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PubMed2005

SMOOTH: a statistical method for successful removal of genotyping errors from high-density genetic linkage data.

High-density genetic linkage maps can be used for purposes such as fine-scale targeted gene cloning and anchoring of physical maps. However, their construction is significantly complicated by even relatively small amounts of scoring errors. Currently available software is not able to solve the ordering ambiguities in marker clusters, which inhibits the application of high-density maps. A statistical method named SMOOTH was developed to remove genotyping errors from genetic linkage data during the mapping process. The program SMOOTH calculates the difference between the observed and predicted values of data points based on data points of neighbouring loci in a given marker order. Highly improbable data points are removed by the program in an iterative process with a mapping algorithm that recalculates the map after cleaning. SMOOTH has been tested with simulated data and experimental mapping data from potato. The simulations prove that this method is able to detect a high amount of scoring errors and demonstrates that the program enables mapping software to successfully construct a very accurate high-density map. In potato the application of the program resulted in a reliable placement of nearly 1,000 markers in one linkage group.

Algorithms↗
PubMedDate not supplied

Refining phenotype characterization in genetic linkage studies of schizophrenia.

A definitive replicable genetic linkage for a major locus underlying the susceptibility to schizophrenia has not been identified to date. Although there are several possible explanations for the failure to find linkage in schizophrenia, one major problem is that the range of phenotypic expressions of the genes for schizophrenia has not been clarified. A more refined understanding of the various phenotypic expressions of a gene related to schizophrenia would enhance the power of studies designed to detect a genetic linkage with a major chromosomal locus and would benefit other strategies for understanding the etiology of schizophrenia. The genes for schizophrenia may be frequently expressed in relatives of schizophrenic patients, although with less severe symptoms than those of chronic schizophrenia. Two series of findings support this notion. Nonschizophrenic relatives of schizophrenic patients demonstrate an increased incidence of nonpsychotic schizophrenia-like symptoms and traits, and they manifest deficit performances on several different laboratory tests of neurocognitive functioning. A more refined phenotypic expression of a schizophrenia-related gene may thus be indicated by personality traits and subclinical neurocognitive deficits. These personality traits and neurocognitive deficits are considered here as possible aids in the identification of affected cases in genetic linkage studies of schizophrenia. Terminology for different indicators of neurocognitive deficits is introduced, and the relative utility of personality traits and indicators of neurocognitive deficit for genetic linkage studies is discussed. As specific examples, schizophrenia-related personality traits that are unrelated to affective symptoms and performance deficits on tasks of eye tracking and continuous attention are considered for strategies for broadening phenotype characterization without reducing the specificity of affected case identification.

Eye Movements↗
PubMed2001

Integration of the Aedes aegypti mosquito genetic linkage and physical maps.

Two approaches were used to correlate the Aedes aegypti genetic linkage map to the physical map. STS markers were developed for previously mapped RFLP-based genetic markers so that large genomic clones from cosmid libraries could be found and placed to the metaphase chromosome physical maps using standard FISH methods. Eight cosmids were identified that contained eight RFLP marker sequences, and these cosmids were located on the metaphase chromosomes. Twenty-one cDNAs were mapped directly to metaphase chromosomes using a FISH amplification procedure. The chromosome numbering schemes of the genetic linkage and physical maps corresponded directly and the orientations of the genetic linkage maps for chromosomes 2 and 3 were inverted relative to the physical maps. While the chromosome 2 linkage map represented essentially 100% of chromosome 2, approximately 65% of the chromosome 1 linkage map mapped to only 36% of the short p-arm and 83% of the chromosome 3 physical map contained the complete genetic linkage map. Since the genetic linkage map is a RFLP cDNA-based map, these data also provide a minimal estimate for the size of the euchromatic regions. The implications of these findings on positional cloning in A. aegypti are discussed.

Aedes↗
PubMed2000

Microsatellite marker based genetic linkage maps of Oreochromis aureus and O. niloticus (Cichlidae): extensive linkage group segment homologies revealed.

Partial genetic linkage maps, based on microsatellite markers, were constructed for two tilapia species, Oreochromis aureus and Oreochromis niloticus using an interspecific backcross population. The linkage map for O. aureus comprised 28 markers on 10 linkage groups and covered 212.8 CM. Nine markers were mapped to four linkage groups on an O. niloticus female linkage map covering 40.6 CM. Results revealed a high degree of conservation of synteny between the linkage groups defined in O. aureus and the previously published genetic linkage map of O. niloticus.

Animals↗
PubMed1987

Construction of multilocus genetic linkage maps in humans.

Human genetic linkage maps are most accurately constructed by using information from many loci simultaneously. Traditional methods for such multilocus linkage analysis are computationally prohibitive in general, even with supercomputers. The problem has acquired practical importance because of the current international collaboration aimed at constructing a complete human linkage map of DNA markers through the study of three-generation pedigrees. We describe here several alternative algorithms for constructing human linkage maps given a specified gene order. One method allows maximum-likelihood multilocus linkage maps for dozens of DNA markers in such three-generation pedigrees to be constructed in minutes.

Algorithms↗
PubMed1994

Automated construction of genetic linkage maps using an expert system (MultiMap): a human genome linkage map.

High-resolution genetic linkage maps are indispensable for positional cloning of disease genes. Current procedures for map construction, although aided considerably by many existing computer programs, require extensive user-intervention at each of many repetitive steps. This is time consuming, labour intensive and increases the chance of error. We have developed an expert system computer program, MultiMap, which automates this step-by-step procedure. MultiMap is based on a novel map construction algorithm and allows investigator control of marker locus characteristics, such as informativeness, scorability or distance to nearest neighbours. We used MultiMap to construct a human genetic map at an average resolution of 6 cM, using published genotypes at 1266 microsatellite markers, and further extended this map by adding 397 VNTR and polymorphic gene markers.

Algorithms↗
PubMed1981

Inheritance and genetic linkage of transcobalamin II.

The genetic polymorphism of the vitamin B12 transport protein transcobalamin II (TC II) was studied in the Caucasian population and in families. There are five codominent alleles of TC II which show a Mendelian mode of inheritance. No genetic linkage of TC II was found with gene loci for ADA, GLO I, Pi, HLA, AB0 and AK1. TC II like proteins could be detected on autoradiograph of PAGE in two patients with congenital homozygosity for functional TC II deficiency. These vitamin B12 binding proteins in the patients' serum were shown not to be normal R-proteins.

Adenylate Kinase↗
PubMed1992

Systematic detection of errors in genetic linkage data.

Construction of dense genetic linkage maps is hampered, in practice, by the occurrence of laboratory typing errors. Even relatively low error rates cause substantial map expansion and interfere with the determination of correct genetic order. Here, we describe a systematic method for overcoming these difficulties, based on incorporating the possibility of error into the usual likelihood model for linkage analysis. Using this approach, it is possible to construct genetic maps allowing for error and to identify the typings most likely to be in error. The method has been implemented for F2 intercrosses between two inbred strains, a situation relevant to the construction of genetic maps in experimental organisms. Tests involving both simulated and real data are presented, showing that the method detects the vast majority of errors.

Animals↗
PubMed1997

Genetic linkage study of familial Mediterranean fever (FMF) to 16p13.3 and evidence for genetic heterogeneity in the Turkish population.

Familial Mediterranean fever (FMF) is an autosomal recessive condition that is almost entirely restricted to the non-Askhenazi Jews, Arabs, Armenians, and Turks. Genetic linkage study of a large group of non-Turkish families has previously mapped the FMF locus to the 16p13.3 region and shown that this locus resides 0.305 cM distal to D16S246. Furthermore, allelic association has also been shown with D16S3070 (75%) and D16S3275 (66%). However, no genetic heterogeneity has been described for any of the three major reported groups of FMF families. Here, we describe the genetic linkage relationship of the fourth major group of Turkish families and report the first evidence for genetic heterogeneity of this condition. Two point linkage analysis and haplotype inspection of 15 DNA markers from the reported region of the FMF locus identified tight linkage in a group of six Turkish FMF families. A maximum lod score of 9.115 at theta = 0.00 was observed for D16S3024. Nine other DNA markers provided similar evidence of linkage with lod score values of above 5.21. However, two other FMF families were completely unlinked to this region of chromosome 16. Haplotype construction of DNA markers in five consanguineous linked families showed that a segment of homozygosity has been conserved for D16S3070 and D16S2617. No other DNA markers showed any such conservation. Therefore, we suggested that these two markers reside in close proximity to the FMF locus. Furthermore, we observed 80% allelic association with D16S2617 but no association with D16S3070 or any other DNA markers from the FMF critical region. In summary, we conclude that our Turkish families are also linked to the reported FMF locus at 16p13.3, there is a genetic heterogeneity for this condition at least in our group of Turkish families, and D16S2617 is in linkage disequilibrium in the Turkish FMF families. Combination of this study with previously published observations suggests that the FMF locus resides between D16S246 and D16S3070/D16S2617 and within a region of about 250-300 kb.

Adolescent↗
PubMed2003

[Research progress in forest tree genetic linkage map construction and its future prospects].

The research progress in genetic linkage map construction of forest tree species both at home and abroad were reviewed in the paper. Two main problems involved in the field were discussed. One was the limitation of the number of individuals of mapping populations and the other was the random markers mostly employed by the majority of studies. These problems have resulted in crossing combination specificity in the constructed maps and the QTLs located on the basis of the maps. As a result,the QTLs discovered up to now have low credibility and poor practicability in marker-assisted selection. Therefore considering the biological characteristics of forest tree species,the selection of the most suitable genetic markers is crucial to obtain a high quality genetic linkage map, and it is both important and necessary to carry out comparative genetic mapping. Progress in the ongoing expressed sequence tag (EST) sequencing projects were summarized and EST polymorphism (ESTP), the most informative and highly conservative marker with known function,as well as the main ESTP detection techniques were elaborated. It was pointed out that ESTP markers should be integrated into the present studies of genetic linkage map construction, QTL mapping and genome comparative mapping. Finally the future prospects in the fields of genetic linkage map and QTL mapping were discussed. In China, such studies around Populus, especially in the local Populus species should make a breakthrough in the related fields.

English Abstract↗
PubMed2002

Exact genetic linkage computations for general pedigrees.

MOTIVATION: Genetic linkage analysis is a useful statistical tool for mapping disease genes and for associating functionality of genes with their location on the chromosome. There is a need for a program that computes multipoint likelihood on general pedigrees with many markers that also deals with two-locus disease models. RESULTS: In this paper we present algorithms for performing exact multipoint likelihood calculations on general pedigrees with a large number of highly polymorphic markers, taking into account a variety of disease models. We have implemented these algorithms in a new computer program called SUPERLINK which outperforms leading linkage software with regards to functionality, speed, memory requirements and extensibility.

Algorithms↗
PubMed1999

Application of the RLGS image analysis tool (RAT) to the construction of a genetic linkage map of recombinant inbred strain SMXA.

The construction of a genetic linkage map is the first, fundamental step to analyze the genetic properties of any organism. For this purpose, the restriction landmark genome scanning method (RLGS) can be used and has been shown to have high productivity in various genetic analyses. However, construction of a genetic linkage map by the RLGS method is laborious, because hundreds of spots must be scored, usually by visual observation. In order to reduce human involvement in the data processing, we developed an image analysis software, RAT (RLGS Analysis Tool). We evaluated its accuracy and feasibility by comparing the parental distribution patterns of RLGS spots obtained by RAT and by human observation, using Syrian hamster strain backcross progeny. We then used RAT to construct a genetic linkage map of the recombinant inbred strain SMXA. We were able to obtain 121 progenitor strain-specific spots that were assigned to a specific chromosome.

Animals↗
PubMed1997

Location on the human genetic linkage map of 26 genes involved in blood coagulation.

Several human genetic linkage maps have been constructed as part of the Human Genome Project. These maps show the positional order of closely linked, highly informative AC-repeat polymorphisms on each human chromosome, and are extremely useful in genetic linkage analysis of inheritable diseases. For a candidate gene approach the current linkage maps are less useful, since they consist mainly of anonymous markers rather than of specific genes. This situation also applies for inheritable disorders of blood coagulation. Numerous genes are involved in the blood coagulation cascade and its regulation, and can be considered as candidate genes for unexplained haemophilia and thrombophilia. We have selected 29 candidate genes that seem to be the ones most likely to be involved in thrombophilia. For 19 genes genotype data were already present in the CEPH database (version 7.0). We typed 7 additional genes in the CEPH reference families, i.e. the factor V, factor XII, protein C, protein S, prothrombin, thrombomodulin, and heparin cofactor II gene. The genotype data were used to integrate these 26 genes in the current genetic linkage map, and to identify closely linked AC-repeat polymorphisms. This information will benefit the investigation of inheritable disorders of blood coagulation, especially thrombophilia.

Base Sequence↗
PubMed1992

A genetic linkage map of human chromosome 9q.

A genetic linkage map of human chromosome 9q, spanning a sex-equal distance of 125 cM, has been developed by genotyping 26 loci in the Venezuelan Reference Pedigree. The loci include 12 anonymous microsatellite markers reported by Kwiatkowski et al. (1992), several classical systems previously assigned to chromosome 9q, and polymorphisms for the genes tenacin (HXB), gelsolin (GSN), adenylate kinase 1 (AK1), arginosuccinate synthetase (ASS), ABL oncogene (ABL1), ABO blood group (ABO), and dopamine beta-hydroxylase (DBH). Only a marginally significant sex difference is found along the entire length of the map and results from one interval, between D9S58 and D9S59, that displays an excess of female recombination. A comparison of the genetic map to the existing physical data suggests that there is increased recombination in the 9q34 region with a recombination event occurring every 125-400 kb. This map should be useful in further characterizing the relationship between physical distance and genetic distance, as well as for genetic linkage studies of diseases that map to chromosome 9q, including multiple self-healing squamous epithelioma (MSSE), Gorlin syndrome (NBCCS), xeroderma pigmentosum (XPA), nail-patella syndrome (NPS1), torsion dystonia (DYT1), and tuberous sclerosis (TSC1).

Base Sequence↗
PubMed1989

Genetic linkage in schizophrenia: perspectives from genetic epidemiology.

Research on the genetic epidemiology of schizophrenia is briefly and selectively reviewed. The following three salient features of schizophrenia that represent challenges to the design of linkage studies are identified: (1) The analysis of twin and family data has consistently failed to identify a single major gene effect upon schizophrenia risk; (2) the ascertainment of multiplex families does not guarantee the sampling of families who are segregating for the major gene even if a major gene effect exists; and (3) environmental influences appear to play an essential role in the etiology of at least some forms of schizophrenia. The implications of these features for the design of linkage studies in schizophrenia are discussed.

Diseases in Twins↗
PubMed1987

Genetic linkage: sampling issues and multipoint mapping.

Genetic linkage is an important tool in determining the genetic contribution to the etiology of behavior disorders and psychiatric disease. Successful linkage studies employ large sample sizes. It is of particular relevance in psychiatric diseases, where the clinical workup is so extensive, to evaluate sample requirements critically. Recent studies indicate that extensive sampling, out to second-degree relatives, will not assist in identifying linkages although it may inflate the sample size considerably. The impact of the assumption about the mode of inheritance of the psychiatric trait and the effect of reduced penetrance are discussed. Multipoint mapping has the added advantage of using information from many markers simultaneously. This is helpful both in identifying individuals at risk to develop disease and in locating a gene with sufficient precision to determine the gene product. There are complications in applying multipoint mapping but these are generally of a technical nature and soluble. Recent suggestions for handling complications for multipoint mapping are evaluated. The correct design of the sampling procedure for selecting families and for selecting marker loci to use will greatly reduce the volume of work required for linkage studies and enhance the chances for success.

Chromosome Aberrations↗
PubMed1987

Von Recklinghausen neurofibromatosis and genetic linkage studies: clinical considerations.

For genetic linkage purposes, a subject at risk for Von Recklinghausen neurofibromatosis (VRNF) is one who has a first degree relative with independently documented VRNF. The presence of one or more of the designated criteria establishes the phenotypic diagnosis of VRNF in a subject at risk regardless of age. The absence of all of these criteria excludes the phenotypic diagnosis for all at risk subjects over five years of age. The absence of all the criteria in subjects at risk below five years of age or the presence of equivocal or merely suggestive findings neither excludes nor substantiates the phenotypic diagnosis of VRNF; rather, that subject should be removed from the preliminary scoring and analyses of the data.

Genetic Linkage↗