Analysis of chromosome 1q42.2-43 in 152 families with high risk of prostate cancer

One hundred fifty-two families with prostate cancer were analyzed for linkage to markers spanning a 20-cM region of 1q42.2-43, the location of a putative prostate cancer-susceptibility locus (PCAP). No significant evidence for linkage was found, by use of both parametric and nonparametric tests, in our total data set, which included 522 genotyped affected men. Rejection of linkage may reflect locus heterogeneity or the confounding effects of sporadic disease in older-onset cases; therefore, pedigrees were stratified into homogeneous subsets based on mean age at diagnosis of prostate cancer and number of affected men. Analyses of these subsets also detected no significant evidence for linkage, although LOD scores were positive at higher recombination fractions, which is consistent with the presence of a small proportion of families with linkage. The most suggestive evidence of linkage was in families with at least five affected men (nonparametric linkage score of 1.2; P=.1). If heterogeneity is assumed, an estimated 4%-9% of these 152 families may show linkage in this region. We conclude that the putative PCAP locus does not account for a large proportion of these families with prostate cancer, although the linkage of a small subset is compatible with these data.     

Selection in Complex Genetic Systems I. the Symmetric Equilibria of the Three-Locus Symmetric Viability Model

The symmetric equilibria of the three-locus symmetric viability model are determined and their stability analyzed. For tight linkage there may be four stable equilibria, each characterized by having one pair of complementary chromosomes in high frequencies, with all others low. For looser linkage the only stable symmetric equilibrium is that with complete linkage equilibrium. For intermediate recombination values both types of equilibria may be stable. A new class of equilibria with all pairwise linkage disequilibria zero, but with third order linkage disequilibrium, has been discovered. It may be stable for tight linkage.     

Effects of epistasis on tests for linkage in self-pollinated species

Summary Tests for linkage based on covariances among relatives in self-pollinated species are usually based upon an assumption that epistasis is not important. This study was conducted to determine the impact of epistasis on, and to investigate the sensitivity of, such tests. Thirty covariances were calculated for each of ten non-epistatic and ten epistatic genetic models with varying probabilities of recombination between two coupling or repulsion loci. Each set of covariances was tested for linkage by comparing covariances calculated for the model with those expected for an additive-dominance model with no linkage. Results showed that the test for linkage is quite insensitive to the effects of linkage due to the disproportionate influence of inbreeding. Repulsion linkages should be easier to detect than coupling linkages for all models. Epistasis was found to mimic or counteract the effects of linkage. Tests for linkage based on covariances within a hierarchical mating design appear to be insensitive to linkage and may confuse the effects of linkage and epistasis.     

Construction of an Integrated Map of Haliotis diversicolor Using Microsatellite Markers

Small abalone, Haliotis diversicolor, is naturally distributed along the coastal waters of East Asia from Japan to the Philippines. It is an economically important maricultured species in southern China and Taiwan. Genetic linkage maps for small abalone were constructed using a total of 308 simple sequence repeat markers including 297 novel markers. Segregation data on 96 progeny were genotyped using a pseudo-testcross strategy. Sixteen linkage groups were identified in both female and male maps, consistent with the haploid chromosome number. The female linkage map covered 758.3 cM, with an average interval of 5.2 cM. The male linkage map spanned a total genetic distance of 676.2 cM, with an average interval of 4.5 cM. An integrated map was constructed by incorporating the homologous parental linkage groups, resulting in 16 linkage groups with a total of 762.1 cM. Genome coverage of the integrated linkage map was approximately 80.7%. The genetic linkage maps of small abalone may facilitate marker-assisted selection and quantitative trait loci mapping.     

Hammerhead cleavage of the phosphorodithioate linkage

Under standard reaction conditions, a hammerhead ribozyme with a phosphorodithioate linkage at the cleavage site cleaved to the expected products with a rate about 500-fold slower than the corresponding phosphodiester linkage. When the greater stability of the dithioate linkage to nonenzymatic nucleophilic attack is taken into account, the hammerhead is remarkably effective at cleaving the dithioate linkage considering that the R(P)-phosphoromonothioate linkage is virtually inactive. On the basis of experiments determining the Mg(2+) concentration dependence of the cleavage rate and the stimulation of cleavage by thiophilic Cd(2+) ion, the lesser catalytic rate enhancement of the dithioate linkage is primarily due to the loss of a single Mg(2+) ion bound near the cleavage site. These results are qualitatively similar to, but quantitatively different from, similar experiments examining the hammerhead cleavage properties of the R(P)-phosphoromonothioate linkage. The dithioate linkage thus promises to be a valuable alternative phosphate analogue to the monothioate linkage in studying the mechanisms of RNA catalysis.     

Modeling linkage disequilibrium in natural populations: the example of the Soay sheep population of St. Kilda, Scotland

The use of linkage disequilibrium to localize the genes underlying quantitative traits has received considerable attention in the livestock genetics community over the past few years. This has resulted in the investigation of linkage disequilibrium structures of several domestic livestock populations to assess their potential use in fine-mapping efforts. However, the linkage disequilibrium structure of free-living populations has been less well investigated. As the direct evaluation of linkage disequilibrium can be both time consuming and expensive the use of simulations that include as many aspects of population history as possible is advocated as an alternative. A simulation of the linkage disequilibrium structure of the Soay sheep population of St. Kilda, Scotland, is provided as an example. The simulated population showed significant decline of linkage disequilibrium with genetic distance and low levels of background linkage disequilibrium, indicating that the Soay sheep population is a viable resource for linkage disequilibrium fine mapping of quantitative trait loci.     

Examining the effect of linkage disequilibrium on multipoint linkage analysis

Most linkage programs assume linkage equilibrium among multiple linked markers. This assumption may lead to bias for tightly linked markers where strong linkage disequilibrium (LD) exists. We used simulated data from Genetic Analysis Workshop 14 to examine the possible effect of LD on multipoint linkage analysis. Single-nucleotide polymorphism packets from a non-disease-related region that was generated with LD were used for both model-free and parametric linkage analyses. Results showed that high LD among markers can induce false-positive evidence of linkage for affected sib-pair analysis when parental data are missing. Bias can be eliminated with parental data and can be reduced when additional markers not in LD are included in the analyses.     

Ignoring linkage disequilibrium among tightly linked markers induces false-positive evidence of linkage for affected sib pair analysis

Most multipoint linkage programs assume linkage equilibrium among the markers being studied. The assumption is appropriate for the study of sparsely spaced markers with intermarker distances exceeding a few centimorgans, because linkage equilibrium is expected over these intervals for almost all populations. However, with recent advancements in high-throughput genotyping technology, much denser markers are available, and linkage disequilibrium (LD) may exist among the markers. Applying linkage analyses that assume linkage equilibrium to dense markers may lead to bias. Here, we demonstrated that, when some or all of the parental genotypes are missing, assuming linkage equilibrium among tightly linked markers where strong LD exists can cause apparent oversharing of multipoint identity by descent (IBD) between sib pairs and false-positive evidence for multipoint model-free linkage analysis of affected sib pair data. LD can also mimic linkage between a disease locus and multiple tightly linked markers, thus causing false-positive evidence of linkage using parametric models, particularly when heterogeneity LOD score approaches are applied. Bias can be eliminated by inclusion of parental genotype data and can be reduced when additional unaffected siblings are included in the analysis.     

Population genetics of modifiers of meiotic drive III. Equilibrium analysis of a general model for the genetic control of segregation distortion

Prout, Bungaard and Bryant (1973, Theor. Popul. Biol. 4, 446–465) presented the first formal treatment of a model of meiotic drive involving a modifier locus which controls the intensity of drive. They studied the equilibrium behavior in the simplest model where it is assumed that drive is maximal when not suppressed. In that case there is one polymorphic equilibrium at which there is linkage disequilibrium. The equilibrium solutions in the general model of meiotic drive proposed by Prout, et al. are given in this paper together with a stability analysis. It is shown that up to three polymorphic equilibria may exist, two of which are in linkage disequilibrium and one in linkage equilibrium. These equilibria exhibit behavior qualitatively opposite to what is widely accepted as the usual for two locus systems and which is not seem in the simple case originally treated. The polymorphic equilibria with linkage disequilibrium may be stable for loose linkage and not for tight while that with linkage equilibrium is stable in an interval of relatively tight linkage values.     

An amplified fragment length polymorphism map of the silkworm

The silkworm (Bombyx mori L.) is a lepidopteran insect with a long history of significant agricultural value. We have constructed the first amplified fragment length polymorphism (AFLP) genetic linkage map of the silkworm B. mori at a LOD score of 2.5. The mapping AFLP markers were genotyped in 47 progeny from a backcross population of the cross no. 782 x od100. A total of 1248 (60.7%) polymorphic AFLP markers were detected with 35 PstI/TaqI primer combinations. Each of the primer combinations generated an average of 35.7 polymorphic AFLP markers. A total of 545 (44%) polymorphic markers are consistent with the expected segregation ratio of 1:1 at the significance level of P = 0.05. Of the 545 polymorphic markers, 356 were assigned to 30 linkage groups. The number of markers on linkage groups ranged from 4 to 36. There were 21 major linkage groups with 7-36 markers and 9 relatively small linkage groups with 4-6 markers. The 30 linkage groups varied in length from 37.4 to 691.0 cM. The total length of this AFLP linkage map was 6512 cM. Genetic distances between two neighboring markers on the same linkage group ranged from 0.2 to 47 cM with an average of 18.2 cM. The sex-linked gene od was located between the markers P1T3B40 and P3T3B27 at the end of group 3, indicating that AFLP linkage group 3 was the Z (sex) chromosome. This work provides an essential basic map for constructing a denser linkage map and for mapping genes underlying agronomically important traits in the silkworm B. mori L.     

Linkage analysis of "necessary" disease loci versus "susceptibility" loci.

The association of some diseases with specific alleles of certain genetic markers has been difficult to explain. Several explanations have been proposed for the phenomenon of association, e.g. the existence of multiple, interacting genes (epistasis) or a disease locus in linkage disequilibrium with the marker locus. One might suppose that when marker data from families with associated diseases are analyzed for linkage, the existence of the association would assure that linkage will be found, and found at a tight recombination fraction. In fact, however, linkage analyses of some diseases associated with HLA, as well as diseases associated with alleles at other loci located throughout the genome, show significant evidence against linkage, and others show loose linkage, to the puzzlement of many researchers. In part, the puzzlement arises because linkage analysis is ideal for looking for loci that are necessary, even if not sufficient, for disease expression but may be much less useful for finding loci that are neither necessary nor sufficient for disease expression (so-called susceptibility loci). This work explores what happens when one looks for linkage to susceptibility loci. A susceptibility locus in this case means that the allele increases risk but is neither necessary nor sufficient for disease expression. It might be either an allele at the marker locus itself that is increasing susceptibility or an allele at a locus in linkage disequilibrium with the marker. This work uses computer simulation to examine how linkage analyses behave when confronted with data from such a model.(ABSTRACT TRUNCATED AT 250 WORDS)     

Multilocus linkage analysis in humans: detection of linkage and estimation of recombination.

Multilocus linkage analysis is investigated from the viewpoint of the efficiency of recombination estimates under different strategies for detecting linkage and determining gene order within a linkage group. We consider the appropriateness of assuming no interference with data available in human genetic studies. Examples are given to show the significance of multilocus analysis in humans. A computer program package, LINKAGE, for multilocus linkage analysis is described.     

Linkage analysis of human chromosome 4: exclusion of autosomal dominant retinitis pigmentosa (ADRP) and detection of new linkage groups

As part of our ongoing linkage studies of degenerative retinal diseases, we tested seven DNA markers and two classical genetic markers from chromosome 4 in two extended families with autosomal dominant retinitis pigmentosa (ADRP). Our goals were (1) to detect or exclude linkage of ADRP to markers spanning most of chromosome 4 and (2) to contribute useful new information regarding the linkage map of this chromosome. Our results exclude linkage of ADRP from more than 82% of chromosome 4. We detected four new linkage relationships: loose linkage of K082 (D4S10) and G1E5 (D4S21) at a distance of 21 cM; loose linkage of 4F2 (D4S18) and GC protein at a distance of 19 cM; tight linkage (i.e., no recombinants) between B3D (D4S44), B5A (D4S40), and the MNS blood group; and tight linkage between 4F2 and GDS5 (D4S23). These data, combined with previously reported data, exclude ADRP from approximately 35% of the human genome.     

Status of the search for a major genetic locus for affective disorder in the Old Order Amish

Summary We have resumed the search for an autosomal linkage with affective disorder in the Old Order Amish and report the pairwise linkage results after screening 185 marked loci. No positive evidence of genetic linkage was found, and we estimate that roughly 23% of the autosomal genome has been excluded from linkage.     

The B subunit of coagulation factor XIII is linked to renin and the Duffy blood group to alpha-spectrin on human chromosome 1

Family linkage studies were used to detect two linkage relationships on human chromosome 1. The B subunit of coagulation factor XIII showed significant linkage to renin with a maximum lod score of 5.071 at a distance of 10 cM. Significant linkage was also shown between the Duffy blood group and alpha-spectrin with linkage results giving a combined lod score of 3.194 at 5 cM.     

The genetic linkage between the PKU locus and the loci for Amylase1, Amylase2, Fy,PGM1, and Rh and the question of assignment of the PKU locus to chromosome No. 1

Summary The alpha-amylase loci Amy₁ and Amy₂ and other loci on chromosome 1 were investigated for their linkage relationship to the PKU locus. Ten families were informative for the study of linkage between PKU/Amy, 20 for PKU-Fy, 11 for PKU/PGM₁, and 10 for PKU/Rh linkage. The probabilities of linkage at different recombinant fractions were calculated according to Bayes' theorem. The results are in striking contrast with those of Kamaryt et al. who found strong evidence for close linkage between the amylase loci and the PKU locus, whereas with our results close linkage can be excluded; loose linkage is possible but unlikely. The results are discussed with regard to the genetic heterogeneity of phenylketonuria.     

The second generation of the International Equine Gene Mapping Workshop half-sibling linkage map

A low-density, male-based linkage map was constructed as one of the objectives of the International Equine Gene Mapping Workshop. Here we report the second generation map based on testing 503 half-sibling offspring from 13 sire families for 344 informative markers using the CRIMAP program. The multipoint linkage analysis localized 310 markers (90%) with 257 markers being linearly ordered. The map included 34 linkage groups representing all 31 autosomes and spanning 2262 cM with an average interval between loci of 10.1 cM. This map is a milestone in that it is the first map with linkage groups assigned to each of the 31 automosomes and a single linkage group to all but three chromosomes.     

A posterior probability of linkage-based re-analysis of schizophrenia data yields evidence of linkage to chromosomes 1 and 17

OBJECTIVE: Linkage analysis using 22 Canadian pedigrees identified a promising schizophrenia candidate region on 1q23 with a maximum 2-point HLOD under a recessive model of 5.8 [Brzustowicz et al. 2000]. In the current study, we revisited this data set using a Bayesian linkage analysis technique, namely the posterior probability of linkage (PPL). METHODS: The PPL has been developed as an alternative to traditional linkage analysis. It differs from both LOD scores and 'non-parametric' methods in that it directly measures the probability of linkage given the data, and incorporates prior genomic information. RESULTS: As expected, PPL results for 1q23 supported the previously observed linkage, with an estimated multipoint PPL of 99.7%. However, the PPL supported two further results: a second peak on chromosome 1 at 1p13 with a multipoint with PPL of 70% and a chromosome 17 marker (D17S784 at 17q25) with a multipoint PPL of 44%. CONCLUSIONS: The PPL-based analysis presented has the advantage over other likelihood-based linkage methods in that it avoids maximization and produces a less complex view of the strength of evidence for linkage.     

Reappraisal of the genetic map of Chlamydomonas reinhardtii

In Chlamydomonas reinhardtii, we have found that linkage groups XII and XIII define only a single linkage group and that linkage groups XVI and XVII also define a single linkage group. The interdigitation of the genetic maps of linkage groups XII and XIII and of XVI and XVII is presented. At present, 17 linkage groups that display Mendelian segregation have been identified in C. reinhardtii.     

A comparative genetic map of the turkey genome

Genetic markers (microsatellites and SNPs) were used to create and compare maps of the turkey and chicken genomes. A physical map of the chicken genome was built by comparing sequences of turkey markers with the chicken whole-genome sequence by BLAST analysis. A genetic linkage map of the turkey genome (Meleagris gallopavo) was developed by segregation analysis of genetic markers within the University of Minnesota/Nicholas Turkey Breeding Farms (UMN/NTBF) resource population. This linkage map of the turkey genome includes 314 loci arranged into 29 linkage groups. An additional 40 markers are tentatively placed within linkage groups based on two-point LOD scores and 16 markers remain unlinked. Total map distance contained within linkage groups is 2,011 cM with the longest linkage group (47 loci) measuring 413.3 cM. Average marker interval over the 29 linkage groups was 6.4 cM. All but one turkey linkage group could be aligned with the physical map of the chicken genome. The present genetic map of the turkey provides a comparative framework for future genomic studies.