Genetic studies of human apolipoproteins. IX. Apolipoprotein D polymorphism and its relation to serum lipoprotein lipid levels.

Apolipoprotein D (APO D) is a constituent of plasma high-density lipoproteins. Its precise role in lipid metabolism is not well established, though it may be involved in cholesterol esterification and cholester ester transport to the liver for catabolism. No genetic polymorphism has been reported in the APO D gene product. To investigate the extent of genetic variation at the APO D structural locus, we have developed an isoelectric focusing-immunoblotting technique and have screened a large number of plasma samples from U.S. whites, U.S. blacks, Nigerian blacks, the Aleuts of the Pribilof Islands, Eskimo groups from Kodiak Island and St. Lawrence Island, and Amerindian populations from Mexico and Canada. Except for the U.S. blacks and Nigerian blacks, the APO D locus is monomorphic in all other population groups tested. In populations with black ancestry, the products of two alleles, APO D*1 and APO D*2, have been observed at respective allele frequencies .987 and .013 in U.S. blacks and .978 and .022 in Nigerian blacks. The detection of a unique protein polymorphism in blacks makes APO D a useful black marker of significance in anthropogenetics and racial admixture studies. In addition to the interindividual variation observed, APO D reveals extensive intraindividual molecular variation with a multiple banding pattern. The basis of this molecular variation is explained, in part, by variation in the number of terminal sialic acid residues. We have investigated the effect of the APO D polymorphism on triglycerides, total cholesterol, LDL-, VLDL-, HDL-, and HDL3 cholesterol in 352 Nigerian blacks (190 males and 162 females).(ABSTRACT TRUNCATED AT 250 WORDS)     

Population genetics of the HRAS1 minisatellite locus.

Several years ago it was reported that rare HRAS1 VNTR alleles occurred more frequently in U.S. Caucasian cancer patients than in unaffected controls. Such an association, in theory, could be caused by undetected population heterogeneity. Also, in a study clearly relevant to this issue, it was recently reported that significant deviations from Hardy-Weinberg equilibrium exist at this locus in a sample of U.S. Caucasians. These considerations motivate our population genetic analysis of the HRAS1 locus. From published studies of the HRAS1 VNTR locus, which classified alleles into types, we found only small differences in the allele frequency distributions of samples from various European nations, although there were larger differences among ethnic groups (African American, Caucasian, and Oriental). In an analysis of variation of rare-allele frequencies among samples from four European nations, most of the variance was attributable to molecular methodology, and very samples from four European nations, most of the variance was attributable to molecular methodology, and very little of the variance was accounted for by nationality. In addition, we showed that mixture of European subpopulations should result in only minor deviations from expected genotype proportions in a Caucasian database and demonstrated that there was no significant deviation from Hardy-Weinberg equilibrium in our HRAS1 data.     

Genetic Variability of Flight Metabolism in DROSOPHILA MELANOGASTER . III. Effects of Gpdh Allozymes and Environmental Temperature on Power Output

The effect of allozyme variation at the sn-glycerol-3-phosphate dehydrogenase (Gpdh) locus on variation in the mechanical power output of the flight muscles of Drosophila melanogaster was investigated. The influence of different rearing and flight temperatures and of their interactions with the Gpdh allozymic genotypes (allotypes) on flight ability also were analyzed. Populations from three continents were used, and Gpdh allotypes were generated from crosses between randomly paired isofemale lines made autozygous for each of the two alleles by inbreeding. Measurements made during tethered flight, together with wing morphology, were used to estimate power output using both Weis-Fogh's and Ellington's formulas. Analyses of variance (ANOVA) indicated significant main effects for both environmental components (rearing and flight temperatures) but for only one of the three genetic components (genetic backgrounds within continent); Gpdh allotypes and populations (continent of origin) were not significant. The interaction between rearing and flight temperature was highly significant, indicating some physiological adaptation. The effect of Gpdh allozymes depended on both rearing and flight temperature and was either significant or marginally so, depending on which set of formulas was used. In either case, the S/S allotype showed a 2-4% greater power output than the F/F allotype at low temperature for both interactions. In addition, the S/S allotype showed significantly greater power output than the F/F allotype among flies raised at 15 degrees and flown at 15 degrees, whereas the reverse was true for flies raised at 30 degrees and flown at 30 degrees. Significant differences among the three allotypes for GPDH activity level were found in general, with S/S having the highest, F/S intermediate and F/F the lowest activity, and an inverse relationship existed between rearing temperature and activity. The temperature effects on power output are consistent with the geographical and seasonal variation observed at the Gpdh locus in nature. In general, the results show that Gpdh can be considered a minor polygene affecting quantitative variation in the power output during flight and that genotype-by-environment interaction is an important component of that effect.     

Genetic studies of low-abundance human plasma proteins. VI. Polymorphism of hemopexin.

An analytical isoelectric focusing method in 3 M urea followed by immunoblotting has been devised to detect genetic and biochemical variation in the glycoprotein hemopexin (HPX) in human plasma or serum. HPX reveals extensive microheterogeneity with multiple major and minor components that are susceptible to neuraminidase treatment, suggesting that the observed biochemical variation is due to differences in sialic acid content between HPX isoproteins. However, charge differences that persist in HPX isoproteins following neuraminidase treatment suggest the presence of genetically determined HPX variation, and this is confirmed by population and family studies. HPX was found to be monomorphic, with an invariant pattern, in U.S. whites; but it is polymorphic in U.S. blacks, with three alleles controlled by a single locus, a situation that demonstrates an autosomal codominant pattern of inheritance. The HPX 1, HPX 2, and HPX 3 allele frequencies in U.S. blacks are .941, .018, and .041, respectively.     

Allozyme polymorphisms of maize populations from southwestern China

Maize (Zea mays L.) is one of the most-important food crops in southwestern China. The diversity of maize populations from southwestern China has been evaluated on the basis of agronomic and morphological data, but not on marker data. Our objectives were to evaluate the allozyme polymorphism of these populations, and group the populations on the basis of allozyme data. We analyzed 27 maize populations from southwestern China and two populations [BS13(S)C2 and Lancaster] from the USA for genetic variation at 18 allozyme loci. We found a total of 69 alleles at 18 allozyme loci with an average of 3.8 alleles per locus. Compared with inbreds, hybrids, and populations from the U.S. Corn Belt, the 27 Chinese populations had a significantly higher (p<0.01) number of allozyme alleles per locus. Maize populations from southwestern China have accumulated abundant genetic diversity, and might be valuable germplasm for broadening the genetic base of U.S. Corn Belt breeding germplasm. The analyses of allele-frequency distributions and the expected heterozygosity also reflected the differences between the Chinese and the U.S. germplasm. The Chinese populations might be valuable germplasm for complementing U.S. Corn Belt breeding germplasm. The analysis of gene diversity showed that 77% of the allozyme variation resided within populations and 23% between populations. This result suggested that breeders should identify one or a few Chinese populations with the best agronomic performance, and exploit the genetic variation within these selected populations. Cluster analysis classified the 29 populations into four main groups. Groupings based on allozyme data could be useful for classifying the populations into different heterotic groups and, consequently, exploiting them in hybrid breeding. Received: 12 October 2000 / Accepted: 13 March 2001     

Molecular markers reveal genetic isolation and phylogeography of the S and F intersterility groups of the wood-decay fungus Heterobasidion annosum

The root-rot fungus Heterobasidion annosum (Fr.) Bref. species complex consists of three intersterility groups (S, F, and P), separated by their host affinity. The phylogenetic relationship of the species complex was studied, with the focus on the S and F groups, by comparing DNA sequences of four nuclear gene fragments: calmodulin, glyceraldehyde 3-phosphate dehydrogenase, heat stress protein 80-1, and elongation factor 1-alpha, and one anonymous locus, from 29 fungal isolates originating from Europe, Asia, and North America. The phylogeny of each separate gene locus as well as the combined dataset consisted of three main clades: European F group isolates, Euroasian S group isolates, and North American S group isolates, suggesting them to be separated into phylogenetic species. The results also support the hypothesis of an early separation between the S and F groups, indicating that their distribution have followed their host tree species for a considerable time period.     

Genetic studies of human apolipoproteins. IV. Structural heterogeneity of apolipoprotein H (beta 2-glycoprotein I).

Human beta 2-glycoprotein I has recently been identified as a component of several human plasma lipoprotein fractions and therefore termed as apolipoprotein H. Its metabolic function in lipid metabolism is not known with certainty, though it may be involved in very-low-density-lipoprotein metabolism. Previously, inherited quantitative variation in beta 2-glycoprotein I has been suggested in man. In this investigation, we document the evidence of genetically determined structural polymorphism of apolipoprotein H or beta 2-glycoprotein I by using thin-layer polyacrylamide isoelectric focusing gels followed by immunological identification by double antibody staining. The apolipoprotein H structural locus is characterized by the occurrence of three common alleles in U.S. whites and blacks. The frequency distributions of the three alleles designated APO H1, APO H2, and APO H3 are .059, .882, and .059 in whites and .017, .902, and .068 in blacks, respectively. In addition, the gene product of a fourth allele, APO H4, has been observed at polymorphic frequency in black individuals and may represent a black marker variant. Family data confirm the hypothesis of four alleles at a single APO H gene locus with an autosomal codominant pattern of inheritance.     

Linkage disequilibrium and modification of risk for Huntington disease.

The major limitation in performing predictive testing for Huntington disease (HD) is the unavailability of DNA from crucial family members. In our program approximately 20% (36/183) of persons have been excluded from predictive testing because of this reason. The major aim of this study was to examine whether data derived from linkage disequilibrium could modify risk analysis for persons at risk for HD. As a first step, we assessed whether the previously reported linkage disequilibrium between alleles recognized by probe pBS674E-D at locus D4S95 remained significant in a much larger data set. A total of 1,150 chromosomes from 622 individuals--200 affected and 422 unaffected--from 118 families were assessed. Significant haplotype association was detected with AccI and MboI RFLPs at the locus D4S95, with all the families (P = .00003), as well as for a subset from the United Kingdom (P = .0037). Data derived from linkage disequilibrium studies using D4S95 modifies the risk for HD, especially in persons of U.K. descent. Utilization of this approach for risk modification of HD awaits both validation of these data and additional information concerning ethnic-specific alleles at the D4S95 locus.     

Analysis of four diverse population groups indicates that a subset of cystic fibrosis mutations occur in common among Caucasians.

To determine the nature and frequency of non-delta F508 cystic fibrosis (CF) mutations among diverse populations, we have sequenced exons 9-12 and 19-23 of the CF transmembrane conductance regulator (CFTR) gene from 128 CF chromosomes (39 U.S. Caucasian, 27 African-American, 42 Northern Irish, and 20 Israeli chromosomes). These regions were chosen because they encode the two putative ATP-binding folds of CFTR, domains which appear to have functional significance. In addition, CFTR exons 1 and 2 were analyzed in the American patients. Mutations were found on 49 of the 128 CF chromosomes. Nineteen different mutations were observed; six were novel, while the remaining 13 had been reported previously by our group or by other investigators. Six of nine different mutations found in African-American patients were unique to that population. However, the vast majority of the mutations found in U.S. Caucasians (eight of nine), Northern Irish (four of five), and Israelis (three of three) also occurred in other Caucasian groups. The preponderance of previously reported mutations in these three groups suggested that a subset of the non-delta F508 mutations occur in common among Caucasians. A survey of mutation frequencies in other Caucasian groups confirmed this observation. Unfortunately, this subset accounts for less than half of non-delta F508 CF mutations in most groups. These data suggest that screening for delta F508 and this select group of mutations will efficiently and economically maximize the number of CF mutations identified in Caucasian groups. However, it will be difficult to detect more than 90% of mutant CFTR alleles except in ethnically and geographically discrete populations where CF is the result of founder effect.     

Polymorphism of intron-1 in the voltage-gated sodium channel gene of Anopheles gambiae s.s. populations from Cameroon with emphasis on insecticide knockdown resistance mutations

Sequence variation at the intron-1 of the voltage-gated sodium channel gene in Anopheles gambiae M- and S-forms from Cameroon was assessed to explore the number of mutational events originating knockdown resistance ( kdr ) alleles. Mosquitoes were sampled between December 2005 and June 2006 from three geographical areas: (i) Magba in the western region; (ii) Loum, Tiko, Douala, Kribi, and Campo along the Atlantic coast; and (iii) Bertoua, in the eastern continental plateau. Both 1014S and 1014F kdr alleles were found in the S-form with overall frequencies of 14% and 42% respectively. Only the 1014F allele was found in the M-form at lower frequency (11%). Analysis of a 455 bp region of intron-1 upstream the kdr locus revealed four independent mutation events originating kdr alleles, here named MS1 -1014F, S1-1014S and S2-1014S kdr- intron-1 haplotypes in S-form and MS3-1014F kdr- intron-1 haplotype in the M-form. Furthermore, there was evidence for mutual introgression of kdr 1014F allele between the two molecular forms, MS1 and MS3 being widely shared by them. Although no M/S hybrid was observed in analysed samples, this wide distribution of haplotypes MS1 and MS3 suggests inter-form hybridizing at significant level and emphasizes the rapid diffusion of the kdr alleles in Africa. The mosaic of genetic events found in Cameroon is representative of the situation in the West–Central African region and highlights the importance of evaluating the spatial and temporal evolution of kdr alleles for a better management of insecticide resistance.     

Genetic studies of low-abundance human plasma proteins. V. Evidence for a second orosomucoid structural locus (ORM2) expressed in plasma.

Orosomucoid (ORM) or alpha-1-acid glycoprotein is an acute-phase protein of human plasma whose function is suggested to be the competitive inhibition of cellular recognition by infective agents. Genetically determined variation in ORM has been reported, with two major alleles segregating in all populations studied to date. Isoelectric focusing-immunoblotting studies of ORM revealed the presence of isoprotein species that did not segregate with the predominant alleles at the ORM locus and suggested the expression of a second structural gene locus for orosomucoid (ORM2). Genetically independent variation consistent with expression of the ORM2 locus was observed in plasma samples from American blacks but was not observed in U.S. whites or sampled populations of North- and South-American Indians, Eskimos, Aleuts, or New Guinea Highlanders. The population allele frequencies for this locus were .958, .025, .006, and .011 for alleles ORM*1, ORM2*2, ORM2*3, and ORM2*4, respectively. Family studies confirm the autosomal codominant inheritance of the observed phenotypes.     

Molecular and morphological evidence reveals introgression in swarms of the invasive taxa Fallopia japonica, F. sachalinensis, and F. xbohemica (Polygonaceae) in the United States

Fallopia japonica (Japanese knotweed, Polygonaceae) is a well-known East Asian perennial that is established throughout the U.S. and Europe. Another congener, F. sachalinensis, and their hybrid, F. ×bohemica, also persist on both continents. Their invasive success is primarily attributed to their ability to spread via clonal growth. However, mounting evidence suggests invasion history and dynamics differ between continents and that sexual reproduction is more common than previously assumed. We used published morphological traits designed to distinguish the three taxa to characterize their distribution in 24 New England towns. We found continuous variation of all five traits, with 84% of our 81 individuals having at least one trait outside parental limits. Hierarchical cluster analysis, along with two chloroplast and one nuclear species-specific markers, suggests the presence of intercrossing, segregating hybrids, and likely introgression between F1 hybrids and F. japonica. Our markers also show the first evidence of bidirectional hybridization between parental taxa in the U.S., emphasizing the complex structure of populations in our region. This study is a first step toward unraveling the evolutionary forces that have made these taxa such aggressive invaders in the U.S. The data may also affect management strategies originally designed for largely monomorphic, clonal populations.     

Genetic variation in the acorn barnacle from allozymes to population genomics

Understanding the patterns of genetic variation within and among populations is a central problem in population and evolutionary genetics. We examine this question in the acorn barnacle, Semibalanus balanoides, in which the allozyme loci Mpi and Gpi have been implicated in balancing selection due to varying selective pressures at different spatial scales. We review the patterns of genetic variation at the Mpi locus, compare this to levels of population differentiation at mtDNA and microsatellites, and place these data in the context of genome-wide variation from high-throughput sequencing of population samples spanning the North Atlantic. Despite considerable geographic variation in the patterns of selection at the Mpi allozyme, this locus shows rather low levels of population differentiation at ecological and trans-oceanic scales (F(ST)?～?5%). Pooled population sequencing was performed on samples from Rhode Island (RI), Maine (ME), and Southwold, England (UK). Analysis of more than 650 million reads identified approximately 335,000 high-quality SNPs in 19 million base pairs of the S. balanoides genome. Much variation is shared across the Atlantic, but there are significant examples of strong population differentiation among samples from RI, ME, and UK. An F(ST) outlier screen of more than 22,000 contigs provided a genome-wide context for interpretation of earlier studies on allozymes, mtDNA, and microsatellites. F(ST) values for allozymes, mtDNA and microsatellites are close to the genome-wide average for random SNPs, with the exception of the trans-Atlantic F(ST) for mtDNA. The majority of F(ST) outliers were unique between individual pairs of populations, but some genes show shared patterns of excess differentiation. These data indicate that gene flow is high, that selection is strong on a subset of genes, and that a variety of genes are experiencing diversifying selection at large spatial scales. This survey of polymorphism in S. balanoides provides a number of genomic tools that promise to make this a powerful model for ecological genomics of the rocky intertidal.     

Identification of a human specificAlu insertion in the factor XIIIB gene

The factor XIIIB gene was examined to determine the nature of a previously described 300 bp restriction fragment length polymorphism (RFLP) seen in the human population. Polymerase chain reaction analysis of different regions within the factor XIIIB gene was carried out to define a high resolution map of the region encompassing the polymorphism, followed by DNA sequence analysis. AnAlu insertion was found to be the source of this variation. ThisAlu repeat is a member of the human specific-1 (HS-1) subfamily, although one of the five diagnostic nucleotides is a cattarhine specific (CS) subfamily mutation, suggesting that it may represent an intermediate form in the evolution between these two subfamilies. Subsequently, we developed a PCR-based assay to detect the polymorphism, rendering it a more useful marker for genetic linkage studies and genome mapping. This insertion is also a valuable polymorphism for human population studies, as demonstrated by the large variations in allele frequencies seen in three population groups.     

Paragonimus ohirai: genetic control of tetrazolium oxidase isozymes

The Japanese lung fluke, Paragonimus ohirai, has three electrophoretic variants: F, FS, and S of tetrazolium oxidase (EC 1.15.1.1). Variant flukes were crossed in the laboratory. In both crosses, S X S and F X F, parental phenotypes appeared in all respective F1 progeny. In a cross of F X S, all F1 individuals derived from each parent showed the same phenotype (FS) indicating a heterozygote. On the other hand, from the cross of FS X S, 13 of FS and 11 S were observed from a parent (FS) while 2 FS and 1 S were recovered in three clones from the other parent (S). In the case of a cross between FS X F, a parent (F) produced 9 FS and 18 F clones in the offspring, numbers not significantly different from the expected values of Mendelian inheritance at the 0.01 level. The breeding data indicate that the tetrazolium oxidase isozymes of P. ohirai are controlled by two alleles, ToF and ToS, at a single locus.     

Generation of a new adenovirus type 12-inducible fragile site by insertion of an artificial U2 locus in the human genome.

Infection with adenovirus type 12 (Ad12) induces four fragile sites in the human genome (H.F. Stich, G.L. van Hoosier, and J.J. Trentin, Exp. Cell Res. 34:400-403, 1964; H. zur Hausen, J. Virol. 1:1174-1185, 1967). The major site, at 17q21-22, contains the U2 gene cluster, which is specifically disrupted by infection in at least a percentage of the cells (D.M. Durnam, J.C. Menninger, S.H. Chandler, P.P. Smith, and J.K. McDougall, Mol. Cell. Biol. 8:1863-1867, 1988). For direct assessment of whether the U2 locus is the target of the Ad12 effect, an artificial locus, constructed in vitro and consisting of tandem arrays of the U2 6-kbp monomer, was transfected into human cells. We report that integration of this artificial locus on the p arm of chromosome 13 creates a new Ad12-inducible fragile site.     

Molecular evolution of shattering loci in U.S. weedy rice

Cultivated rice fields worldwide are plagued with weedy rice, a conspecific weed of cultivated rice (Oryza sativa L.). The persistence of weedy rice has been attributed, in part, to its ability to shatter (disperse) seed prior to crop harvesting. In the United States, separately evolved weedy rice groups have been shown to share genomic identity with exotic domesticated cultivars. Here, we investigate the shattering phenotype in a collection of U.S. weedy rice accessions, as well as wild and cultivated relatives. We find that all U.S. weedy rice groups shatter seeds easily, despite multiple origins, and in contrast to a decrease in shattering ability seen in cultivated groups. We assessed allelic identity and diversity at the major shattering locus, sh4, in weedy rice; we find that all cultivated and weedy rice, regardless of population, share similar haplotypes at sh4, and all contain a single derived mutation associated with decreased seed shattering. Our data constitute the strongest evidence to date of an evolution of weeds from domesticated backgrounds. The combination of a shared cultivar sh4 allele and a highly shattering phenotype, suggests that U.S. weedy rice have re‐acquired the shattering trait after divergence from their progenitors through alternative genetic mechanisms.     

Measuring Selection Coefficients Affecting the Alcohol Dehydrogenase Polymorphism in DROSOPHILA MELANOGASTER

This paper describes a perturbation experiment on the frequency of the F and S Alcohol dehydrogenase (Adh) alleles of D. melanogaster. Fifty-four iso-female lines set up from three wild populations and with initial F frequencies of either 0.25, 0.50 or 0.75 were maintained on standard laboratory food medium at 22 degrees. At generations 4, 12 and 20 the lines were again scored for Adh gene frequencies. Maximum likelihood procedures were used to estimate selection coefficients for the Adh genotypes. An analysis of deviance was used to compare the coefficients against expectations under the hypotheses of neutrality and of constant values for the three base populations, and for the three initial gene frequency classes. Highly-significant departures from neutrality were observed; over all 54 lines, the set of relative fitnesses for S/S:F/S:F/F was estimated as 1.00:1.08:1.08. In addition, there were significant differences between lines in the outcome of selection which were not attributable to differences between base populations or initial F frequencies. These residual between-line differences, as well as some between-generation, within-line differences are discussed in terms of linkage disequilibria with background genes and electrophoretically cryptic variation at the Adh locus.     

Genetic studies of human apolipoproteins. XX. Genetic polymorphism of apolipoprotein J and its impact on quantitative lipid traits in normolipidemic subjects.

Apolipoprotein J (apo J) is a newly identified member of a growing family of proteins associated with various lipoprotein particles. Apo J is a glycoprotein which exists in the plasma associated with high-density lipoprotein subfractions which also contain apo A-I and cholesteryl ester transfer protein (CETP). We have investigated the possible existence of genetic polymorphism at the apo J structural locus and have evaluated its role in lipid metabolism. By employing isoelectric focusing and immunoblotting techniques, we have screened plasma or serum samples from six population groups: U.S. whites, Amerindians, Eskimos, New Guineans, U.S. blacks, and Nigerian blacks. Apo J revealed a common two-allele polymorphism only in populations with African ancestry and was found to be monomorphic in all other population groups tested. The genetic basis of the two alleles designated--APO J*1 and APO J*2, at a single structural locus, apo J-- was confirmed in a large number of segregating families. In the U.S. blacks, the frequencies of the APO J*1 and APO J*2 alleles were .76 and .24, respectively, and in the Nigerian blacks these values were .72 and .28, respectively. In addition, a single example of a rare allele designated APO J*3 was also encountered in the U.S. black sample. In Nigerian blacks, the apo J polymorphism's impact on seven quantitative lipid traits--total cholesterol, LDL-cholesterol, HDL-cholesterol, HDL3-cholesterol, HDL2-cholesterol, VLDL-cholesterol, and triglycerides--was investigated. No significant impact of the apo J polymorphism was observed for any of these lipid traits.     

Tight linkage of the gene for spinocerebellar ataxia to D6S89 on the short arm of chromosome 6 in a kindred for which close linkage to both HLA and F13A1 is excluded.

A locus for an autosomal dominant form of spinocerebellar ataxia (SCA1) has been assigned to the short arm of chromosome 6 on the basis of linkage to the major histocompatibility system (HLA). In this study of a five-generation American black family, close linkage between the disease locus and both HLA and the coagulation factor XIIIA (F13A1) locus was excluded, and lod scores for all locations of the disease locus between HLA and F13A1 were less than -1.4. These results suggest that the locus causing spinocerebellar ataxia in this family is not in this region. However, the disease locus was found to be closely linked to a microsatellite polymorphism, D6S89, which is between HLA and F13A1. The maximum lod score for SCA1 and D6S89 is 4.90 at a recombination fraction of 0, both in males and in females. These data show that exclusion of close linkage to the HLA complex and F13A1 in a kindred with spinocerebellar ataxia does not rule out the possibility that the disease locus in that family is on 6p. Accordingly, all families segregating a dominantly inherited ataxia should be evaluated for linkage to D6S89, to determine whether the locus causing the disease is SCA1.