Mesial temporal lobe epilepsy with childhood febrile seizure.

OBJECTIVES: To evaluate the demographic and clinical manifestations of patients with mesial temporal sclerosis and temporal lobe epilepsy (MTS-TLE) with childhood febrile seizure (FS) and establishing the potential differences as compared to those without FS. We also investigated the surgery outcome in these two groups of patients. MATERIALS AND METHODS: In this retrospective study, all patients with a clinical diagnosis of drug-resistant TLE due to mesial temporal sclerosis, who underwent epilepsy surgery at Jefferson Comprehensive Epilepsy Center, were recruited. Patients were prospectively registered in a database from 1986 through 2014. Postsurgical outcome was classified into two groups; seizure-free or relapsed. Clinical manifestations and outcome were compared between patients with MTS-TLE with FS and those without FS. RESULTS: Two hundred and sixty-two patients were eligible for this study. One hundred and seventy patients (64.9%) did not have FS in their childhood, while 92 patients (35.1%) reported experiencing FS in their childhood. Demographic and clinical characteristics of these two groups of patients were not different. Postoperative seizure outcome was not statistically different between these two groups of patients (P = 0.19). CONCLUSIONS: When MTS is the pathological substrate of TLE, clinical manifestations and response to surgical treatment of patients are very similar in patients with history of febrile seizure in their childhood compared to those without such an experience. In other words, when the subgroup of patients with MTS-TLE and drug-resistant seizures is examined history of childhood febrile seizure loses its value as a distinguishing factor in characteristics or predictive factor for surgery outcome.

Seasonality of birth in patients with temporal lobe epilepsy.

OBJECTIVES: We investigated the seasonal pattern in births of patients with temporal lobe epilepsy and mesial temporal sclerosis. We hypothesized that the seasonal pattern in births of these patients is different from that in the general population. MATERIALS AND METHODS: In this retrospective study, all patients who were evaluated for epilepsy surgery at Jefferson Comprehensive Epilepsy Center, Thomas Jefferson, Philadelphia, USA, between 1986 and 2014 and had a diagnosis of mesial temporal sclerosis (made by definite imaging findings of atrophy and/or sclerosis) were included. The seasonality in births of patients was compared with the seasonal pattern in the live births of the general population from Pennsylvania State. RESULTS: Two hundred and eighty-two patients (146 females and 136 males) were studied. The seasonality pattern in birth of patients was not statistically different from that in the general population. CONCLUSIONS: The observed contradictory findings among various studies indicate the need for further studies to elucidate whether season of birth brings the possibility of acquiring various epilepsy syndromes in the future. To investigate any possible association between season of birth and epilepsy, we suggest avoid pooling all patients with epilepsy together.

Gene differences between Caucasian, Negro, and Japanese populations.

The numbers of gene (codon) differences per locus between two randomly chosen genomes within and between Caucasian, Negro, and Japanese populations have been estimated from gene frequency data for protein loci. The estimated number of gene differences between individuals from different populations is only slightly greater than the number between individuals from the same population.

Genomic drift and copy number variation of chemosensory receptor genes in humans and mice.

Recent studies about the structural variation of genomic sequences have shown that there is a large amount of copy number variations (CNVs) of genes within species. Analyzing Redon et al.'s (2006) crude data on copy number variable regions (CNVRs), we previously showed that CNVs are particularly high for chemosensory receptor genes in human populations. In this paper, we reanalyzed the CNVs of these genes using more refined data by Perry et al. (2008). The results showed that the extent of CNVs is somewhat lower in this dataset than in the previous one, but that the extent is still substantial for olfactory receptor (OR), vomeronasal receptor (VR), and taste receptor (TR) genes. We also studied the CNVs for chemosensory receptor genes in mice, using CNVR data obtained from inbred strains. It was found that the extent of CNVs is quite substantial but is lower than that for human populations. However, because the mouse data came from inbred strains and might be biased, this conclusion should be regarded as tentative. Despite this reservation, the distribution of gene copy number for the OR gene family was approximately normal in both humans and mice, suggesting that genomic drift caused by random duplication and deletion of genes plays important roles in determining the evolutionary change of chemosensation.

Estimation of average heterozygosity and genetic distance from a small number of individuals.

The magnitudes of the systematic biases involved in sample heterozygosity and sample genetic distances are evaluated, and formulae for obtaining unbiased estimates of average heterozygosity and genetic distance are developed. It is also shown that the number of individuals to be used for estimating average heterozygosity can be very small if a large number of loci are studied and the average heterozygosity is low. The number of individuals to be used for estimating genetic distance can also be very small if the genetic distance is large and the average heterozygosity of the two species compared is low.

Population dynamics of sex-determining alleles in honey bees and self-incompatibility alleles in plants.

Mathematical theories of the population dynamics of sex-determining alleles in honey bees are developed. It is shown that in an infinitely large population the equilibrium frequency of a sex allele is 1/n, where n is the number of alleles in the population, and the asymptotic rate of approach to this equilibrium is 2/(3n) per generation. Formulae for the distribution of allele frequencies and the effective and actual numbers of alleles that can be maintained in a finite population are derived by taking into account the population size and mutation rate. It is shown that the allele frequencies in a finite population may deviate considerably from 1/n. Using these results, available data on the number of sex alleles in honey bee populations are discussed. It is also shown that the number of self-incompatibility alleles in plants can be studied in a much simpler way by the method used in this paper. A brief discussion about general overdominant selection is presented.

Gene genealogy and variance of interpopulational nucleotide differences.

A mathematical theory is developed for computing the probability that m genes sampled from one population (species) and n genes sampled from another are derived from l genes that existed at the time of population splitting. The expected time of divergence between the two most closely related genes sampled from two different populations and the time of divergence (coalescence) of all genes sampled are studied by using this theory. It is shown that the time of divergence between the two most closely related genes can be used as an approximate estimate of the time of population splitting (T) only when T identical to t/(2N) is small, where t and N are the number of generations and the effective population size, respectively. The variance of Nei and Li's estimate (d) of the number of net nucleotide differences between two populations is also studied. It is shown that the standard error (Sd) of d is larger than the mean when T is small (T much less than 1). In this case, Sd is reduced considerably by increasing sample size. When T is large (T greater than 1), however, a large proportion of the variance of d is caused by stochastic factors, and increase in the sample size does not help to reduce Sd. To reduce the stochastic variance of d, one must use data from many independent unlinked gene loci.

Allelic genealogy under overdominant and frequency-dependent selection and polymorphism of major histocompatibility complex loci.

To explain the long-term persistence of polymorphic alleles (trans-specific polymorphism) at the major histocompatibility complex (MHC) loci in rodents and primates, a computer simulation study was conducted about the coalescence time of different alleles sampled under various forms of selection. At the same time, average heterozygosity, the number of alleles in a sample, and the rate of codon substitution were examined to explain the mechanism of maintenance of polymorphism at the MHC loci. The results obtained are as follows. (1) The coalescence time for neutral alleles is too short to explain the trans-specific polymorphism at the MHC loci. (2) Under overdominant selection, the coalescence time can be tens of millions of years, depending on the parameter values used. The average heterozygosity and the number of alleles observed are also high enough to explain MHC polymorphism. (3) The pathogen adaptation model proposed by Snell is incapable of explaining MHC polymorphism, since the coalescence time for this model is too short and the expected heterozygosity and the expected number of alleles are too small. (4) From the mathematical point of view, the minority advantage model of frequency-dependent selection is capable of explaining a high degree of polymorphism and trans-specific polymorphism. (5) The molecular mimicry hypothesis also gives a sufficiently long coalescence time when the mutation rate is low in the host but very high in the parasite. However, the expected heterozygosity and the expected number of alleles tend to be too small. (6) Consideration of the molecular mechanism of the function of MHC molecules and other biological observations suggest that the most important factor for the maintenance of MHC polymorphism is overdominant selection. However, some experiments are necessary to distinguish between the overdominance and frequency-dependent selection hypotheses.

Genetic distances and reconstruction of phylogenetic trees from microsatellite DNA.

Recently many investigators have used microsatellite DNA loci for studying the evolutionary relationships of closely related populations or species, and some authors proposed new genetic distance measures for this purpose. However, the efficiencies of these distance measures in obtaining the correct tree topology remains unclear. We therefore investigated the probability of obtaining the correct topology (PC) for these new distances as well as traditional distance measures by using computer simulation. We used both the infinite-allele model (IAM) and the stepwise mutation model (SMM), which seem to be appropriate for classical markers and microsatellite loci, respectively. The results show that in both the IAM and SMM CAVALLI-SFORZA and EDWARDS' chord distance (DC) and NEI et al.'s DA distance generally show higher PC values than other distance measures, whether the bottleneck effect exists or not. For estimating evolutionary times, however, NEI's standard distance and GOLDSTEIN et al.'s (delta mu)2 are more appropriate than other distances. Microsatellite DNA seems to be very useful for clarifying the evolutionary relationships of closely related populations.

Evolution of Antennapedia-class homeobox genes.

Antennapedia (Antp)-class homeobox genes are involved in the determination of pattern formation along the anterior-posterior axis of the animal embryo. A phylogenetic analysis of Antp-class homeodomains of the nematode, Drosophila, amphioxus, mouse, and human indicates that the 13 cognate group genes of this gene family can be divided into two major groups, i.e., groups I and II. Group I genes can further be divided into subgroups A (cognate groups 1-2), B (cognate group 3), and C (cognate groups 4-8), and group II genes can be divided into subgroups D (cognate groups 9-10) and E (cognate groups 11-13), though this classification is somewhat ambiguous. Evolutionary distances among different amino acid sequences suggest that the divergence between group I and group II genes occurred approximately 1000 million years (MY) ago, and the five different subgroups were formed by approximately 600 MY ago, probably before the divergence of Pseudocoelomates (e.g., nematodes) and Coelomates (e.g., insects and chordates). Our results show that the genes that are phylogenetically close are also closely located in the chromosome, suggesting that the colinearity between the gene expression and gene arrangement was generated by successive tandem gene duplications and that the gene arrangement has been maintained by some sort of selection.

Hidden genetic variability within electromorphs in finite populations.

The amount of hidden genetic variability within electromorphs in finite populations is studied by using the infinite site model and stepwise mutation model simultaneously. A formula is developed for the bivariate probability generating function for the number of codon differences and the number of electromorph state differences between two randomly chosen cistrons. Using this formula, the distribution as well as the mean and variance of the number of codon differences between two identical or nonidentical electromorphs are studied. The distribution of the number of codon differences between two randomly chosen identical electromorphs is similar to the geometric distribution but more leptokurtic. Studies are also made on the number of codon differences between two electromorphs chosen at random one from each of two populations which have been separated for an arbitrary number of generations. It is shown that the amount of hidden genetic variability is very large if the product of effective population size and mutation rate is large.

Maximum likelihood estimation of the number of nucleotide substitutions from restriction sites data.

A simple method of the maximum likelihood estimation of the number of nucleotide substitutions is presented for the case where restriction sites data from many different restriction enzymes are available. An iteration method, based on nucleotide counting, is also developed. This method is simpler than the maximum likelihood method but gives the same estimate. A formula for computing the variance of a maximum likelihood estimate is also presented.

DNA polymorphism detectable by restriction endonucleases.

Data on DNA polymorphisms detected by restriction endonucleases are rapidly accumulating. With the aim of analyzing these data, several different measures of nucleon (DNA segment) diversity within and between populations are proposed, and statistical methods for estimating these quantities are developed. These statistical methods are applicable to both nuclear and nonnuclear DNAs. When evolutionary change of nucleons occurs mainly by mutation and genetic drift, all the measures can be expressed in terms of the product of mutation rate per nucleon and effective population size. A method for estimating nucleotide diversity from nucleon diversity is also presented under certain assumptions. It is shown that DNA divergence between two populations can be studied either by the average number of restriction site differences or by the average number of nucleotide differences. In either case, a large number of different restriction enzymes should be used for studying phylogenetic relationships among related organisms, since the effect of stochastic factors on these quantities is very large. The statistical methods developed have been applied to data of Shah and Langley on mitochondrial (mt)DNA from Drosophila melanogaster, simulans and virilis. This application has suggested that the evolutionary change of mtDNA in higher animals occurs mainly by nucleotide substitution rather than by deletion and insertion. The evolutionary distances among the three species have also been estimated.

Genetic variability maintained by mutation and overdominant selection in finite populations.

Mathematical properties of the overdominance model with mutation and random genetic drift are studied by using the method of stochastic differential equations (Itô and McKean 1974). It is shown that overdominant selection is very powerful in increasing the mean heterozygosity as compared with neutral mutations, and if 2Ns (N = effective population size; s = selective disadvantage for homozygotes) is larger than 10, a very low mutation rate is sufficient to explain the observed level of allozyme polymorphism. The distribution of heterozygosity for overdominant genes is considerably different from that of neutral mutations, and if the ratio of selection coefficient (s) to mutation rate (nu) is large and the mean heterozygosity (h) is lower than 0.2, single-locus heterozygosity is either approximately 0 or 0.5. If h increases further, however, heterozygosity shows a multiple-peak distribution. Reflecting this type of distribution, the relationship between the mean and variance of heterozygosity is considerably different from that for neutral genes. When s/v is large, the proportion of polymorphic loci increases approximately linearly with mean heterozygosity. The distribution of allele frequencies is also drastically different from that of neutral genes, and generally shows a peak at the intermediate gene frequency. Implications of these results on the maintenance of allozyme polymorphism are discussed.

Genetic drift and estimation of effective population size.

The statistical properties of the standardized variance of gene frequency changes (a quantity equivalent to Wright's inbreeding coefficient) in a random mating population are studied, and new formulae for estimating the effective population size are developed. The accuracy of the formulae depends on the ratio of sample size to effective size, the number of generations involved (t), and the number of loci or alleles used. It is shown that the standardized variance approximately follows the chi(2) distribution unless t is very large, and the confidence interval of the estimate of effective size can be obtained by using this property. Application of the formulae to data from an isolated population of Dacus oleae has shown that the effective size of this population is about one tenth of the minimum census size, though there was a possibility that the procedure of sampling genes was improper.

Probability of fixation and mean fixation time of an overdominant mutation.

The probability of fixation of an overdominant mutation in a finite population depends on the equilibrium gene frequency in an infinite population (m) and the product (A) of population size and selection intensity. If m < 0.5 (disadvantageous overdominant genes), the probability is generally much lower than that of neutral genes; but if m is close to 0.5 and A is relatively small, it becomes higher. If m > 0.5 (advantageous overdominant genes), the probability is largely determined by the fitness of heterozygotes rather than that of mutant homozygotes. Thus, overdominance enhances the probability of fixation of advantageous mutations. The average number of generations until fixation of an overdominant mutation also depends on m and A. This average time is long when m is close to 0.5 but short when m is close to 0 or 1. This dependence on m and A is similar to that of Robertson's retardation factor.

Sampling variances of heterozygosity and genetic distance.

Mathematical formulae for the sampling variances of average heterozygosity and Nei's genetic distance are developed. These sampling variances are decomposed into their two components, i.e. the inter-locus and intra-locus variances. The relationship between the number of loci and the number of individuals per locus to be examined for estimating average heterozygosity and genetic distance is also discussed. The utility of the inter-locus variance of heterozygosity for studying the mechanism of maintenance of genetic variability in populations is indicated.

A simple method for estimating average number of nucleotide substitutions within and between populations from restriction data.

A simple method is proposed for estimating the average number of nucleotide substitutions per site within and between populations for the case where a large number of individuals are examined for many restriction enzymes. This method gives essentially the same results as those obtained by Nei and Li's method but saves a large amount of computer time. The variances of the quantities estimated can be obtained by the jackknife method, and these variances are very similar to those obtained by Nei and Jin's more sophisticated method. A similar method can also be applied to DNA sequence data.

Ancient interlocus exon exchange in the history of the HLA-A locus.

The major histocompatibility complex (MHC) in humans and chimpanzees includes three classical class I loci, A, B and C, which encode glycoproteins expressed on the surface of all nucleated cells. There are also several nonclassical class I loci including E, which have more limited expression. By analyzing published sequences, we have shown that in exons 4 and 5, A locus alleles from both humans and chimpanzees are much more similar to E than to B or C alleles, whereas in exons 2 and 3 alleles from all three classical class I loci are much more similar to each other than any one is to E. We propose that some 20 million years ago, interlocus recombination led to the formation of a hybrid gene in which exons 2 and 3 were derived from the original A locus and exons 4 and 5 were derived from the E locus. The fact that such an ancient event can still be detected suggests that interlocus recombination is rare in the MHC and does not significantly contribute to MHC polymorphism, which is known to be extremely high. The present finding, however, supports Gilbert's idea that exons in a gene may occasionally be replaced by those from another gene in the evolutionary process.

A new method of inference of ancestral nucleotide and amino acid sequences.

A statistical method was developed for reconstructing the nucleotide or amino acid sequences of extinct ancestors, given the phylogeny and sequences of the extant species. A model of nucleotide or amino acid substitution was employed to analyze data of the present-day sequences, and maximum likelihood estimates of parameters such as branch lengths were used to compare the posterior probabilities of assignments of character states (nucleotides or amino acids) to interior nodes of the tree; the assignment having the highest probability was the best reconstruction at the site. The lysozyme c sequences of six mammals were analyzed by using the likelihood and parsimony methods. The new likelihood-based method was found to be superior to the parsimony method. The probability that the amino acids for all interior nodes at a site reconstructed by the new method are correct was calculated to be 0.91, 0.86, and 0.73 for all, variable, and parsimony-informative sites, respectively, whereas the corresponding probabilities for the parsimony method were 0.84, 0.76, and 0.51, respectively. The probability that an amino acid in an ancestral sequence is correctly reconstructed by the likelihood analysis ranged from 91.3 to 98.7% for the four ancestral sequences.