ability from each of the four domains. In skeletal muscle troponin C all domains retained their calcium-binding activity; however, like parvalbumins, domains III and IV acquired high affinity properties. Cardiac troponin C lost its binding activity from domain I but otherwise resembled the skeletal muscle form. Finally, intestinal calcium-binding protein evolved by deletion of domains III and IV. Positive selection could be implicated in these evolutionary changes in that the rate of fixation of mutations substantially increased in the mid portions of those domains which were loosing calcium-binding activity. Likewise, when the cation binding sites were changing from low to high affinity, an accelerated rate of fixed mutations was observed. Once this new functional parameter was selected these regions showed a remarkable conservatism, as did those binding sites which were maintaining the lower affinity. Moreover even in sequence regions not directly involved in cation binding, the lineage of troponin C because very conservative over the past 300 million years, perhaps becuase of the necessity for maintaining specific interfaces in order for the molecule to interact with troponin I and T in a functional thin myofilament. A similar phenomenon was observed in domain II of the regulatory light chains of the myosin lineage suggesting a possible binding site with the heavy chain of myosin.

Amino Acid Sequence

Evolution of methionine initiator and phenylalanine transfer RNAs.

Sequence data from methionine initiator and phenylalanine transfer RNAs were used to construct phylogenetic trees by the maximum parsimony method. Although eukaryotes, prokaryotes and chloroplasts appear related to a common ancestor, no firm conclusion can be drawn at this time about mitochondrial-coded transfer RNAs. tRNA evolution is not appropriately described by random hit models, since the various regions of the molecule differ sharply in their mutational fixation rates. "Hot" mutational spots are identified in the Tpsic, the amino acceptor and the upper anticodon stems; the D arm and the loop areas on the other hand are highly conserved. Crucial tertiary interactions are thus essentially preserved while most of the double helical domain undergoes base pair interchange. Transitions are about half as costly as transversions, suggesting that base pair interchanges proceed mostly through G-U and A-C intermediates. There is a preponderance of replacements starting from G and C but this bias appears to follow the high G + C content of the easily mutated base paired regions.

Animals