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PubMed1992

A Monte Carlo method for combined segregation and linkage analysis.

We introduce a Monte Carlo approach to combined segregation and linkage analysis of a quantitative trait observed in an extended pedigree. In conjunction with the Monte Carlo method of likelihood-ratio evaluation proposed by Thompson and Guo, the method provides for estimation and hypothesis testing. The greatest attraction of this approach is its ability to handle complex genetic models and large pedigrees. Two examples illustrate the practicality of the method. One is of simulated data on a large pedigree; the other is a reanalysis of published data previously analyzed by other methods.

Algorithms↗
PubMed1975

Genetics of acheiropodia (the handless and footless families of Brazil). VI. Formal genetic analysis.

A genetic analysis is presented of data from 22 Brazilian sibships with cases of acheiropodia (the handless and footless families of Brazil). Segregation analysis performed using a 16K CDC 3100 computer showed a segregation frequency of .245 +/- .040, which is close to the expected value of .25. No sporadic cases were detected. The ascertainment of the probands was through multiple incomplete selection (pi = .55 +/- .07). The data are consistent with the hypothesis of an extremely rare autosomal recessive gene as the etiological factor in acheiropodia. Prevalence is estimated as 29 +/- 4, which is the same as the number of high risk cases; gene frequency equals .0009 +/- .0005, and the incidence at birth is 4 times 10(-6) by the indirect method or 7 times 10(-6) by the direct method. The frequency of heterozygotes at birth is assumed to be 0.18% (450 times the frequency of affected). Population size is approximately 10 million, and the number of founders on a unique-mutation hypothesis is estimated as about 500. All these estimates are first approximations and must be accepted with caution.

Abnormalities, Multiple↗
PubMed1988

Genetic analysis of expulsion of adult Trichinella spiralis in NFS, C3H/He, and B10.BR mice.

The genetics of T. spiralis rejection from the intestine was examined in inbred mice belonging to three phenotypic categories of expulsion: strong (NFS), intermediate (C3H), and weak (B10.BR). Experiments used various worm doses to analyze the day of worm rejection, defined as the day at which 98% expulsion of the infectious dose occurred. The F1 of NFS (strong) x B10.BR (weak) was a strong responder and the F1 of the cross C3H (intermediate) x B10.BR (weak) was intermediate. Analysis of time of rejection among offspring of the (NFS/B10.BR) x B10.BR backcross showed three segregating phenotypic categories which occurred in a ratio of 1:2:1 strong:intermediate:weak. Segregation analysis of C3H/B10.BR intercross (F2) mice produced a ratio of 3:1, intermediate:weak. The backcross C3H/B10.BR to the C3H parent produced 100% intermediate offspring and the backcross to the B10.BR parent segregated in a 1:1 ratio of intermediate:weak. Taken together the results of both sets of crosses demonstrated that strong responsiveness was a consequence of the additive effects of two dominant genes; either gene by itself conferred intermediate responsiveness. The additive nature of these dominant genes suggested that two distinct processes each lead to the expression of worm expulsion that is phenotypically intermediate and kinetically identical.

Animals↗
PubMed1977

Extrachromosomal inheritance in Schizosaccharomyces pombe. IV. Isolation and genetic characterization of mutants resistant to chloramphenicol and erythromycin using the mutator properties of mutant anar-8.

Spontaneous chloramphenicol (capr)- and erythromycin (eryr)-resistant mutants were isolated from strain ade7-50 h- and the antimycin-resistant mutant anar-8 ade 7-50 h- of Schizosaccharomyces pombe (Sch. p.). By mitotic segregation analysis all 154 capr- and 120 eryr-mutants derived from ade 7-50 h- proved to be recessive chromosomal, whereas all 108 capr- and 200 eryr-mutants originating from anar-8 were extrachromosomally inherited. The rate of spontaneous capr- and eryr-mutants was about hundredfold in anar-8 compared to ade 7-50 h-. Growth of capr- and eryr-mutants was not inhibited by chloramphenicol or erythromycin, respectively, in glucose-medium and only slightly in glycerol-medium at concentrations which completely inhibited anar-8. By mitotic segregation-, tetrad-, and mitotic haploidization-analysis the extrachromosomal inheritance of mutants derived from anar-8 was established. Segregational patterns of capr- and eryr-determinants during mitosis, meiosis, and mitotic haploidization of diploids are discussed.

Ascomycota↗
PubMed1993

Genetic epidemiological studies of early-onset deafness in the U.S. school-age population.

Profound, early-onset deafness is present in 4-11 per 10,000 children, and is attributable to genetic causes in at least 50% of cases. Family history questionnaires were sent to 26,152 families of children with profound, early-onset deafness not known to be related to an environmental cause. The probands were ascertained through the 1988-89 Gallaudet University Annual Survey of Hearing Impaired Children and Youth. The analysis is based on the responses that were received from 8,756 families. Classical segregation analysis was used to analyze the family data, and to estimate the proportions of sporadic, recessive and dominant causes of deafness in the families. These data were consistent with 37.2% of the cases due to sporadic causes, and 62.8% due to genetic causes (47.1% recessive, and 15.7% dominant). An earlier study using the 1969-70 Annual Survey found 49.3% sporadic cases and 50.6% genetic, demonstrating that the proportion of sporadic cases of early-onset deafness has significantly decreased since 1970.

Chi-Square Distribution↗
PubMed1997

High-resolution linkage map of mouse chromosome 13 in the vicinity of the host resistance locus Lgn1.

Natural resistance of inbred mouse strains to infection with Legionella pneumophila is controlled by the expression of a single dominant gene on chromosome 13, designated Lgn1. The genetic difference at Lgn1 is phenotypically expressed as the presence or absence of intracellular replication of L. pneumophila in host macrophages. In our effort to identify the Lgn1 gene by positional cloning, we have generated a high-resolution linkage map of the Lgn1 chromosomal region. For this, we have carried out extensive segregation analysis in a total of 1270 (A/J x C57BL/6J) x A/J informative backcross mice segregating the resistance allele of C57BL/6J and the susceptibility allele of A/J. Additional segregation analyses were carried out in three preexisting panels of C57BL/6J x Mus spretus interspecific backcross mice. A total of 39 DNA markers were mapped within an interval of approximately 30 cM overlapping the Lgn1 region. Combined pedigree analyses for the 5.4-cM segment overlapping Lgn1 indicated the locus order and the interlocus distances (in cM): D13Mit128-(1.4)-D13Mit194-(0.1)-D13Mit147-(0.9)-D13 Mit36-(0.9)-D13Mit146-(0.2)-Lgn1/D13Mit37-(1.0)- D13Mit70. Additional genetic linkage studies of markers not informative in the A/J x C57BL/6J cross positioned D13Mit30, -72, -195, and -203, D13Gor4, D13Hun35, and Mtap5 in the immediate vicinity of the Lgn1 locus. The marker density and resolution of this genetic linkage map should allow the construction of a physical map of the region and the isolation of YAC clones overlapping the gene.

Animals↗
PubMed1991

Identification of markers associated with quantitative trait loci in chickens by DNA fingerprinting.

Three approaches for identifying VNTR alleles associated with quantitative traits in chickens are described. One approach is based on the comparison of well-defined selected and non-selected control strains. The second approach is based on analyzing chickens within a breeding population ranked according to specific traits and the third approach involves segregation analysis. In this latter approach a large number of offspring of a single male segregating for a quantitative trait are produced and tested for trait association of the male DNA fingerprinting bands. In all cases pooled DNA samples of birds, rather than individual samples, are analyzed and band intensity is assumed to reflect the relative frequency of an allele. Examples from the literature and from our laboratory indicate that these methods permit the identification of DNA fingerprinting bands associated with quantitative traits. After developing locus-specific probes for these bands it should ultimately be possible to detect and map quantitative trait loci.

Animals↗
PubMed1992

Duchenne muscular dystrophy: gene and gene product; mechanism of mutation in the gene.

The X-linked gene responsible for Duchenne muscular dystrophy encodes dystrophin, a high-molecular-weight cytoskeletal protein. Studies in several laboratories have revealed deletion of one or more exons in 60% of affected boys; quantitative analysis in our laboratory has detected duplication of exons in another 6%. The severe Duchenne phenotype is associated with deletions or duplications that shift the reading frame of the message, whereas the milder Becker muscular dystrophy is associated with deletions or duplications that maintain the reading frame. Patients who have neither deletion nor duplication may have nonsense mutations, one of which has been detected by predicting the site of the mutation from the size of the truncated protein. Rare females with the disease have a translocation that disrupts the dystrophin gene on one X chromosome and causes non-random inactivation of the normal X, resulting in the expression of the disease. The high frequency of new mutation provides an opportunity to study the mechanism of chromosomal rearrangement that is characteristic of the disease. Our laboratory has focused on the translocations in females and on duplications in affected males. The X-autosome translocations of affected females are all de novo events that originated in the paternal set of chromosomes. Molecular characterization of the translocation junctions revealed reciprocal translocation with both deletion and addition of nucleotides at the junction, suggestive of a breakage and reunion mechanism. Duplications studied to date are all tandem in nature and sequence analysis of duplication junctions has revealed both homologous and non-homologous recombination. Marker segregation analysis has revealed that five out of five duplications originated in a single X chromosome of one of the maternal grandparents, suggesting that the recombination event is unequal sister chromatid exchange.

Chromosome Aberrations↗
PubMed1999

Total body fat and abdominal visceral fat response to exercise training in the HERITAGE Family Study: evidence for major locus but no multifactorial effects.

The familial etiology of the response in total fat mass (FM) and abdominal visceral fat (AVF) to 20 weeks of exercise training was investigated in families participating in the HERITAGE Family Study. AVF (measured by computed tomographic scanning) and FM (measured by underwater weighing techniques) were assessed at baseline (in a sedentary state) and after 20 weeks of exercise training. The response AVF (AVFdelta) and response FM (FMdelta) were computed as the simple delta values (posttraining - baseline) and adjusted for the effects of sex, generation, and a polynomial in age using multiple regression analysis. To index the AVF response independently of the response in FM and the initial level of visceral fat, the AVFdelta was also adjusted for age and baseline AVF (AVFB) and FMdelta. Familial correlation analysis was used to investigate the multifactorial familial effects (polygenic and/or familial environmental), and segregation analysis was used to search for major gene effects. For the age-adjusted AVFdelta, a putative recessive locus accounting for 18% of the variance (q2 = 1%) was detected. Adjusting AVFdelta for AVFB and FMdelta slightly increased the percentage of variance accounted for (to 26%, q2 = 3%) but did not radically alter the pattern of the parameter estimates. For FMdelta, a putative dominant locus accounting for 31% of the variance (q2 = 49%) was noted. In conclusion, the results were consistent across methods in suggesting that there is little evidence of a multifactorial heritability for either AVFdelta or FMdelta. Rather, the familial etiology of the response to exercise training appears to be primarily due to putative major genes (a recessive locus for AVFdelta and a dominant locus for FMdelta). In addition, a pleiotropic/oligogenic system underlying these variables was inferred. That is, the putative loci for FMdelta and/or AVFB also may impact the AVFdelta, with an additional independent major locus effect on AVFdelta after the former influences have been removed.

Abdomen↗
PubMed1985

A family study of genetic and environmental factors determining polymorphic hydroxylation of debrisoquin.

Debrisoquin hydroxylation capacity determined as the ratio of debrisoquin to 4-OH-debrisoquin (DMR) in urine after a single oral dose (10 mg) was studied in 52 nuclear families comprising 226 subjects. The relative importance of genetic and environmental factors for DMR was studied by path analysis. There was a significant negative correlation between DMR and coffee intake but no significant correlations between DMR and sex, age, alcohol intake, or smoking habits. Path analysis showed that genetic heritability was 0.79 while cultural heritability was only 0.06. Complex segregation analysis gave evidence for a major locus with incomplete dominance (d = 0.28) between a recessive and an additive gene. The frequency of the major gene was 0.31, allowing an estimate of the frequency of slow hydroxylators in the Swedish population of 9.4%. There was also evidence for a multifactorial component accounting for 14% of the total variation. It was not possible to distinguish between the different genotypes within the rapid hydroxylator phenotype. Our data agree with previous studies in British and German populations showing that two alleles at a major autosomal locus can explain most of the observed variation in DMR. The frequency of slow hydroxylators in Sweden is very similar to that reported in other European studies. The debrisoquin metabolic phenotype seems to be extensively controlled by a monogenic system and not significantly influenced by environmental factors or age.

Administration, Oral↗
PubMed2005

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.

Animals↗
PubMed2003

A quantitative trait locus on chromosome 16q influences variation in plasma HDL-C levels in Mexican Americans.

OBJECTIVE: We conducted a whole-genome, multipoint linkage screen to localize a previously reported major locus accounting for 56% to 67% of the additive genetic effects on covariate-adjusted plasma HDL cholesterol (HDL-C) levels in Mexican Americans from the San Antonio Family Heart Study (SAFHS). METHODS AND RESULTS: After using complex segregation analysis to recover the major locus in 472 SAFHS participants from 10 genotyped families, we incorporated covariates required to detect that major locus, including plasma levels of triglycerides and apolipoprotein A-I, in a maximum-likelihood-based variance-components linkage screen. Only chromosome 16 exhibited convincing evidence for a quantitative trait locus (QTL), with a peak multipoint log of the odds (LOD)=3.73 (P=0.000034). Subsequent penetrance model-based linkage analysis, incorporating genotypes at the marker locus nearest the multipoint peak (D16S518) into the segregation model, detected linkage with the previously detected major locus (LOD=2.73, P=0.000642). Initial estimates place this QTL within a 15-cM region of chromosome 16q near the structural loci for lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP). CONCLUSIONS: A QTL influencing plasma levels of HDL-C in Mexican Americans from San Antonio maps to a region of human chromosome 16q near LCAT and CETP.

Adolescent↗
PubMed1989

Linkage analysis of the Bcg gene on mouse chromosome 1. Identification of a tightly linked marker.

We have mapped and determined the gene order of five cloned genes in the vicinity of the murine host resistance gene Bcg on mouse chromosome 1. For this, we have used a RFLP-type analysis in panels of 43 recombinant inbred strains, 3 congenic mouse strains, and 186 segregating backcross progeny derived from inbred strains of Bcgr and Bcgs genotypes. The Bcg alleles of segregating animals were established by in vivo infection with Mycobacterium bovis (Bacillus Calmette-Guérin) strain Montreal. Genomic DNA prepared from progenitor mouse strains was isolated, digested with restriction endonucleases, and analyzed by Southern blotting to identify strain-specific RFLP for each DNA marker tested. Among a number of DNA markers tested, Len2, Fn, Vil, Alpi, and Achrg were found to co-segregate with Bcg in mouse strains congenic for this locus. Detailed segregation analysis of the five markers and Bcg showed that Vil was extremely close to Bcg with no recombinant identified, whereas Fn and Len2 were located 4.5 and 9 cM proximal of Bcg, respectively. Alpi and Achrg mapped 5 and 5.5 cM distal from Bcg, respectively. Pedigree analysis in the recombinant inbred strains and backcross animals indicated the gene order: centromere-Len2-Fn-Vil,Bcg-Alpi-Achrg. The tightly linked Vil marker can now be used as an entry point in recombinant genomic DNA libraries to clone sequences overlapping Bcg. This group of five genes flanking Bcg on mouse chromosome 1 is precisely conserved on the telomeric end of the long arm of human chromosome 2q. Our results suggest that a likely location for a putative human homologue to the murine host resistance gene Bcg is the long arm of human chromosome 2 (2q32-qter).

Animals↗
PubMed1993

[Analysis of peripheral blood serotonin in domesticated silver foxes (Vulpes vulpes) as a major gene marker of domesticated behavior].

A segregation analysis of inheritance of the blood serotonin level in a domesticated silver fox population was performed (104 foxes from 4 pedigrees). The results of the analysis point to the effect of a major-gene in the control of this quantitative trait (dominance coefficient of lower level is 0.79), and suggest that breeding for domestic behavior is accompanied by selection against heterozygosity with respect to this major-gene. The lower blood serotonin level revealed in more domesticated foxes (p < 0.02) may be a consequence of this.

Animals↗
PubMed2003

Breast cancer classification and prognosis based on gene expression profiles from a population-based study.

Comprehensive gene expression patterns generated from cDNA microarrays were correlated with detailed clinico-pathological characteristics and clinical outcome in an unselected group of 99 node-negative and node-positive breast cancer patients. Gene expression patterns were found to be strongly associated with estrogen receptor (ER) status and moderately associated with grade, but not associated with menopausal status, nodal status, or tumor size. Hierarchical cluster analysis segregated the tumors into two main groups based on their ER status, which correlated well with basal and luminal characteristics. Cox proportional hazards regression analysis identified 16 genes that were significantly associated with relapse-free survival at a stringent significance level of 0.001 to account for multiple comparisons. Of 231 genes previously reported by others [van't Veer, L. J., et al. (2002) Nature 415, 530-536] as being associated with survival, 93 probe elements overlapped with the set of 7,650 probe elements represented on the arrays used in this study. Hierarchical cluster analysis based on the set of 93 probe elements segregated our population into two distinct subgroups with different relapse-free survival (P < 0.03). The number of these 93 probe elements showing significant univariate association with relapse-free survival (P < 0.05) in the present study was 14, representing 11 unique genes. Genes involved in cell cycle, DNA replication, and chromosomal stability were consistently elevated in the various poor prognostic groups. In addition, glutathione S-transferase M3 emerged as an important survival marker in both studies. When taken together with other array studies, our results highlight the consistent biological and clinical associations with gene expression profiles.

Breast Neoplasms↗
PubMed2001

Assessment of genetic variation and differentiation of hop genotypes by microsatellite and AFLP markers.

Microsatellites have many desirable marker properties and have been increasingly used in crop plants in genetic diversity studies. Here we report on the characterisation of microsatellite markers and on their use for the determination of genetic identities and the assessment of genetic variability among accessions from a germplasm collection of hop. Thirty-two polymorphic alleles were found in the 55 diploid genotypes, with an average number of eight alleles (3.4 effective alleles) for four microsatellite loci. Calculated polymorphic information content values classified three loci as informative markers and two loci as suitable for mapping. The average observed heterozygosity was 0.7 and the common probability of identical genotypes was 3.271 x 10(-4). An additional locus, amplified by one primer pair, was confirmed by segregation analysis of two crosses. The locus discovered was heterozygous, with a null allele in the segregating population. The same range of alleles was detected in nine triploid and five tetraploid hop genotypes. Cultivar heterozygosity varied among all 69 accessions, with only one cultivar being homozygous at four loci. Microsatellite allele polymorphisms distinguished 81% of all genotypes; the same allelic profile was found mainly in clonally selected cultivars. Cultivar-specific alleles were found in some genotypes, as well as a specific distribution of alleles in geographically distinct hop germplasms. The genetic relationship among 41 hop accessions was compared on the basis of microsatellite and AFLP polymorphisms. Genetic similarity dendrograms showed low correlation between the two marker systems. The microsatellite dendrogram grouped genetically related accessions reasonably well, while the AFLP dendrogram showed good clustering of closely related accessions and, additionally, separated two geographically distinct hop germplasms. The results of microsatellite and AFLP analysis are discussed from the point of view of the applicability of the two marker systems for different aspects of germplasm evaluation.

Alleles↗
PubMed2002

Expression and inheritance of nine transgenes in rice.

A total of 66 transgenic rice cell lines were produced by simultaneously transforming rice callus with nine different plasmids/genes. PCR analysis indicated that the co-transformation frequency of each gene was about 70%. All the cell lines carried at least three genes and 11 cell lines carried all nine genes. Thirty-two fertile transgenic plants (R0) were generated from the transgenic cell lines and seeds of 32 transgenic R1 lines and 5 R2 lines were harvested and analyzed for gene inheritance and protein expression. Progeny segregation analysis indicated that the multiple transgenes were integrated into the same locus of the rice genome, resulting in a 3:1 segregation ratio of the transgenes. Expression analysis of all nine transgenes revealed that the transgenes were expressed in all generations (R0, R1, and R2) and about half of the transgenes from each line were expressed. The expression of one transgene appears to have no effect on the expression of another transgene. Among the 66 cell lines, six lines (9.1%) expressed seven or eight transgenes out of the nine transformed genes. All together, our results showed that multiple genes could be delivered into rice cells simultaneously and cell lines expressing multiple genes could be generated. The results and procedures reported here should be useful in designing multi-plasmid transformation experiments such as those required for plant metabolic engineering.

Acetyltransferases↗
PubMed1993

X-linked lymphoproliferative disease. Detection of a paternally inherited mutation in a German family using haplotype analysis.

OBJECTIVE: To study the inheritance of the X-linked lymphoproliferative disease (XLP) locus in a German family. DESIGN: Haplotype segregation analysis. SETTING: Departments of Pediatrics and Human Genetics, University of Würzburg and University of Ulm, Federal Republic of Germany. PARTICIPANTS: Fourteen members of a family with XLP. INTERVENTIONS: None. MEASUREMENTS/MAIN RESULTS: Using molecular genetic techniques, we diagnosed the XLP status of the members of a German family. Restriction fragment length polymorphism analysis with closely linked polymorphic X-chromosomal DNA markers (Xq25-q27) revealed XLP carrier status in a female infant. Moreover, the XLP mutation was suggested to have occurred in the germ cell of the grandfather. CONCLUSION: This is the first report of a paternally inherited XLP mutation. The recurrence risk for germ cell mosaicism in XLP may be similar to that of X-linked Duchenne muscular dystrophy.

Base Sequence↗