PKU locus: Genetic linkage with human amylase (Amy) loci and assignment to linkage group I

Summary The linked alpha-amylase loci Amy 1 and Amy 2 were evaluated for their linkage relationship to the PKU locus using data collected from two (one Czech and one Polish) groups of families. The five sibships informative for Amy 1: PKU give a score of 1.505 at =0.00 and the eight sibships informative for Amy 2: PKU give a score of 2.709 at =0.00. Due to the tandem position of Amy 1 and Amy 2 loci, these data could be combined, and linkage between Amy and PKU loci established with a score 4.214 at =0.00. The practical significance of the linkage, especially for identifying PKU allele carriers, is emphasized.     

Spinocerebellar ataxia: multipoint linkage analysis of genes associated with the disease locus

Summary Spinocerebellar ataxia (SCA) was studied in a seven-generation (Schut-Swier) kindred using linkage analysis to localize further the autosomal dominant, HLA-linked, disease-producing SCA1 locus relative to four other loci that map to the short arm of human chromosome 6. Genotypes for each locus were determined in as many individuals as possible from a total of 162 affected and unaffected family members that were studied. A maximum pairwise lod score of 8.52 ( _m = 0.10, _f = 0.22) for linkage between SCA1 and HLA-A was observed. Multipoint linkage analyses for the SCA1, HLA-A, F13A, D6S7, and GLO1 loci revealed that the SCA1 locus is most probably located telomeric to HLA-A, with a likely location between HLA-A and F13A.     

Evidence for Close Linkage of Human Amylase Loci

HUMAN α-amylase (α-1,4-glucan 4-glucanohydrolase, E.C. 3.2.1.1) is primarily in the pancreas and salivary glands and can be detected in serum and urine (UAmy) as well as in saliva (SaAmy) and duodenal secretions. The SaAmy locus (Amy₁) has at least three mutant alleles with the combined frequency of electrophoretic variant phenotypes totalling approximately 0.01 in Caucasian Americans¹. Subsequently, UAmy was shown to be a convenient source of pancreatic amylase. The pancreatic amylase locus (Amy₂) has at least two mutant alleles in Caucasian and Afro-Americans². The variant UAmy Ss is common in Caucasians whereas UAmy Sp has been found only in Afro-Americans; the frequency of variant phenotypes is 0·086 in each population².     

Genetic map of rat Chromosome 5 including the fatty (fa) locus

Thirteen loci, including the obesity gene fatty (fa), were incorporated into a linkage map of rat Chromosome (Chr) 5. These loci were mapped in obese (fa/fa) progeny of a cross between BN×13M-fa/+ F₁ animals. Obese rats were scored for BN and 13M alleles at four loci (Ifna, D1S85h, C8b, and Lck1) by restriction fragment length polymorphisms and at eight additional loci (Glut1, Sv4j2, R251, R735, R980, R252, R371, and R1138) by simple sequence length polymorphisms (SSLP). The resulting map spans 67.3 cM of Chr 5, presenting nine previously unmapped loci and one locus (Lck1) previously assigned to Chr 5 by use of somatic cell hybrid lines. Seven of the eight SSLP loci are newly identified; the SSLP linkage group alone spans 56.8 cM. The order of the loci is Sv4j2-R251-R735-R980-R1138-Ifna-fa-D1S85h-C8b-(Glut1-R252-R371)-Lck1. One locus, D1S85h, was found to lie only 0.4 cM from fa, close enough to serve as a reliable marker for the prediction of phenotype from genotype, and will be useful also for studies on the development of obesity in the fatty rat.     

The achondroplasia gene is not linked to the locus for neurofibromatosis 1 on chromosome 17

Summary We have investigated genetic linkage of von Recklinghausen neurofibromatosis (NF1) and achondroplasia (ACH) using chromosome-17 markers that are known to be linked to NF1. Physical proximity of the two loci was suggested by the report of a patient with mental retardation and the de novo occurrence of both NF1 and ACH. Since the chance of de novo occurrence of these two disorders in one individual is 1 in 600 million, this suggested a chromosomal deletion as a single unifying molecular event and also that the ACH and NF1 loci might be physically close. To test this, we performed linkage analysis on a three-generation family with ACH. We used seven DNA probes that are tightly linked to the NF1 locus, including DNA sequences that are known to flank the NF1 locus on the centromeric and telomeric side. We detected two recombinants between the ACH trait and markers flanking the NF1 locus. In one recombinant, the flanking markers themselves were nonrecombinant. Multi-point linkage analysis excluded the ACH locus from a region surrounding the NF1 locus that spans more than 15cM (lod score < -2). Therefore, analysis of this ACH pedigree suggests that the ACH locus is not linked to the NF1 locus on chromosome 17.     

Mapping of the linkage group GLO-Bf-HLA-B,C, A-PGM3

Summary This study confirms close linkage for the GLO-Bf-HLA-B,C,A complex, and proves linkage between the MHC loci and PGM₃. For GLO-PGM₃ and Bf-PGM₃, respectively, loose linkage seems to be likely, and close linkage can be excluded. Our mapping data on chromosomle 6 favor the hypothesis that the PGM₃ locus is situated on the HLA-A side of the MHC complex. Yet fine-structure mapping should be confirmed only by segregation analyses in crossover families by testing simultaneously all of the relevant marker loci within uniform family material.     

On the power of experimental designs for the detection of linkage between marker loci and quantitative loci in crosses between inbred lines

Summary The power of experiments aimed at detecting linkage between a quantitative locus and a marker locus, both segregating in the backross or F₂ generation of a cross between two inbred lines, is examined. Given that the two lines are close to fixation for alternative alleles of both marker locus and quantitative locus, it is concluded that experiments involving a few thousand offspring should be able to detect close linkages involving quantitative loci (or groups of loci) having rather modest effects (i.e., that contribute, say, 1% of the total phenotypic variance in the F₂).     

A genome-wide analysis of wide compatibility in rice and the precise location of the S5 locus in the molecular map

 The discovery of wide-compatibility varieties (WCVs) that are able to produce normal fertility hybrids when crossed both to indica and japonica rice has enabled the fertility barrier between indica and japonica subspecies to be broken and provided the possibility of developing inter-subspecific hybrids in rice breeding programs. However, a considerable variation in the fertility level of hybrids from the same WCV crossed to different varieties has often been observed. One hypothesis for this variable fertility is that additional genes are involved in hybrid fertility besides the wide-compatibility gene (WCG). To assess such a possibility, we performed a genome-wide analysis by assaying a large population from a three-way cross ‘02428’/‘Nanjing 11’//‘Balilla’ using a total of 171 RFLP probes detecting 191 polymorphic loci distributed throughout the entire rice linkage map. Our analysis recovered 3 loci conferring significant effects on hybrid fertility. The major locus on chromosome 6 coincided in chromosomal location with the previously identified S ₅ locus, and the 2 minor loci that mapped to chromosomes 2 and 12, respectively, were apparently distinct from all previously reported hybrid sterility genes. Interaction between the indica and japonica alleles at each of the loci caused a reduction in hybrid fertility. The joint effect of the 2 minor loci could lead to partial sterility even in the presence of the WCG. The location of the S ₅ locus on the molecular marker linkage map was determined to be approximately 1.0 cM from the RFLP locus R2349. This tight linkage will be useful for marker-aided transfer of the WCG in hybrid rice breeding and for map-based cloning. Received: 5 February 1997 / Accepted: 4 April 1997     

Linkage of the Igl-1 structural and regulatory genes to Akv-2 on chromosome 16

Evidence is presented here for a close linkage between Akv-2, an ecotropic provirus found uniquely on chromosome 16 of AKR/N mice, and the immunoglobulin ₁ light chain locus, Igl-1. No recombinants between the Igl-1 locus and Akv-2 were found by Southern blot analysis of DNA obtained from progeny of the backcross of (AKR/N × SJL/J)F₁ to SJL/J, indicating that these genes map within 5.9 cM of each other. A probe specific for the flanking sequence of Akv-2 was used to detect the provirus, while one specific for the IgI-1 constant region was used to determine which allele of the structural gene was expressed in the backcross mice. The constant region of Igl-1 differs between AKR/N and SJL/J with respect to a site for the restriction endonuclease KpnI. This backcross was also used to seek recombinants between the regulatory, Igl-1r, and structural, Igl-1, loci of the immunoglobulin light chain locus, since the existence of such recombinants would prove that these loci are distinct. Since only parental types were recovered in the offspring, the structural and regulatory loci are no more than 2.3 cM apart, and the implications of this finding are discussed.Deceased.     

Biochemical genetics of aldehyde reductase in the mouse: Ahr-1—A new locus linked to the alcohol dehydrogenase gene complex on chromosome 3

Electrophoretic and activity variants for a liver aldehyde reductase (AHR-A₂) among strains of Mus musculus have been used in genetic analyses to demonstrate close linkage between the locus encoding this enzyme (designated Ahr-1) and the alcohol dehydrogenase gene complex on chromosome 3. No recombinants were observed between Adh-3 (encoding alcohol dehydrogenase C₂; ADH-C₂) and Ahr-1 among 42 backcross animals. Moreover, linkage disequilibrium between these loci was observed among 58 of 60 strains of mice examined and among seven recombinant inbred strains derived from C57 BL/6J and BALB/c mice. Liver hexonate dehydrogenase (HDH-A) was electrophoretically invariant among the strains examined. Gel filtration analyses demonstrated that AHR-A₂ and HDH-A had native molecular weights of approximately 80,000 and 32,000, respectively. Three-banded allozyme patterns for AHR-A₂ in CBA/H × castaneus hybrid animals were consistent with a dimeric subunit structure. Comparative substrate and coenzyme specificities for AHR-A₂, HDH-A, and ADH-A₂ (liver ADH isozyme) were examined. AHR-A₂ exhibited a defined specificity toward p-nitrobenzaldehyde as substrate, whereas the other enzymes exhibited broad specificities toward various aliphatic, aromatic, and monosaccharide aldehydes. It is proposed that Ahr-1 is a product of a gene duplication event during mammalian evolution of the primordial mammalian Adh locus and that considerable divergence in catalytic properties has subsequently occurred.     

Quantitative trait loci affecting cotton fiber are linked to the t1 locus in upland cotton

Pilose (T ₁), a dominant marker in upland cotton, has been associated with coarse, short fibers. Pilose was, thereby, considered to be pleiotropic on fiber fineness and length. However, a pilose-expressing line with a fiber of average fineness was recently identified. This finding does not support pleiotropy between T ₁ and fiber traits, but is indicative of linkage between pilose and loci influencing fiber characteristics. To understand the relationship between T ₁ and fiber traits, a pilose line with short, coarse fiber was crossed to two t ₁ lines with standard fiber characteristics. One hundred and forty-nine F₂-derived F₃ lines were developed from one cross, and 60 F₂-derived F₃ lines from the other. Seven fiber traits (elongation, maturity, micronaire reading, perimeter, 2.5% span length, strength, and wall thickness) were measured. Segregation was normal, as indicated by allelic frequencies of 0.5 for T ₁ and t ₁, and segregation ratios of 121 for marker genotypes. The association of homozygous T ₁ lines with fibers of average fineness was again observed. Linkage between T ₁ and loci affecting micronaire, perimeter, 2.5% span length, strength, and wall thickness was found in both populations. Significant additive and non-additive gene effects for each of these traits at the marker locus were found as well. The pilose marker accounted for 10–75% of the phenotypic variation associated with each trait. In conclusion, the t ₁ locus is linked to numerous loci that influence fiber traits, and this linkage has previously been misinterpreted as pleiotropy.     

Novel susceptibility locus at 22q11 for diabetic nephropathy in type 1 diabetes

Background

Diabetic nephropathy (DN) affects about 30% of patients with type 1 diabetes (T1D) and contributes to serious morbidity and mortality. So far only the 3q21–q25 region has repeatedly been indicated as a susceptibility region for DN. The aim of this study was to search for new DN susceptibility loci in Finnish, Danish and French T1D families.

Methods and Results

We performed a genome-wide linkage study using 384 microsatellite markers. A total of 175 T1D families were studied, of which 94 originated from Finland, 46 from Denmark and 35 from France. The whole sample set consisted of 556 individuals including 42 sib-pairs concordant and 84 sib-pairs discordant for DN. Two-point and multi-point non-parametric linkage analyses were performed using the Analyze package and the MERLIN software. A novel DN locus on 22q11 was identified in the joint analysis of the Finnish, Danish and French families by genome-wide multipoint non-parametric linkage analysis using the Kong and Cox linear model (NPL_pairs LOD score 3.58). Nominal or suggestive evidence of linkage to this locus was also detected when the three populations were analyzed separately. Suggestive evidence of linkage was found to six additional loci in the Finnish and French sample sets.

Conclusions

This study identified a novel DN locus at chromosome 22q11 with significant evidence of linkage to DN. Our results suggest that this locus may be of importance in European populations. In addition, this study supports previously indicated DN loci on 3q21–q25 and 19q13.     

Environmental Determination of Selective Significance or Neutrality of Amylase Variants in DROSOPHILA MELANOGASTER

Strains homozygous at the amylase locus were derived from a polymorphic laboratory population of Drosophila melanogaster. The Amy ^4,6 strain has higher enzyme activity than the Amy¹ strain.——Maltose has the same nutritional value as starch.——The effect of starch in pure culture depends on the yeast level. At low yeast level increasing starch increases survival, at high yeast level increasing starch increases mean dry weight. The strains do not differ in survival or mean dry weight in pure culture.——In mixed cultures at 50% input of Amy ^4,6 and Amy¹ as larvae the percentage Amy^4,6 in adults increases with increasing starch at low yeast levels, but equals input frequency at high yeast levels. No increase in percentage Amy^4,6 in adults is present with increasing maltose at low yeast levels in mixed culture. The increase in percentage Amy^4,6 with increasing starch must be due to selection on the amylase locus working by competition for food in the larval stage. The single locus selection coefficient is determined by the environment and can reach quite high values.——Viability selection in the presence of starch is in the direction indicated by the enzyme activities.     

Immunological relationships and post-translational modifications of human salivary amylase (Amy1) and pancreatic amylase (Amy2) isozymes

Electrophoretic phenotypes of human salivary amylase (Amy₁) and pancreatic amylase (Amy₂) consist of complex isozyme patterns which may result from post-translational modifications of the primary products of the amylase loci. Biochemical separation of the two molecular weight families of salivary amylase and development of a new electrophoretic system have allowed the identification of complete isozyme patterns corresponding to variant alleles in Amy ₁ and Amy₂ heterozygotes. Further, immunological studies show no nonidentities among salivary isozymes and among pancreatic isozymes, which is to be expected if each series is derived from a single gene product. Both results support the hypothesis that the primary products of the amylase loci undergo post-translational modifications. Salivary and pancreatic amylase appear to be immunologically identical.This investigation was supported in part by PHS Research Grant GM-19178.Supported by PHS Training Grant DE 119.Supported by PHS Training Grant GM 1056.     

Localization of the human GLO gene locus

Summary Data on the linkage relation between the GLO locus and the HLA, Bf, and PGM ₃ loci are presented. The family material includes 49 GLO/HLA-B (and/or Bf) segregating matings with 134 children informative on 199 parental meioses. Of phase-known meioses, 3 are recombinants and 75 nonrecombinants; linkage is therefore proven. From the total material a distance of 2.5 cM between GLO and HLA-B/Bf is calculated; and from the segregation in some informative family groups it is shown that GLO is situated between PGM ₃ and HLA-B/Bf.     

Mapping the nucleolus organizer region,seed protein loci and isozyme loci on chromosome 1R in rye

Summary The nucleolus organizer region located on the short arm of chromosome 1R of rye consists of a large cluster of genes that code for ribosomal RNA (designated the Nor-R1 locus). The genes in the cluster are separated by spacer regions which can vary in length in different rye lines. Differences in the spacer regions were scored in two families of F₂ progeny. Segregation also occurred, in one or both of the families, at two seed protein loci and at two isozyme loci also located on chromosome 1R. The seed protein loci were identified as the Sec 1 locus controlling -secalins located on the short arm of chromosome 1R and the Sec 3 locus controlling high-molecular-weight secalins located on the long arm of 1R. The two isozyme loci were the Gpi-R1 locus controlling glucose-phosphate isomerase isozymes and the Pgd 2 locus controlling phosphogluconate dehydrogenase isozymes. The data indicated linkage between all five loci and map distances were calculated. The results indicate a gene order: Pgd 2 ... Sec 3 ... [centromere] ... Nor-R1 ... Gpi-R1 ... Sec 1. Evidence was obtained that rye possesses a minor 5S RNA locus (chromosome location unknown) in addition to the major 5S RNA locus previously shown to be located on the short arm of chromosome 1R.     

Pas1 is a common lung cancer susceptibility locus in three mouse strains

Inherited predisposition to lung cancer is a phenotypic trait shared by different mouse inbred strains that show either a high or an intermediate predisposition. Other strains are instead genetically resistant. The Pas1 locus is the major determinant of lung cancer predisposition in the A/J strain (Gariboldi et al. 1993). To define the determinants of susceptibility to lung tumorigenesis in the highly susceptible SWR/J and in the intermediately susceptible BALB/c mice, we analyzed (BALB/c × SWR/J)F₂ and (BALB/c × C3H/He)F₂ crosses by genetic linkage experiments. The present results provide unequivocal evidence that the same Pas1/+ allele that leads to lung cancer predisposition is shared by A/J, SWR/J, and BALB/c strains. The intermediate susceptibility of the BALB/c strain would result by interaction of Pas1 locus with lung cancer resistance loci. Received: 18 April 1997 / Accepted: 15 June 1997     

Association of dominant loci for resistance to Pseudomonas syringae pv. pisi with linkage groups II, VI and VII of Pisum sativum

Morphological characters, isoenzymes and recombinant inbred lines were employed to assign four loci for resistance to Pseudomonas syringae pv pisi to genetic linkage groups in Pisum sativum. A total of five morphological markers and 11 isoenzyme loci were screened in two independent F₂ P. sativum populations: Vinco × Hurst’s Greenshaft (V×HGS) and Partridge × Early Onward (P×EO). Mapping was also carried out in two recombinant inbred populations, unrelated to the F₂ populations. Previously reported linkage between resistance genes Ppi3 and Ppi4 was confirmed. Linkage was also detected between resistance gene Ppi2 and the isoenzyme locus Aldo (linkage group VII). The linked loci Ppi3 and Ppi4 were associated with a (linkage group II). A further resistance gene Ppi1 was associated with linkage group VI close to the hilum colour gene P1. RAPD markers tested in the cross P×EO were not well targeted; however, one marker, OPA-20_0.71, showed linkage to Ppi3. Received: 3 July 2000 / Accepted: 27 October 2000     

The dynamics of interlocus associations in the three-locus hitchhiking model

The hitchhiking effects of a selected locus upon the dynamics of the pairwise association,D _nn between two neutral loci is examined analytically for the special case where at least one of the neutral loci is in linkage equilibrium with the selected locus. The results apply approximately whenever the product of the pairwise associations between the selected locus and each neutral locus is negligible with respect to the three-way linkage disequilibrium. It is shown that precisely four broad classes of trajectories are possible, whether the selected locus is between (nsn) or to one side (snn) of the neutral loci, and whatever the mode of selection operating.D _nn may: (1) decay rapidly to zero, at a rate faster in each generation than that expected for two isolated neutral loci; (2) monotonically decay to zero at a rate which is slower in every generation than under the usual neutral regime; (3) increase initially and/or in intermediate periods before eventually slowly decaying to zero; or (4) exhibit type 1 behavior in the first segment of the trajectory and either type 2 or 3 behavior in the subsequent generations, with the transition marked by a change in sign. The nature of a given trajectory is largely determined by the direction of gene frequency change at the selected locus, and the initial signs of bothD _nn and the three-way linkage disequilibrium.The single most important consequence of these results is that there is no simple relation between the amount of pairwise association between two neutral markers and the recombination fraction between them. Several factors influencing the magnitude of the hitchhiking effect are also examined. It is shown that, all else being equal, the greater the three-way linkage disequilibrium, the greater the departure ofD _nn from the expected neutral dynamic. Increased recombination among the loci reduces the hitchhiking effect onD _nn . The dependence of the behavior upon the exact position of the selected locus is also determined both within and betweennsn andsnn chromosomal systems. An interesting discovery is that given equivalentnsn andsnn systems, with each having the same recombination between their two neutral loci,D _nn will deviate more from the standard neutral dynamic in thesnn system if its selected locus is sufficiently tightly linked to the neutral loci.     

Exclusion of two candidate pigment loci,c and b,part of chromosome 11p,and 33 random polymorphic markers as the locus for tyrosinase-positive oculocutaneous albinism

The locus for Tyrosinase-Positive Oculocutaneous Albinism (ty-pos OCA) has not yet been localised. The search for the ty-pos OCA locus has included a search for linkage to candidate pigment loci and a candidate chromosomal region, as well as a random search using highly polymorphic markers in 42 families, including 271 individuals of whom 79 are affected. The lod scores for the tyrosinase (TYR) locus (11q14–q21), homologous to the albino locus, c, in the mouse and the CAS2/TRP1 locus (9p22-pter), homologous to the brown locus, b, in the mouse were -5.89 and -7.22, respectively, at a recombination fraction of =0.01, thus excluding them from being the ty-pos OCA locus. In the candidate chromosomal region, 11p, four loci (probes) were tested, SAA (pSAA82), CALC (pHC36), HBB (Gamma-globin haplotype) and an AC repeat polymorphism at the Wilm's Tumour locus (WT1). A portion of 11p was excluded with the following lod scores: pSAA82 lod=-2.05 at =0.10; pHC36 lod=-3.87 at =0.05; gamma-globin haplotype lod=-2.80 at =0.10; and WT1 lod=-2.34 at =0.10. Thirty-three polymorphic markers randomly distributed on 13 different chromosomes were all excluded from close linkage to ty-pos OCA.