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At least 649 records · Page 36Linked to original sources
PubMed2000

Retinoblastoma protein enhances the fidelity of chromosome segregation mediated by hsHec1p.

Retinoblastoma protein (Rb) plays important roles in cell cycle progression and cellular differentiation. It may also participate in M phase events, although heretofore only circumstantial evidence has suggested such involvement. Here we show that Rb interacts, through an IxCxE motif and specifically during G(2)/M phase, with hsHec1p, a protein essential for proper chromosome segregation. The interaction between Rb and hsHec1p was reconstituted in a yeast strain in which human hsHEC1 rescues the null mutation of scHEC1. Expression of Rb reduced chromosome segregation errors fivefold in yeast cells sustained by a temperature-sensitive (ts) hshec1-113 allele and enhanced the ability of wild-type hsHec1p to suppress lethality caused by a ts smc1 mutation. The interaction between Hec1p and Smc1p was important for the specific DNA-binding activity of Smc1p. Expression of Rb restored part of the inactivated function of hshec1-113p and thereby increased the DNA-binding activity of Smc1p. Rb thus increased the fidelity of chromosome segregation mediated by hsHec1p in a heterologous yeast system.

Amino Acid Motifs↗
PubMed2005

A novel role for the mitotic spindle during DNA segregation in yeast: promoting 2 microm plasmid-cohesin association.

The 2 microm circle plasmid in Saccharomyces cerevisiae is a model for a stable, high-copy-number, extrachromosomal "selfish" DNA element. By combining a partitioning system and an amplification system, the plasmid ensures its stable propagation and copy number maintenance, even though it does not provide any selective advantage to its host. Recent evidence suggests that the partitioning system couples plasmid segregation to chromosome segregation. We now demonstrate an unexpected and unconventional role for the mitotic spindle in the plasmid-partitioning pathway. The spindle specifies the nuclear address of the 2 microm circle and promotes recruitment of the cohesin complex to the plasmid-partitioning locus STB. Only the nuclear microtubules, and not the cytoplasmic ones, are required for loading cohesin at STB. In cells recovering from nocodazole-induced spindle depolymerization and G(2)/M arrest, cohesin-STB association can be established coincident with spindle restoration. This postreplication recruitment of cohesin is not functional in equipartitioning. However, normally acquired cohesin can be inactivated after replication without causing plasmid missegregation. In the mtw1-1 mutant yeast strain, the plasmid cosegregates with the spindle and the spindle-associated chromosomes; by contrast, a substantial number of the chromosomes are not associated with the spindle. These results are consistent with a model in which the spindle promotes plasmid segregation in a chromosome-linked fashion.

Cell Cycle↗
PubMed2005

Suppressors of Bir1p (Survivin) identify roles for the chromosomal passenger protein Pic1p (INCENP) and the replication initiation factor Psf2p in chromosome segregation.

Fission yeast Bir1p/Cut17p/Pbh1p, the homolog of human Survivin, is a conserved chromosomal passenger protein that is required for cell division and cytokinesis. To study how Bir1p promotes accurate segregation of chromosomes, we generated and analyzed a temperature-sensitive allele, bir1-46, and carried out genetic screens to find genes that interact with bir1(+). We identified Psf2p, a component of the GINS complex required for DNA replication initiation, as a high-copy-number suppressor of the bir1-46 growth defect. Loss of Psf2p function by depletion or deletion or by use of a temperature-sensitive allele, psf2-209, resulted in chromosome missegregation that was associated with mislocalization of Bir1p. We also found that the human homolog of Psf2p, PSF2, was required for proper chromosome segregation. In addition, we observed that high-copy-number expression of Pic1p, the fission yeast homolog of INCENP (inner centromere protein), suppressed bir1-46. Pic1p exhibited a localization pattern typical of chromosomal passenger proteins. Deletion of pic1(+) caused chromosome missegregation phenotypes similar to those of bir1-46. Our data suggest that Bir1p and Pic1p act as part of a conserved chromosomal passenger complex and that Psf2p/GINS indirectly affects the localization and function of this complex in chromosome segregation, perhaps through an S-phase role in centromere replication.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Mechanisms for chromosome and plasmid segregation.

The fundamental problems in duplicating and transmitting genetic information posed by the geometric and topological features of DNA, combined with its large size, are qualitatively similar for prokaryotic and eukaryotic chromosomes. The evolutionary solutions to these problems reveal common themes. However, depending on differences in their organization, ploidy, and copy number, chromosomes and plasmids display distinct segregation strategies as well. In bacteria, chromosome duplication, likely mediated by a stationary replication factory, is accompanied by rapid, directed migration of the daughter duplexes with assistance from DNA-compacting and perhaps translocating proteins. The segregation of unit-copy or low-copy bacterial plasmids is also regulated spatially and temporally by their respective partitioning systems. Eukaryotic chromosomes utilize variations of a basic pairing and unpairing mechanism for faithful segregation during mitosis and meiosis. Rather surprisingly, the yeast plasmid 2-micron circle also resorts to a similar scheme for equal partitioning during mitosis.

Adenosine Triphosphatases↗
PubMed2005

Anti-proliferative effects, cell cycle G2/M phase arrest and blocking of chromosome segregation by probimane and MST-16 in human tumor cell lines.

BACKGROUND: Anticancer bisdioxopiperazines, including ICRF-154, razoxane (Raz, ICRF-159) and ICRF-193, are a family of anticancer agents developed in the UK, especially targeting metastases of neoplasms. Two other bisdioxopiperazine derivatives, probimane (Pro) and MST-16, were synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. Cytotoxic activities and mechanisms of Raz (+)-steroisomer (ICRF-187, dexrazoxane), Pro and MST-16 against tumor cells were evaluated by MTT colorimetry, flow cytometry and karyotyping. RESULTS: Pro was cytotoxic to human tumor cell lines in vitro (IC50<50 microM for 48 h). Four human tumor cell lines (SCG-7901, K562, A549 and HL60) were susceptible to Pro at low inhibitory concentrations (IC50 values < 10 microM for 48 h). Although the IC50 against HeLa cell line of vincristine (VCR, 4.56 microM), doxorubicin (Dox, 1.12 microM) and 5-fluoruouracil (5-Fu, 0.232 microM) are lower than Pro (5.12 microM), ICRF-187 (129 microM) and MST-16 (26.4 microM), VCR, Dox and 5-Fu shows a low dose-related - high cytotoxic activity. Time-response studies showed that the cytotoxic effects of Pro are increased for 3 days in human tumor cells, whereas VCR, Dox and 5-Fu showed decreased cytotoxic action after 24 h. Cell cycle G2/M phase arrest and chromosome segregation blocking by Pro and MST-16 were noted. Although there was similar effects of Pro and MST-16 on chromosome segregation blocking action and cell cycle G2/M phase arrest at 1- 4 microM, cytotoxicity of Pro against tumor cells was higher than that of MST-16 in vitro by a factor of 3- 10 folds. Our data show that Pro may be more effective against lung cancer and leukemia while ICRF-187 and MST-16 shows similar IC50 values only against leukemia. CONCLUSION: It suggests that Pro has a wider spectrum of cytotoxic effects against human tumor cells than other bisdioxopiperazines, especially against solid tumors, and with a single cytotoxic pathway of Pro and MST-16 affecting chromosome segregation and leading also to cell G2/ M phase arrests, which finally reduces cell division rates. Pro may be more potent than MST-16 in cytotoxicity. High dose- and time- responses of Pro, when compared with VCR, 5-Fu and Dox, were seen that suggest a selectivity of Pro against tumor growth. Compounds of bisdioxopiperazines family may keep up their cytotoxic effects longer than many other anticancer drugs.

Antineoplastic Agents↗
PubMed2003

TbAGO1, an argonaute protein required for RNA interference, is involved in mitosis and chromosome segregation in Trypanosoma brucei.

BACKGROUND: RNA silencing processes are widespread in almost all eukaryotic organisms. They have various functions including genome protection, and the control of gene expression, development and heterochromatin formation. RNA interference (RNAi) is the post-transcriptional destruction of RNA, which is mediated by a ribonucleoprotein complex that contains, among several components, RNA helicases and Argonaute proteins. RNAi is functional in trypanosomes, protozoan parasites that separated very early from the main eukaryotic lineage and exhibit several intriguing features in terms of the control of gene expression. In this report, we investigated the functions of RNAi in Trypanosoma brucei. RESULTS: By searching through genome databases, novel Argonaute-like proteins were identified in several protozoa that belong to the kinetoplastid order, a group of organisms that diverged early from the main eukaryotic lineage. T. brucei possesses two Argonaute-like genes termed TbAGO1 and TbPWI1. Dual transient transfection assays suggest that TbAGO1, but not TbPWI1, is involved in RNAi. The entire coding region of TbAGO1 was deleted by double gene knockout. TbAGO1-/- cells turned out to be completely resistant to RNAi generated either by transfected double-stranded RNA or by expression of an inverted repeat. TbAGO1-/- cells were viable but showed a dramatically reduced growth rate. This was probably due to defects in mitosis and abnormal chromosome segregation as revealed by in situ analysis. The RNAi and growth phenotypes were complemented by the inducible expression of a GFP::TbAGO1 fusion protein that revealed the cytoplasmic location of the protein. CONCLUSIONS: The requirement of TbAGO1 for RNAi in trypanosomes demonstrates the evolutionary ancient involvement of Argonaute proteins in RNAi silencing processes. RNAi-deficient TbAGO1-/- cells showed numerous defects in chromosome segregation and mitotic spindle assembly. We propose a working hypothesis in which RNAi would be involved in heterochromatin formation at the centromere and therefore in chromosome segregation.

Animals↗
PubMed2004

Novel small GTPase subfamily capable of associating with tubulin is required for chromosome segregation.

The small GTPase superfamily, which includes the Ras, Rho/Rac, Rab, Arf and Ran subfamilies, serves as a signal transducer to regulate cell proliferation and differentiation, actin cytoskeleton, membrane trafficking, and nuclear transport. Here, we identify novel GTPases (human Gie1 and Gie2) that form a distinct subfamily of the small GTPases in terms of their sequences and intracellular function. Gie stands for 'novel GTPase indispensable for equal segregation of chromosomes', and this subfamily is conserved in multicellular organisms. Expression of dominant-negative Gie mutants in mammalian cells or knockdown of Gie transcripts using RNA interference in Drosophila S2 cells induced abnormal morphology in the chromosome segregation. Gie protein has ability to bind to tubulin and localizes with microtubules on the spindle mid-zone in late mitosis. Furthermore, overexpression of Gie mutants that lack putative effector domains but have tubulin-binding ability induced micronucleus formation. Thus, this is the first report showing that a small GTPase subfamily capable of associating with microtubules might be involved in chromosome segregation.

ADP-Ribosylation Factors↗
PubMed2001

Mitotic segregation of viral and cellular acentric extrachromosomal molecules by chromosome tethering.

Mitotic chromosome segregation is mediated by spindle microtubules attached to centromeres. Recent studies, however, revealed that acentric DNA molecules, such as viral replicons and double minute chromosomes, can efficiently segregate into daughter cells by associating with mitotic chromosomes. Based on this similarity between viral and cellular acentric molecules, we introduced Epstein-Barr virus vectors into cells harboring double minute chromosomes and compared their mitotic behaviors. We added lac operator repeats to an Epstein-Barr virus vector, which enabled us to readily identify the transgene in cells expressing a fusion protein between the lac repressor and green fluorescent protein. Unexpectedly, we found that Epstein-Barr virus vectors integrated into the acentric double minute chromosomes, but not into normal chromosomes, in all of the six stably transfected clones examined. While transiently transfected Epstein-Barr virus vectors randomly associated with wheel-shaped prometaphase chromosome rosettes, the chimeras of double minute chromosomes and Epstein-Barr virus vectors in stably transfected clones always attached to the periphery of chromosome rosettes. These chimeric acentric molecules faithfully represented the behavior of native double minute chromosomes, providing a tool for analyzing their behavior in living cells throughout the cell cycle. Further detailed analyses, including real-time observations, revealed that double minute chromosomes appeared to be repelled from the spindle poles at the same time that they attached to the chromosome periphery, while centromeric regions were pulled poleward by the attached microtubules. Disrupting microtubule organization eliminated such peripheral localization of double minute chromosomes, but it did not affect their association with chromosomes. The results suggest a model in which double minute chromosomes, but not Epstein-Barr virus vectors, are subject to the microtubule-mediated antipolar force, while they both employ chromosome tethering strategies to increase their segregation to daughter cells.

Centromere↗
PubMed2001

Role of chromosomal passenger complex in chromosome segregation and cytokinesis.

Chromosomal passenger proteins associate with chromosomes early in mitosis and transfer to the spindle at ana/telophase. Recent results show that aurora B/AIM-1 (aurora and Ipl1-like midbody-associated protein kinase), which is responsible for mitotic histone H3 phosphorylation, INCENP (Inner Centromere protein) and Survivin/BIR are in a macromolecular complex as novel chromosomal passenger proteins. Aurora B/AIM-1 can bind to Survivin and the C-terminal region of INCENP, respectively, and colocalizes with both proteins to the centromeres, midzone and midbody. Disruption of either aurora B/AIM-1 or INCENP function leads to sever defects in chromosome segregation and cytokinesis. Moreover, the formation of the central spindle through anaphase to cytokinesis is also disrupted severely. These data suggest that chromosomal passenger complex is required for proper chromosome segregation by phosphorylating histone H3, and cytokinesis by ensuring the correct assembly of the midzone and midbody microtubule. Chromosomal passenger protein complex may couple chromosome segregation with cytokinesis.

Animals↗
PubMed2000

Segregation analysis of diabetic nephropathy in Pima Indians.

Familial aggregation of diabetic nephropathy suggests the existence of genes determining susceptibility to nephropathy in addition to those leading to diabetes. In the present study, complex segregation analysis was performed in diabetic members of Pima Indian families to determine whether familial aggregation of nephropathy in this population could reflect the action of a single major gene. Nephropathy, defined by a urinary protein-to-creatinine ratio (PCR) > or = 500 mg/g, was analyzed as a discrete trait in a class C regressive logistic model. Individuals with PCR <500 mg/g were considered unaffected. Segregation analysis was performed both for nephropathy at the last examination (prevalent cases) and for duration of diabetes at the onset of nephropathy (incident cases). The REGD program was used for the analysis of the prevalent cases and the REGTL program for the incident cases, both from the Statistical Analysis for Genetic Epidemiology package (Case Western University, Cleveland, OH). The analysis of prevalent cases included 2,107 Pima Indians from 715 nuclear families. A subset of 504 of these families containing 1,403 individuals was used in the analysis of incident cases. Analysis of prevalent cases supported the existence of a gene with a major role, in that hypotheses of no major effect and of no transmission of a major effect were rejected (P = 0.00001; P = 0.003), whereas Mendelian transmission was not rejected (P = 0.85). A dominant model provided the best fit, but a recessive model could not be rejected. The analysis of incident cases, however, did not support a major gene effect on duration of diabetes at the onset of nephropathy, and analyses of lifetime occurrence of nephropathy were inconclusive. The analysis of prevalent cases supports the hypothesis of a major genetic effect on susceptibility to diabetic nephropathy in Pima Indians, but the analysis of incident cases does not support a genetic effect on duration of diabetes at the onset of nephropathy. The discrepancy may reflect the difficulty in precisely dating onset of nephropathy. The parameters of the model derived from segregation analysis of prevalent cases may be useful in linkage studies to detect nephropathy susceptibility loci.

Adult↗
PubMed1999

Segregation analysis reveals a major gene effect in compact and cancellous bone mineral density in 2 populations.

Involvement of genetic factors in determining bone mineral density (BMD) is doubtless. However, the exact nature of the genes governing BMD variation and sources for genetic determination of BMD of different parts of bone (compact and cancellous) have not been completely studied. The results of the complex segregation analyses performed in our previous study (Livshits et al. 1996) on a Turkmenian sample strongly support the hypothesis that a single Mendelian locus has a large effect on BMD. The parameter estimates for both types of bone tissue were so similar that we could assume a common gene effect for BMD variation of cancellous and compact bone. The objectives of the present study are to test again the possibility of major gene control of BMD in a different ethnic sample of pedigrees, namely, the Chuvasha. In addition, we report here the results of a bivariate segregation analysis of compact and cancellous BMD performed in both the Turkemenian and the Chuvasha samples of pedigrees. The results of the present study closely resemble the results obtained on the Turkmenian pedigrees. Likewise, the major finding of the present study is that there is a significant major gene effect on both compact and cancellous BMD; polygenic hypotheses were clearly rejected. Moreover, the results of the bivariate segregation analysis in both the Chuvasha and Turkmenian samples were similar. They lead to acceptance of the hypothesis that there is a single major locus with pleiotropy to both compact and cancellous bone.

Adolescent↗
PubMed2000

Behavior of sex chromosomes, autosomes, and the spindle during nonrandom segregation in a flea beetle.

We have analyzed autosome, sex chromosome, and spindle behavior in spermatocytes of the flea beetle, Alagoasa bicolor. In this species, males have very large X and Y chromosomes, which, although they are never physically connected, always segregate to opposite spindle poles at anaphase I, thus preserving the sex ratio in the next generation. We find that the sex chromosomes are partitioned to a peripheral spindle domain early in prometaphase I and that their segregation can be accounted for mainly by their reorientation from the parallel to the linear configuration, and little by chromosome-to-pole movement. Further, the behavior of the autosomes and that of the sex chromosomes seem to have little to do with each other. Spindle elongation is minimal; barely segregating the large sex chromosomes into the daughter cells at telophase I.

Animals↗
PubMed2001

Segregation patterns and heteroplasmy prevalence in Leber's hereditary optic neuropathy.

PURPOSE: To investigate the segregation pattern of the mitochondrial DNA mutation at nucleotide position 3460 responsible for Leber's hereditary optic neuropathy (LHON) and to determine the prevalence of heteroplasmy for the three primary LHON mutations at positions 11778, 3460, and 14484. METHODS: Segregation analysis was performed in a cross-sectional study by determining the level of heteroplasmy in blood leukocytes of 23 LHON patients and unaffected carriers from four unrelated families. One family comprising two affected and three unaffected carriers was followed over 5.5 years for a longitudinal segregation analysis of heteroplasmy. The percentage of mutant mtDNA was determined using a novel procedure of fluorescence-based primer extension and restriction fragment length polymorphism analysis. The prevalence of heteroplasmy was assessed by determining the number of genealogically unrelated LHON pedigrees with heteroplasmic maternal family members from the LHON patient records of the Department of Ophthalmology, University of Tübingen, Germany. RESULTS: The authors observed a marked variability in the degree of heteroplasmy levels within each pedigree and a tendency toward a higher mutant allele frequency in offspring generations. Disease expression was correlated with higher levels of mutant mtDNA molecules. Longitudinal analysis revealed no statistically significant decrease in the heteroplasmy level in the family studied but a reduction of 11% and 12% in one affected and one unaffected individual, respectively. In 167 genealogically unrelated LHON families the prevalence of heteroplasmy was 5.6%, 40%, and 36.4% for the 11778, 3460, and 14484 LHON mutations, respectively. CONCLUSIONS: Cross-sectional studies of heteroplasmy for the 3460 LHON mutation suggest that the genotype shifts toward a higher mutational load in offspring generations. Long-term decrease in the blood mutant load in single cases indicates negative selection of the mutant allele in the hematopoietic cell system. The prevalence of heteroplasmy varies significantly between the different primary LHON mutations, suggesting genotypical differences in disease expression.

Chromosome Segregation↗
PubMed1997

Racial residential segregation and the concentration of low- and high-income households in the 45 largest U.S. metropolitan areas.

"The objectives of this paper are to determine the relationship between racial residential segregation and (1) the spatial concentration of low- and high-income households, and (2) the socioeconomic characteristics of racial minority households. The three largest racial minority groups are compared (blacks, Hispanics, and Asians) in the largest 45 metropolitan areas in the United States. Data were obtained from the U.S. bureau of the Census' Population and Housing Summary Tape files. The results revealed that residential segregation of blacks was distinctly different from Asians and Hispanics. Moreover, for Asians and Hispanics, their socioeconomic characteristics matter in their level of residential segregation. For black households, however, their socioeconomic characteristics matter little."

Black or African American↗
PubMedDate not supplied

[Effect of gametocidal chromosome 4S' on the phenotype segregation ratio in genetic analysis of common wheat lines].

Using experimental data on genetic analysis of introgressive lines for the character "hairy leaf sheath" controlled by the "cuckoo" chromosome 4S1, the algorithm for calculation of the theoretical segregation ratio in F2 was developed. Segregation distortion is caused by non-viability of the majority of gametes lacking the chromosome 4S1. The frequency of functioning gametes without the chromosome 4S1 is determined by the probability p versus the theoretically expected ratio 7 nonviable: 9 viable ones. Since segregation involves two characters, gamete viability and hairiness, the ratio 15 hairy: 1 hairless was used as a basis for search of the frequency p by maximum-likelihood method using 16 populations F2 from crossing the lines differing in the character studied.

Chromosome Segregation↗
PubMed1996

Segregation analysis of two lung function indices in a random sample of young families: the Humboldt Family Study.

The Humboldt Family Study was conducted in the town of Humboldt, Saskatchewan, in 1993. Familial correlations and segregation analyses of lung function were carried out in 799 individuals in 214 nuclear families that included 214 fathers, 214 mothers, and 371 children. Forced expiratory volume in 1 second (FEV1) and maximal mid-expiratory flow rate (MMFR) were first regressed on age, height, weight, and their quadratic and cubic terms as well as on smoking status in four groups separately (mothers, fathers, daughters, and sons), with terms significant at the 0.10 level being retained. Residual phenotypes were standardized within the four groups. Class D regressive models were used to perform familial correlations and segregation analyses. For both FEV1 and MMFR, father-mother correlations were not significantly different from zero, and mother-offspring, father-offspring, and sibling-sibling correlations showed no statistically significant difference from each other. Based on the "polygenic" models, the estimated intraclass correlation is 0.132 (+/- 0.035) for FEV1 and 0.171 (+/- 0.039) for MMFR, and the narrow-sense heritability is 0.264 for FEV1 and 0.342 for MMFR. Segregation analysis shows that the "mixed" model with both single locus and polygenic components had a better fit for FEV1 than single-locus or polygenic only models. However, the model which included a nontransmitted environmental factor [tau(AA) = tau(AB) = tau(BB) = qA] and polygenic loci had a better fit than the Mendelian model [tau(AA) = 1, tau(AB) = 1/2, tau(BB) = 0] [Akaike's information criterion (AIC) = 2219.47 vs. AIC = 2222.14]. For MMFR, the Mendelian "mixed" model gave a nonsignificant improvement in loge likelihood compared to the simple polygenic model. Comparison of the single-locus model and Mendelian "mixed" model shows no difference in fitting the data. This study suggests that FEV1 and MMFR are controlled by many loci with no major effects and/or common environmental factors.

Adolescent↗
PubMed1997

Prior segregation analysis and the power to detect linkage.

Complex parametric segregation and linkage analysis was performed on the simulated quantitative trait Q1 for all 200 replicates of the nuclear families data set. The segregation analysis inferred a major gene in 46% of the replicates. Among all replicates, including those that rejected a major gene, the power to detect suggestive linkage to any of three loci affecting Q1 was 0.600 and the false positive rate was 0.002. Among the replicates where a major gene was found, the power to detect suggestive linkage was 0.652 and the false positive rate was also 0.002. Thus, for purposes of linkage to this complex trait, a prior segregation then linkage analysis approach located a gene in 30% of all replicates, whereas a linkage only approach located a gene in 60% of all replicates.

Computer Simulation↗
PubMed1998

Environmental factors can confound identification of a major gene effect: results from a segregation analysis of a simulated population of lung cancer families.

Proper control of environmental factors can be crucial to the identification of genes that influence susceptibility to a complex trait, especially for a trait such as lung cancer, for which the environmental factor (smoking) accounts for a significant etiologic fraction of the disease. An earlier segregation analysis of 337 Louisiana families, which incorporated direct measure of tobacco consumption, provided evidence for autosomal codominant inheritance of a major gene that influenced age at onset of lung cancer. Subsequent analyses were performed in which the families were stratified into two subsets based on birth cohort of the proband; results suggested the presence of heterogeneity that were postulated to reflect the influence of cohort trends in tobacco consumption. To evaluate this hypothesis further, we simulated a population of three-generation pedigrees in which an autosomal dominant mode of susceptibility to lung cancer was transmitted, but tobacco use varied across generations corresponding to published trends in smoking. A total of 200,000 individuals in families of various sizes, ages, and cigarette smoking habits were simulated from 1900 to 1980. From this population, 324 families (2,405 individuals) with 380 cases of lung cancer were ascertained through 328 lung cancer probands. Complex segregation analysis was performed using the REGTL program of S.A.G.E. in which pack-years of tobacco exposure were incorporated directly into the likelihood calculations. Although the no major gene, environmental, and Mendelian recessive hypotheses were rejected, both dominant and codominant transmission provided a good fit to the data. Thus in a population of simulated families with autosomal dominant susceptibility to lung cancer, intergenerational differences in tobacco consumption led to the detection of autosomal codominant transmission as an acceptable hypothesis. These results underscore the potential danger of segregation analysis of complex traits in which exposure to known environmental influences may differ across generations.

Computer Simulation↗