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PubMed1993

Linkage localization of X-linked Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathy, is a heterogeneous group of slowly progressive, degenerative disorders of peripheral nerve. X-linked CMT (CMTX) (McKusick 302800), a subdivision of type I, or demyelinating, CMT is an X-linked dominant condition with variable penetrance. Previous linkage analysis using RFLPs demonstrated linkage to markers on the proximal long and short arms of the X chromosome, with the more likely localization on the proximal long arm of the X chromosome. Available variable simple-sequence repeats (VSSRs) broaden the possibilities for linkage analysis. This paper presents new linkage data and recombination analysis derived from work with four VSSR markers--AR, PGKP1, DXS453, and DXYS1X--in addition to analysis using RFLP markers described elsewhere. These studies localize the CMTX gene to the proximal Xq segment between PGKP1 (Xq11.2-12) and DXS72 (Xq21.1), with a combined maximum multipoint lod score of 15.3 at DXS453 (theta = 0).

Charcot-Marie-Tooth Disease↗

PubMed1995

Most liver epithelial cell lines from C3B6F1 mice exhibit parentally-biased loss of heterozygosity at the Lci (Liver cell immortalization) locus on chromosome 4.

Liver epithelial cell lines established from F1 animals generated from hepatocarcinogen-sensitive C3H/HeJ and -resistant C57BL/6J mice were analysed for loss of heterozygosity at more than 60 simple sequence repeat marker loci distributed over all of the autosomal chromosomes. Nineteen of 20 clonal cell lines showed loss of heterozygosity at a chromosome 4 locus, designated Lci (Liver cell immortalization) and in most of the cases (18 of 19), alleles from the hepatocarcinogen-resistant parental strain, C57BL/6J, were lost. Detailed deletion mapping localized the putative suppressor gene for immortalization to within a 2 cM interval which includes a cluster of genes for gap junctional proteins. We also observed a loss of heterozygosity on chromosomes 7, 14, or 17 in more than 50% of the cell lines.

Animals↗

PubMed1995

The microsatellite mutator phenotype of colon cancer cells is often recessive.

A new mutator mechanism for tumorigenesis, characterized by somatic genomic instability (SGI) at simple repeated sequences (SRS) or microsatellites, underlies hereditary nonpolyposis colorectal cancer (HNPCC) and some sporadic tumors of the colon and other types. To determine whether the microsatellite mutator phenotype (MMP) is dominant or recessive, we generate somatic cell hybrids between a tumor cell line without SGI at SRS (D98OR) and colon carcinoma cell lines with relative low (HCT-15) and high (LS174-T) SGI at SRS. The normal fidelity of replication of these unstable sequences was observed in each of these cell hybrids. Fusion of HCT-15/DLD-1 low instability cells, with LS174-T, HCT116 and LoVo cell lines, all exhibiting relative high instability, also restored the replication fidelity of SRS in all of the hybrids. Hybrids between the high instability cell lines did not grow possibly because of senescence or apoptosis. These results indicate that, in the cell lines analysed, the characterized mutator phenotype of the mismatch repair system resulting in high SGI at SRS, and the uncharacterized mutator phenotype underlying low SGI at SRS, are both recessive. The results also suggest that different tumor cells of the MMP harbor distinct altered growth-related genes.

Colonic Neoplasms↗

PubMed1996

Determination of the frequency of loss of heterozygosity in esophageal adenocarcinoma by cell sorting, whole genome amplification and microsatellite polymorphisms.

It is well established that the progression to human cancer is characterized by the evolution of clones of cells with accumulated genetic abnormalities. However, technical difficulties limit the ability to study this process in some premalignant and malignant conditions. For example, the progression to esophageal adenocarcinoma in the premalignant condition Barrett's esophagus is characterized by the evolution of genetic and cell cycle abnormalities, but it has been difficult to characterize this process completely because of the small size of biopsies and the relative abundance of genetically normal stromal cells in some esophageal adenocarcinomas and premalignant mucosa. We have combined flow cytometric cell sorting to obtain purified populations of neoplastic cells with whole genome amplification and analysis of microsatellite polymorphisms to determine the frequency of allelic loss on every nonacrocentric autosomal arm in 20 esophageal adenocarcinomas and two high-grade dysplasias. DNA samples of purified flow-sorted aneuploid and corresponding normal tissue were amplified with a degenerate 15mer primer. Aliquots of these reactions were then screened with forty-three highly polymorphic simple sequence repeat markers in PCR-based assays. Allelic losses were observed at polymorphic loci in 38 of the 40 chromosome arms that were analysed and the median fractional allelic loss (FAL) observed in the samples was 0.28. The background allelic loss frequency was estimated at 0.23 with the highest rates of loss observed at 17p (100%), 5q (80%), 9p (64%), 13q (43%), 18q (43%) and 1p (41%). These data represent the first comprehensive allelotype of esophageal adenocarcinoma and show the feasibility of multiloci analyses with small highly purified human biopsy material.

Adenocarcinoma↗

PubMed1996

Interval mapping of quantitative trait loci controlling humoral immunity to exogenous antigens: evidence that non-MHC immune response genes may also influence susceptibility to autoimmunity.

IgG Ab titers elicited to bovine rhodopsin in CFA differ 8- to 10-fold between H2s identical inbred strains A.SW/snJ (high responder) and SJL/snJ (low responder). This variation in IgG Ab titer resulted from a dramatic difference in the rise in Ab titer occurring during the maturation of the T-dependent humoral immune response. To determine the positions of non-MHC genes controlling this quantitative variation in T-dependent humoral immune responsiveness, 206 reciprocal (A.SW/snJ x SJL/snJ)F2 female progeny were immunized and assayed for anti-rhodopsin responsiveness. The genomes of these progeny were screened with 115 polymorphic simple sequence repeat markers covering >90% of the mouse genome. interval mapping analysis localized the positions of these non-MHC immune response genes to genomic intervals on chromosomes 1, 5, and 13. Interestingly, these three intervals coincide exactly with three intervals recently shown to contain genes contributing to susceptibility to systemic lupus erythematosus and/or the production of autoimmune anti-dsDNA Abs. These results suggest that some genes affecting levels of humoral immune responsiveness to exogenous Ag may also play a role in genetic susceptibility to humoral autoimmune diseases. Analyses of the modes of inheritance demonstrated that high responder alleles were inherited from both parental genomes, indicative of epistatic interactions among genes influencing humoral immune responsiveness.

Animals↗

PubMed1996

Compact encoding strategies for DNA sequence similarity search.

Determining whether two DNA sequences are similar is an essential component of DNA sequence analysis. Dynamic programming is the algorithm of choice if computational time is not the most important consideration. Heuristic search tools, such as BLAST, are computationally more efficient, but they may miss some of the sequence similarities (Altschul et al., 1990). These tools often use common k-tuples (words) between the two sequences to determine anchor points for the alignment, and spend most of their computational time extending the alignment beyond these anchor points. We discuss and provide a DNA sequence similarity search implementation (called SENSEI) that improves upon the performance of BLASTN by almost an order of magnitude for comparable sensitivity. This improvement is a result of using compactly encoded scoring tables for k-tuples, encoding bases with a single bit, filtering the sequence to remove the simple sequence repeats using XNUN, and masking the known species-specific repeats in the query sequence. To reduce memory requirements, especially for large genomic DNA query sequences, we recommend generating the neighborhood words from the target sequence at run-time, instead of generating them by preprocessing the query sequence.

Base Sequence↗

PubMed1996

Identification of the Par2 (Pulmonary adenoma resistance) locus on mouse chromosome 18, a major genetic determinant for lung carcinogen resistance in BALB/cByJ mice.

The A/J mouse strain is 14 times more susceptible to urethane-induction of lung carcinogenesis than the BALB/cByJ strain (BALB). The relative resistance of BALB is dominant over the high sensitivity of A/J, since (BALBxA/J)F1 mice are phenotypically similar to the parental BALB mice. BALB mice must thus possess modifier genes suppressing phenotypic expression of the Pas (Pulmonary adenoma susceptibility) genes, which are known to be dominant genetic determinants for lung carcinogenesis in A/J mice. In order to genetically dissect the dominant resistance of the BALB mouse, we performed a linkage analysis to chromosomally map modifier genes by using 130 (A/JxBALB)F1xA/J backcross mice. Each backcross mouse was injected i.p. with urethane (1 mg/g bw) at 6 weeks of age and lung tumors were enumerated after 120 days. When the backcross mice were genotyped at multiple simple sequence repeat marker loci distributed on all the chromosomes, a significant linkage between the presence of a BALB allele and resistance to lung tumor induction was found on distal chromosome 18 (maximum LOD = 12.2). Thus, distal chromosome 18 of the BALB mouse contains a modifier gene for lung carcinogenesis: The locus, designated Par2 (Pulmonary adenoma resistance), accounted for 38% of the phenotypic variance in the backcross population, indicating a major role in protection against lung tumor development.

Adenoma↗

PubMed1996

Cancer of the microsatellite mutator phenotype.

This review focuses on the genomic instability underlying the microsatellite mutator phenotype (MMP) pathway for cancer. MMP was discovered by the application of DNA fingerprinting by Arbitrarily Primed PCR (AP-PCR) to the analysis of somatic genetic alterations in colon tumors. The unbiased nature of AP-PCR permitted to infer, from the mobility shifts observed in some fingerprint bands, the accumulation by a subset of colon tumors of hundreds of thousands of somatic mutations in simple repeated sequences or microsatellites. We deduced that this enormous agglomeration of clonal mutations was due to the previous occurrence of 'mutator mutations' in DNA replication or repair factors leading to a decreased fidelity of replication. These mutator mutations appeared to be the remote cause for the development of these MMP tumors, whose existence unmistakably validated the hypothesis of 'cancer as a mutator phenotype'. Since these original observations, rapid progress has occurred in the field. The mutator mutations were identified as those occurring in members of the DNA mismatch repair gene family, which are also associated with hereditary non-polyposis colorectal cancer (HN-PCC). In this review I discuss the experimental approach that allowed the discovery of MMP and the features of the genomic instability of these tumors. I also review recent developments that affect the understanding of the role of the mismatch repair mutator mutations in the unfolding of MMP during carcinogenesis.

Colorectal Neoplasms, Hereditary Nonpolyposis↗

PubMed1996

Microsatellite instability in aberrant crypt foci from human colons.

Aberrant crypt foci (ACF) are distinct microscopic lesions of the colon thought to be the earliest identifiable precursors of colon cancer. As precursors of colon cancer, ACF may contain mutations in genes that are altered early in colorectal tumorigenesis. Candidates for these genes include APC, K-Ras, and those of the DNA mismatch repair system. Some colon cancers with mutations in DNA mismatch repair genes are characterized by genomic instability at simple repeated sequences, also known as microsatellite instability. In this study, we analyzed 19 ACF (> or = 20 crypts/focus) and adjoining, microscopically normal colonic mucosa from 10 colon cancer patients for the presence of microsatellite instability. DNA from two ACF from two different patients displayed microsatellite instability. None of the DNA samples from normal mucosa displayed microsatellite instability. These observations support the role of ACF as a precursor to colon cancer and provide some evidence that mutations in DNA mismatch repair genes are early somatic events in colon cancer.

Colon↗

PubMed1994

Monoamine oxidases and alcoholism: studies in unrelated alcoholics, normal controls and alcoholic families.

Monoamine oxidases (A and B) are of great interest in connection with alcoholism. Low MAO activity has been found in the brains and the platelets of alcoholics and their relatives supporting the hypothesis that low MAO activity is a biological marker for vulnerability to misuse. In order to determine the role of the MAO genes in alcoholism we have measured MAO-B activity and typed two simple sequence repeats (one in the MAO-A gene and one in the MAO-B gene) in a sample of 133 unrelated alcoholics, 300 subjects from 30 two- and three-generation pedigrees ascertained through an alcoholic proband, and 92 normal controls. The unrelated alcoholic group did not differ in MAO-B activity from normal controls nor were there significant differences between subtypes. We did, however, find significant differences between alcoholic males and females (t = 2.836, p = .005), a difference that was not present in controls. A two-way analysis of variance of MAO-B activity as a function of the allelic variation of each marker locus and diagnosis among male subjects was performed. There was no evidence for mean differences in activity levels for different alleles. The distribution of MAO-A and MAO-B "alleles" in the alcoholic sample differed from that of the control sample. Affected sib pair linkage analysis of MAO genes and alcoholism showed no evidence for an excess of concordant affected sib pairs suggesting that this region of the X-chromosome does not harbor a susceptibility locus.

Adult↗

PubMed1994

Mapping quantitative trait loci for ethanol-induced anesthesia in LSxSS recombinant inbred and F2 mice: methodology and results.

QTL (quantitative trait locus) mapping is an exciting new technique currently being applied to many quantitative traits. We review the animal models and molecular genetic techniques of QTL mapping with particular reference to ethanol-induced anesthesia (sleep time). Sleep time is an easily obtained measure of initial sensitivity to ethanol. We are using three-stage strategy to map QTLs causing the difference in sleep time between selected strains of mice. This project has been expedited by the use of polymorphic genetic markers (simple sequence repeats) which are amplifiable by the polymerase chain reaction. Over 115 strain distribution patterns have been characterized in the 27 LSxSS recombinant inbred strains. Provisional QTLs have been identified in the RI strains and will be confirmed or rejected in an F2 population of 1063 mice. A new statistical technique, interval mapping, allows the use of all polymorphic markers simultaneously to locate QTLs.

Anesthesia↗

PubMed1997

Human GABAA receptor alpha 1 and alpha 3 subunits genes and alcoholism.

gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain. GABA effects are largely mediated by binding to the postsynaptic GABAA receptor, causing the opening of an integral chloride-ion channel. The GABAA antagonists picrotoxin and bicuculline reduce some ethanol-induced behaviors, such as motor impairment, sedation, and hypnosis. The role of this receptor in alcoholism is further supported by effective alleviation of alcohol withdrawal symptoms by GABAA agonists. To determine the role of the GABAA receptor (GABR) genes in the development of alcoholism, we have used alpha 1 and alpha 3 simple sequence repeat polymorphisms in a sample of unrelated alcoholics, alcoholic probands with both parents, and psychiatrically normal controls. For the GABR alpha 1 gene, the differences between allele frequencies, when all alleles were compared together, were not significant between total alcoholics, subtypes of alcoholics, and normal controls. However, for GABR alpha 3, the differences between total alcoholics and normal controls were significant when all alleles were compared together. The differences between subtypes of alcoholics and normal controls were not significant. The results of haplotype relative risk analysis for both genes, GABR alpha 1 and GABR alpha 3, were also negative. It is possible that the sample size in the haplotype relative risk is too small to have power to detect the differences in transmitted versus nontransmitted alleles. There is a need for a replication study in a large family sample that will allow haplotype relative risk or affected sib-pair analysis.

Adult↗

PubMed1997

Loss of heterozygosity at loci on chromosome 4, a common genetic event during the spontaneous immortalization of mouse embryonic fibroblasts.

Spontaneously immortalized fibroblast cell lines derived from embryonic tissues of C3D2F1, mice were analyzed for loss of heterozygosity (LOH) at multiple chromosomal loci to identify candidate suppressor loci for immortalization. Among 47 simple sequence repeat (SSR) loci selected for screening, those on chromosome 4 exhibited an exceptionally high LDH incidence of up to 89%. Only four other chromosomes (8, 11, 12, and 18) showed LOH, with the highest incidence being 33%. To further localize candidate suppressor genes on mouse chromosome 4, detailed deletion mapping was performed with 18 cell lines and 14 SSR markers. The greatest LOH incidence (94%) was observed at the D4Mit14 locus located on distal chromosome 4, indicating that a major suppressor gene resides in this region. On the other hand, at the D4Mit77 locus, 30 cM proximal to the D4Mit14 locus, we found the SSR to be homozygously lost in 39% of the cell lines. Because the D4Mit77 is tightly linked to the tumor suppressor gene p16, for which homozygous deletion has been reported in various human tumor cell lines, we also examined our fibroblast cell lines for gross aberrations of the p16 gene by using the Southern blot method. The p16 gene was found to be homozygously deleted in 56% of the cell lines. Although this result implies that the p16 gene plays a role as a suppressor gene for immortalization, the combined incidence of LOH and homozygous deletion at the D4Mit77 locus was 72%, which is significantly lower than the observed incidence at the D4Mit14 locus. Consequently, we concluded that immortalization of mouse embryonic fibroblasts may involve more than one suppressor gene on chromosome 4.

Animals↗

PubMed1997

Genetic linkage to the collagen alpha 1 (V) gene (COL5A1) in two British Ehlers-Danlos syndrome families with variable type I and II phenotypes.

To investigate the role of COL5A1 as a candidate gene for Ehlers-Danlos syndrome (EDS), we have carried out linkage studies in two large British families with EDS type I/II and type II, respectively. Fourteen living, affected individuals were identified by family history, clinical examination and ultrastructural analysis. A polymorphic intragenic simple sequence repeat at the COL5A1 locus showed linkage to EDS without recombination to give a combined lod score of 5.7. We have previously reported linkage to COL5A1 in an EDS type I/II family which brings the total lod score to 9.8 at zero recombination. Taken together, these data implicate COL5A1 as an important cause of EDS and confirm that types I and II are allelic.

Collagen↗

PubMed1998

Somatic frameshift mutations in DNA mismatch repair and proapoptosis genes in hereditary nonpolyposis colorectal cancer.

An exacerbated genomic instability at simple repeated sequences characterizes cancer of the microsatellite mutator phenotype (MMP). The majority of hereditary nonpolyposis colon cancers (HNPCCs) and about 15% of nonselected ("sporadic") gastrointestinal tumors belong to the MMP pathway of tumorigenesis. Colorectal MMP+ and MMP- tumors exhibit fundamental differences in genotype and phenotype. We have shown previously that "sporadic" MMP+ colon cancers exhibit a paradoxical low incidence of somatic mutations in the p53 tumor suppressor gene and the c-K-ras proto-oncogene. On the other hand, gastrointestinal MMP+ cancers frequently harbor frameshift mutations in genes containing mononucleotide repeats. These include the cell growth regulator gene TGFbetaRII and the proapoptotic gene BAX. We have also recently shown the frequent presence of frameshift mutations in (A)8 and (C)8 tracts within the hMSH3 and hMSH6 DNA mismatch repair genes in sporadic colon cancer of the MMP. Here, we describe the nearly identical incidence of somatic frameshift mutations in these genes in a panel of 27 HNPCC MMP+ cancers: 52% in hMSH3 and BAX and 33% in hMSH6. In contrast, no mutations in any of these genes were found in 10 MMP- cancers of HNPCC patients. These results show that the multistep model for the unfolding of the MMP also applies to HNPCC and further illustrate the importance of the escape from apoptosis in the MMP pathway for gastrointestinal cancer. They also underscore the differences in genotype between tumors with and without enhanced microsatellite instability and the similarities in genotype between tumors of the MMP regardless of their hereditary or sporadic nature.

Adult↗

PubMed1998

Quantitative trait loci affecting 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in the rat.

The incidence of tongue carcinomas (TCs) induced by oral administration of 4-nitroquinoline 1-oxide in rats is strain dependent. The inbred Dark-Agouti (DA) strain showed a much higher susceptibility to large mass-forming infiltrative TCs than did the Wistar-Furth (WF) strain. Our previous study (M. Kitano et al, Jpn. J. Cancer Res., 87: 1097-1101, 1996) on crosses between these two strains postulated a dominant susceptibility gene in DA and a dominant resistance gene in WF rats. The present study mapped these loci by analyzing the backcrosses to each parent with simple sequence repeat polymorphisms. Five quantitative parameters were analyzed: (a) the number of TCs > 5 mm in diameter; (b) the total number of TCs per rat; (c) the diameter of the largest TCs (DTCmax values); (d) the number of non-TC cancers per rat; and (e) and the number of cancers of any site per rat. All of these parameters were closely correlated (P < 0.0001). DA rats had a semidominant gene (Stc1) favoring the development of 4-nitroquinoline 1-oxide-induced cancers on chromosome 19, closely linked to D19Mit9. Peak linkage was observed 4 cM distal from D19Mit9, with a logarithm of the odds (lod) score of 5.72 for the number of large TCs and 6.08 for the DTCmax. On the other hand, WF rats had a semidominant gene (Rtc1) mapped between D1Mit1 and D1Mit3, approximately 20 cM from D1Mit1, with a peak lod score of 3.30 for both the number of large TCs and the DTCmax. The main effect of Rtc1 seemed to be to reduce the size of the TCs. The action of these genes was dose dependent and cooperative. The final incidence of TC in DA, WF, F1, and backcross rats seemed to be explained by combinations of genotype at these two loci. Possible candidate genes for Stc1 and Rtc1 are discussed.

4-Nitroquinoline-1-oxide↗

PubMed1998

Genetics of type II diabetes.

Defining the genetic basis of Type II or non-insulin dependent diabetes mellitus (NIDDM) will accelerate our progress toward understanding its etiology and will provide new therapeutic targets for treatment of this common disease. Here we present a brief overview of the history of the search for diabetes genes and report current strategies employed by our laboratory and by others in this effort. Isolation and subsequent mapping of candidate genes involved in insulin production and action has been a major effort in this field. Our lab has focused on pancreatic islet beta-cell genes, since the insulin lack of NIDDM is often the result of resistance to the action of insulin that is superimposed on a limited ability to produce insulin. A number of islet genes have been evaluated, including those involved in glucose metabolism, islet K+ channel genes, and transcription factors. For each gene, human cDNAs and genomic clones have been isolated and simple sequence repeat polymorphisms (SSRPs) identified. The SSRPs were used to map the genes by linkage in CEPH pedigrees, or sequence-tagged sites (STSs) were used to map the genes to radiation hybrids (RH) or to YAC clones containing SSRPs. The SSRPs have then been used as markers for linkage analyses in families with NIDDM. Mutation screening by single-strand conformational polymorphism analysis and by sequencing has revealed variants that have been tested in association studies. A strategy was devised to generate novel expressed sequence tags (ESTs) from human pancreatic islet genes by differential display of islet mRNA. In the first phase of this project we identified 42 cDNAs that were preferentially expressed in pancreatic islets relative to exocrine tissue. When compared to sequences in GenBank, novel genes were represented by 69%. Enhanced islet expression was confirmed by Northern analysis of RNA. Sequence-tagged sites were synthesized for a number of islet ESTs and used to map these genes to human chromosomes. This strategy provides an effective means to selectively identify and map genes transcribed in human pancreatic islets and to identify novel islet candidate genes for NIDDM. Positional cloning of NIDDM genes in families of various racial groups is being conducted by a number of labs. Although regions of genetic susceptibility are being identified, finding the genes within these regions will be difficult because of the polygenic nature of the disease As an alternative strategy, we have begun to map genes responsible for monogenic disorders of carbohydrate metabolism. Familial hyperinsulinism (HI, OMIM #256450) is a rare recessive disease associated with neonatal hyperinsulinism and life-threatening hypoglycemia. To determine the molecular basis for HI, we mapped the gene in multiplex families to chromosome 11p14-15.1. A candidate gene, the sulfonylurea receptor (SUR1), was mapped to the region and shown to harbor mutations in HI patients. Analysis of 21 identified mutations has revealed the role of SUR1 as a nucleotide regulator of the islet ATP-sensitive K+ channel. The challenge for the future will be to utilize the information provided by the Human Genome Project (i.e., the complete nucleotide sequence and expression maps of the genome) to find diabetes-predisposing genes. Our immediate goals include collecting families with NIDDM for phenotyping and for DNA analysis and continuing to identify suitable candidate genes to be studied in these families.

Diabetes Mellitus, Type 2↗

PubMed1978

Complex and simple sequences in human repeated DNAs.

Highly repeated human DNA sequences were isolated by isopycnic centrifugation, or were eluted from gels after restriction enzyme cleavage. High molecular weight DNA peaks separable from the bulk of the DNA in a variety of gradients were shown to consist of very simple sequences characteristic of simple satellite DNAs; DNA fingerprint studies indicated each of these peaks could consist of tandem repeats of a specific oligonucleotide sequence as low as 10 base pairs (bp) long. All the gradient peaks could be assigned to one of two sequence groups and several "different" buoyant density peaks revealed the same sequence.--Restriction fragment multimers did not share common sequences with the satellite DNAs as judged by hybridization data. They could not be separated by isopycnic centrifugation. Furthermore these highly repeated DNAs were more complex in sequence and more variable than the satellites. Even the smallest (50 bp) fragments by depurination and other direct sequencing methods were shown to be more complex than the high molecular weight satellite peaks.--The idea that subsets of repeated DNAs may be defined by sequence complexity, possibly with discrete or separable functions, is proposed.

Base Sequence↗