Analysis of sequence and structure homologies between thyroglobulin and acetylcholinesterase: possible functional and clinical significance

The homology between thyroglobulin and acetylcholinesterase (1) has been analyzed in detail. It contains 28.3% identical amino acids and extends over 544 residues, involving more than 90% of the acetylcholinesterase molecule and the C-terminal portion of thyroglobulin. The hydropathy profiles of the homologous regions have been determined and compared. Their striking resemblance suggests that both proteins adopt a similar three dimensional structure and militates for some common property. As thyroglobulin and acetylcholinesterase are known to interact with cell membranes, we suggest that the acetylcholinesterase-like domain of thyroglobulin is involved in the binding. These observations demonstrate that thyroglobulin has evolved from the condensation of a duplicated copy of the acetylcholinesterase gene with an archaic thyroglobulin gene encoding the major hormonogenic domain. The extensive homology in hydropathy profiles suggests that the two proteins may share antigenic determinants. If this were the case, it would provide a rationale for the demonstration of immunoreactive thyroglobulin in neurons (2) and the pathogenesis of Grave's ophthalmopathy.     

Should nucleotide sequence analyzing computer algorithms always extend homologies by extending homologies?

Most computer algorithms used for comparing or aligning nucleotide sequences rely on the premise that the best way to extend a homology between the two sequences is to select a match rather than a mismatch. We have tested this assumption and found that it is not always valid.     

Two-dimensional graphic analysis of DNA sequence homologies.

We describe a computer program designed to facilitate the pattern matching analysis of homologies between DNA sequences. It takes advantage of a two-dimensional plot in order to simplify the evaluation of significant structures inherited in the sequences. The program can be divided into three parts, i) algorithm for search of homologies, ii) two-dimensional graphic display of the result, iii) further graphic treatment to enhance significant structures. The power of the graphic display is presented by the following application of the program. We conducted a search for direct repeats in the mouse immunoglobulin kappa-chain genes. Both the five J DNA sequences and other shorter repeats were found. We also found a longer stretch of homology that could indicate the presence of duplicated DNA in the J4, J5 region.     

DNA nucleotide sequence homologies between some zoosporic fungi

Summary Representative species from the monoflagellate Blastocladiales and the biflagellate Saprolegniales were studied for their DNA base composition, heterogeneity, nucleotide sequence homology and divergence. Intergeneric, intrageneric and interstrain DNAs of Blastocladiales were heterogenous. The G+C values for their main component (average 64 percent) and two minor ones (average 52 and 44 percent) were found to be significantly higher than the corresponding values from the biflagellate Saprolegnia ferax (55, 46 and 36 percent respectively). In Allomyces species, the two hybrid, male and female strains were found to have closer homology with their parental types than these last between themselves. Among Blastocladiales, interspecific similarities between the epigynous A. macrogynus and the hypogynous A. arbuscula were higher (average 75 percent) than intergeneric similarities between Allomyces and Blastocladiella (average 58 percent). The biflagellate S. ferax was found to be distantly related to the uniflagellate Allomyces (average 48 percent similarity). The nucleotide sequence divergences obtained from thermal elution data correlated the hybridization values.     

Unrecognized sequence homologies may confound genome-wide association studies

Genome-wide association studies (GWAS) have become a preferred method to identify new genetic susceptibility loci. This technique aims to understanding the molecular etiology of common diseases, but in many cases, it has led to the identification of loci with no obvious biological relevance. Herein, we show that previously unrecognized sequence homologies have caused single-nucleotide polymorphism (SNP) microarrays to incorrectly associate a phenotype to a given locus when in fact the linkage is to another distant locus. Using genetic differences between male and female subjects as a model to study the effect of one specific genomic region on the whole SNP microarray, we provide strong evidence that the use of standard methods for GWAS can be misleading. We suggest a new systematic quality control step in the biological interpretation of previous and future GWAS.     

Extensive sequence homologies among lectins from leguminous plants

The first twenty five residues of the amino terminal sequence of the β chains from lentil and pea lectins, of soybean and peanut agglutinins, and of the R and L subunits of phytohemagglutinin (PHA) were compared. Extensive homologies were found, ranging from near identity in the case of the β chains of lentil and pea lectins, to 24% identity between soybean agglutinin and L-PHA (assuming two deletions in the latter). Despite different sugar binding specificities, a common ancestry for the genes coding for leguminous lectins appears to be very likely.     

Quantitative computer analysis of signal sequence homologies in DNA

Homologies to prokaryotic recognition sites for RNA polymerase,ribosomes, and cyclic-AMP receptor protein (CRP), are analyzedby a new computer program using weighting factors to accountfor the statistical variation at each position of the consensus.Known signal sequence sites are easily detected by this algorithm,and other sites with equally strong homology are found whosebiological function is still unknown. Some sites are biologicallyactive even though they have very weak homology. No arbitrary‘cutoff score’ can distinguish active recognitionsites from inactive homologies; experiments must determine whycertain weak homologies are able to function while others arenot. Received on May 12, 1986; accepted on August 8, 1986     

Genetic and nucleotide sequence homologies in bacillus genomes

Summary The extent of divergence in the organization of the aromatic amino acid cluster among the heterogenetic strains of Bacillus subtilis has been examined by hybridizations to a trp homolog from B. pumilus and bymarker survivals after restriction. The trp operon in the W23, 3610 and 168M genomes exhibit variations in the location of the EcoRI and HindIII cleavage sites consistent with the relative transforming activity of the surviving genes and the history of the strains.     

Rapid significance estimation in local sequence alignment with gaps.

In order to assess the significance of sequence alignments, it is crucial to know the distribution of alignment scores of pairs of random sequences. For gapped local alignment, it is empirically known that the shape of this distribution is of the Gumbel form. However, the determination of the parameters of this distribution is a computationally very expensive task. We present a new algorithmic approach which allows estimation of the more important of the Gumbel parameters at least five times faster than the traditional methods. Actual runtimes of our algorithm between less than a second and a few minutes on a workstation bring significance estimation into the realm of interactive applications.     

Nucleotide sequence homologies in control regions of prokaryotic genomes

Functional recognition sites for several regulatory factors, including RNA polymerase, cyclic adenosine monophosphate receptor protein and ribosomes, do not always have strong consensus nucleotide sequence homology, yet they are capable of biological activity. Using the computer, other nucleotide sequences can be found that have equal or significantly greater consensus homology, but whose biological function has not been characterized. This analysis shows that no arbitrary 'cutoff score' can successfully distinguish active recognition sites from uncharacterized homologies, due to the great natural diversity in the strength and conservation of functional sites. It also predicts that the strong 'cryptic' homologies presented here are of two types: some might already have a biological function which has so far not been detected, whereas certain single-point mutations might be able to confer activity upon the others by correcting a key structural defect.     

Lactose metabolism and lactase gene sequence homologies amongst lactobacilli

A number of strains of Lactobacillus spp., including the thermophilic and mesophilic dairy species, were screened for the presence of β -galactosidase ( β -gal) and phospho- β -galactosidase (pbg) enzyme activities. The majority of lactose fermenting strains exhibited β -gal rather than pbg enzyme activity with the highest levels in the thermophilic dairy species.
Correlation between these enzymes and the presence of specific genetic determinants was sought using probes for β -gal and pbg genes from Lactobacillus casei ssp. casei strain 64H. Southern transfer and filter hybridization showed that the β-gal probe shared homology with one strain of Lact. casei ssp. casei only. Sequences homologous to the pbg gene were detected only in plasmid DNA from the same strain of Lact. casei ssp. casei and with plasmid DNA from an apparently unrelated strain of Lactobacillus which exhibited no pbg activity. Two other strains of Lact. casei ssp. casei appeared to show homology between their chromosomal DNA and the pbg gene probe. No other homologies were detected. Therefore, although lactase activity could be detected in many strains of Lactobacillus spp., the genetic determinants involved did not share extensive homology.     

Assessing a novel approach for predicting local 3D protein structures from sequence

We developed a novel approach for predicting local protein structure from sequence. It relies on the Hybrid Protein Model (HPM), an unsupervised clustering method we previously developed. This model learns three-dimensional protein fragments encoded into a structural alphabet of 16 protein blocks (PBs). Here, we focused on 11-residue fragments encoded as a series of seven PBs and used HPM to cluster them according to their local similarities. We thus built a library of 120 overlapping prototypes (mean fragments from each cluster), with good three-dimensional local approximation, i.e., a mean accuracy of 1.61 A Calpha root-mean-square distance. Our prediction method is intended to optimize the exploitation of the sequence-structure relations deduced from this library of long protein fragments. This was achieved by setting up a system of 120 experts, each defined by logistic regression to optimize the discrimination from sequence of a given prototype relative to the others. For a target sequence window, the experts computed probabilities of sequence-structure compatibility for the prototypes and ranked them, proposing the top scorers as structural candidates. Predictions were defined as successful when a prototype <2.5 A from the true local structure was found among those proposed. Our strategy yielded a prediction rate of 51.2% for an average of 4.2 candidates per sequence window. We also proposed a confidence index to estimate prediction quality. Our approach predicts from sequence alone and will thus provide valuable information for proteins without structural homologs. Candidates will also contribute to global structure prediction by fragment assembly.     

Extensive sequence homologies between Y and other human chromosomes

Twenty-six human Y-chromosome-derived DNA sequences, free of repetitive material, were used to probe male and female genomic blots. We present data from a detailed analysis and chromosomal location of the bands detected by such probes, which demonstrate extensive DNA sequence homology between the mammalian sex chromosomes and autosomes. Under stringent conditions, nine Y-derived probes reacted exclusively with the Y chromosome, 12 probes detected homologous sequences present on both the Y and the X, four probes detected homologies between Y and autosome(s) without any X counterpart and, finally, one probe hybridized to homologous sequences on Y, X and autosome(s). These data are consistent with the hypothesis of a common evolutionary origin for the mammalian sex chromosomes and reveal structural similarities between Y-located and autosomal non-repetitive sequences.     

Evolution of DNA sequence homologies between the sex chromosomes in primate species

Cloned DNA sequences from 18 X-Y homologous loci have been used to examine the evolution of regions of homology between the human X and Y chromosomes. The pattern of X-Y linkage in different primate species has enabled the charting of the chronology of their appearance and removal from the sex chromosomes during evolution. Examination of the pattern of differences in restriction enzyme sites at different loci has been used to estimate the degree of divergence in three different regions of homology. These studies have indicated that (1) blocks of homology have arisen at different points in evolution, (2) different regions of homology are heterogeneous in composition in that they contain X-Y homologous sequences of different age, and (3) the combination of X and Y locations together with the point of evolutionary origin has defined five new patterns of homology.     

DNA base sequence homologies among strains of Streptococcus sanguis.

DNA was isolated from 19 strains and substrains of Streptococcus sanguis and analysed for guanine plus cytosine (GC) contents and base sequence homologies. Three groups could be discerned: group 1 strains had 40-8 to 42-8 mol % GC; group 2, 42-7 to 44-0 mol % GC; group 3, 43-8 to 46-4 mol % GC. DNA homologies between groups 1 and 3 were 40 to 60% at 67 degrees C and 40% at 72 degrees C. The homologies of group 2 towards groups 1 and 3 were much lower. Strains in groups 1 and 3 hydrolysed arginine and aesculin and fermented inulin; group 2 strains did not. Groups 1 and 3 could be considered subspecies of S. sanguis. Group 2 should not be considered S. sanguis.     

Predictability of sequence homologies among lysine-rich histones by immunological distance

The relationship between immunological distance (I.D.) measured by microcomplement fixation and amino acid sequence difference for lysine-rich histones was tested using antisera to lysine-rich histones of known sequence, chicken H1 and H5, goose H5, and trout H1 as well as to trout H5. The best relationship between I.D. (y) and percent sequence difference (x) for lysine-rich histones, y = 2x, applies as well to other histones of known sequence but it differs from y = 5x, reported for other proteins and often used for histones. Although deviations indicate that I.D. is a poor predictor of primary sequence differences among histones, it suggests that trout H5 is more closely related to H1 than to chicken H5.