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PubMed2006

A tumor progression model for hepatocellular carcinoma: bioinformatic analysis of genomic data.

BACKGROUND & AIMS: It is widely recognized that genomic abnormalities underpin the development of human cancers. Aberrant patterns of chromosomal changes may represent useful information that can be used in classifying the complex traits of liver cancer cases for the genetic events involved in tumor carcinogenesis, tumor progression, and prognosis. METHODS: Genome-wide chromosomal aberrations of 158 hepatitis B virus-associated hepatocellular carcinoma (HCC) were studied by comparative genomic hybridization (CGH). By application of a self-organizing tree algorithm, statistically significant CGH events were used to construct an evolutionary tree that could infer patient subgroups with different degrees of tumor progression. The key CGH events in the subgroups were identified. The clinical significance of the groupings and the key CGH events were examined. RESULTS: Based on the patterns of significant chromosomal aberrations derived, 3 HCC subgroups organized in an evolutionary tree were identified. The groupings possessed information reflecting the degrees of tumor progression, including numbers of chromosomal aberrations, tumor stages, tumor sizes, and disease outcome. Gains of 1q21-23 and 8q22-24 were identified as genomic events associated with the early development of HCC. Gain of 3q22-24, however, was identified as 1 of the late genomic events found to be associated with tumor recurrence and poor overall patient survival. CONCLUSIONS: A tumor progression model for HCC was constructed and revealed chromosomal imbalances that were significantly associated with clinical pathologic characteristics of the disease. This model explains a significant part of the variations in clinical outcome among HCC patients.

Adult↗
PubMedDate not supplied

Pathophysiology of plaque instability: insights at the genomic level.

Atherosclerosis and plaque rupture represent complex "traits" of unknown cause that involve multiple genes and their variants. Novel genomic technologies provide us with the tools that will allow for the identification of groupings of genes that determine either susceptibility or resistance relative to the development of atherosclerosis and its thromboembolic complications. This information may, in turn, lead to a clearer understanding of the cause and risk for atherosclerosis. Diagnostic tools, as well as preventive and therapeutic strategies, will be derived from such heightened understanding of the disease process. With this chapter, we have presented the current state of knowledge of atherosclerosis genomics.

Arteriosclerosis↗
PubMed2003

Genetic aspects and genetic epidemiology of parasomnias.

Parasomnias are undesirable phenomena associated with sleep. Many of them run in families, and genetic factors have been long suggested to be involved in their occurrence. This article reviews the present knowledge of the genetics of the major classical behavioral parasomnias as well as present results from genetic epidemiological studies. The level and type of evidence for genetic effects varies much from parasomnia to parasomnia. The genetic factors are best established in enuresis, with several linkages to chromosomal loci, but their functions are not so far known. Environmental causes and gene-environment interactions are most probably also of great importance in the origin of complex traits or disorders such as parasomnias.

Arousal↗
PubMed2004

Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate.

BACKGROUND: Cleft lip or palate (or the two in combination) is a common birth defect that results from a mixture of genetic and environmental factors. We searched for a specific genetic factor contributing to this complex trait by examining large numbers of affected patients and families and evaluating a specific candidate gene. METHODS: We identified the gene that encodes interferon regulatory factor 6 (IRF6) as a candidate gene on the basis of its involvement in an autosomal dominant form of cleft lip and palate, Van der Woude's syndrome. A single-nucleotide polymorphism in this gene results in either a valine or an isoleucine at amino acid position 274 (V274I). We carried out transmission-disequilibrium testing for V274I in 8003 individual subjects in 1968 families derived from 10 populations with ancestry in Asia, Europe, and South America, haplotype and linkage analyses, and case-control analyses, and determined the risk of cleft lip or palate that is associated with genetic variation in IRF6. RESULTS: Strong evidence of overtransmission of the valine (V) allele was found in the entire population data set (P<10(-9)); moreover, the results for some individual populations from South America and Asia were highly significant. Variation at IRF6 was responsible for 12 percent of the genetic contribution to cleft lip or palate and tripled the risk of recurrence in families that had already had one affected child. CONCLUSIONS: DNA-sequence variants associated with IRF6 are major contributors to cleft lip, with or without cleft palate. The contribution of variants in single genes to cleft lip or palate is an important consideration in genetic counseling.

Cleft Lip↗
PubMed2004

Identification of a prostate cancer susceptibility locus on chromosome 7q11-21 in Jewish families.

Results from over a dozen prostate cancer susceptibility genome-wide scans, encompassing some 1,500 hereditary prostate cancer families, indicate that prostate cancer is an extremely heterogeneous disease with multiple loci contributing to overall susceptibility. In an attempt to reduce locus heterogeneity, we performed a genomewide linkage scan for prostate cancer susceptibility genes with 36 Jewish families, which represent a stratification of hereditary prostate cancer families with potentially increased locus homogeneity. The 36 Jewish families represent a combined dataset of 17 Jewish families from the Fred Hutchinson Cancer Research Center-based Prostate Cancer Genetic Research Study dataset and 19 Ashkenazi Jewish families collected at Johns Hopkins University. All available family members, including 94 affected men, were genotyped at markers distributed across the genome with an average interval of <10 centimorgans. Nonparametric multipoint linkage analyses were the primary approach, although parametric analyses were performed as well. Our strongest signal was a significant linkage peak at 7q11-21, with a nonparametric linkage (NPL) score of 3.01 (P = 0.0013). Simulations indicated that this corresponds to a genomewide empirical P = 0.006. All other regions had NPL P values >/=0.02. After genotyping additional markers within the 7q11-21 peak, the NPL score increased to 3.35 (P = 0.0004) at D7S634 with an allele-sharing logarithm of odds of 3.12 (P = 0.00007). These studies highlight the utility of analyzing defined sets of families with a common origin for reducing locus heterogeneity problems associated with studying complex traits.

Adult↗
PubMed2005

Prospects for identifying functional variation across the genome.

The genetic factors contributing to complex trait variation may reside in regulatory, rather than protein-coding portions of the genome. Within noncoding regions, SNPs in regulatory elements are more likely to contribute to phenotypic variation than those in nonregulatory regions. Thus, it is important to be able to identify and annotate noncoding regulatory elements. DNA conservation among diverged species successfully identifies noncoding regulatory regions. However, because rapidly evolving regulatory regions will not generally be conserved across species, these will not detected by using purely conservation-based methods. Here we describe additional approaches that can be used to identify putative regulatory elements via signatures of nonneutral evolution. An examination of the pattern of polymorphism both within and between populations of Drosophila melanogaster, as well as divergence with its sibling species Drosophila simulans, across 24.2 kb of noncoding DNA identifies several nonneutrally evolving regions not identified by conservation. Because different methods tag different regions, it appears that the methods are complementary. Patterns of variation at different elements are consistent with the action of selective sweeps, balancing selection, or population differentiation. Together with regions conserved between D. melanogaster and Drosophila pseudoobscura, we tag 5.3 kb of noncoding DNA as potentially regulatory. Ninety-seven of the 408 common noncoding SNPs surveyed are within putatively regulatory regions. If these methods collectively identify the majority of functional noncoding polymorphisms, genotyping only these SNPs in an association mapping framework would reduce genotyping effort for noncoding regions 4-fold.

Animals↗
PubMed2006

AtALMT1, which encodes a malate transporter, is identified as one of several genes critical for aluminum tolerance in Arabidopsis.

Aluminum (Al) tolerance in Arabidopsis is a genetically complex trait, yet it is mediated by a single physiological mechanism based on Al-activated root malate efflux. We investigated a possible molecular determinant for Al tolerance involving a homolog of the wheat Al-activated malate transporter, ALMT1. This gene, named AtALMT1 (At1g08430), was the best candidate from the 14-member AtALMT family to be involved with Al tolerance based on expression patterns and genomic location. Physiological analysis of a transferred DNA knockout mutant for AtALMT1 as well as electrophysiological examination of the protein expressed in Xenopus oocytes showed that AtALMT1 is critical for Arabidopsis Al tolerance and encodes the Al-activated root malate efflux transporter associated with tolerance. However, gene expression and sequence analysis of AtALMT1 alleles from tolerant Columbia (Col), sensitive Landsberg erecta (Ler), and other ecotypes that varied in Al tolerance suggested that variation observed at AtALMT1 is not correlated with the differences observed in Al tolerance among these ecotypes. Genetic complementation experiments indicated that the Ler allele of AtALMT1 is equally effective as the Col allele in conferring Al tolerance and Al-activated malate release. Finally, fine-scale mapping of a quantitative trait locus (QTL) for Al tolerance on chromosome 1 indicated that AtALMT1 is located proximal to this QTL. These results indicate that AtALMT1 is an essential factor for Al tolerance in Arabidopsis but does not represent the major Al tolerance QTL also found on chromosome 1.

Aluminum↗
PubMed2001

Heart regeneration in adult MRL mice.

The reaction of cardiac tissue to acute injury involves interacting cascades of cellular and molecular responses that encompass inflammation, hormonal signaling, extracellular matrix remodeling, and compensatory adaptation of myocytes. Myocardial regeneration is observed in amphibians, whereas scar formation characterizes cardiac ventricular wound healing in a variety of mammalian injury models. We have previously shown that the MRL mouse strain has an extraordinary capacity to heal surgical wounds, a complex trait that maps to at least seven genetic loci. Here, we extend these studies to cardiac wounds and demonstrate that a severe transmural, cryogenically induced infarction of the right ventricle heals extensively within 60 days, with the restoration of normal myocardium and function. Scarring is markedly reduced in MRL mice compared with C57BL/6 mice, consistent with both the reduced hydroxyproline levels seen after injury and an elevated cardiomyocyte mitotic index of 10-20% for the MRL compared with 1-3% for the C57BL/6. The myocardial response to injury observed in these mice resembles the regenerative process seen in amphibians.

Animals↗
PubMed2002

High-throughput screening for evidence of association by using mass spectrometry genotyping on DNA pools.

To facilitate positional cloning of complex trait susceptibility loci, we are investigating methods to reduce the effort required to identify trait-associated alleles. We examined primer extension analysis by matrix-assisted laser desorptionionization time-of-flight mass spectrometry to screen single-nucleotide polymorphisms (SNPs) for association by using DNA pools. We tested whether this method can accurately estimate allele frequency differences between pools while maintaining the high-throughput nature of assay design, sample handling, and scoring. We follow up interesting allele frequency differences in pools by genotyping individuals. We tested DNA pools of 182, 228, and 499 individuals using 16 SNPs with minor allele frequencies 0.026-0.486 and allele frequency differences 0.001-0.108 that we had genotyped previously on individuals and 381 SNPs that we had not. Precision, as measured by the average standard deviation among 16 semidependent replicates, was 0.021 +/- 0.011 for the 16 SNPs and 0.018 +/- 0.008 for the 291381 SNPs used in further analysis. For the 16 SNPs, the average absolute error in predicting allele frequency differences between pools was 0.009; the largest errors were 0.031, 0.028, and 0.027. We determined that compensating for unequal peak heights in heterozygotes improved precision of allele frequency estimates but had only a very minor effect on accuracy of allele frequency differences between pools. Based on these data and assuming pools of 500 individuals, we conclude that at significance level 0.05 we would have 95% (82%) power to detect population allele frequency differences of 0.07 for control allele frequencies of 0.10 (0.50).

Alleles↗
PubMed1993

Inheritance of freezing resistance in tuber-bearing Solanum species: evidence for independent genetic control of nonacclimated freezing tolerance and cold acclimation capacity.

Frost or winter survival is regarded as a complex trait with polygenic inheritance. Two major components of this survival in crop plants are freezing tolerance in the nonacclimated state and cold acclimation capacity. To date researchers have not distinguished the two components as separate heritable traits. The mode of inheritance of these two traits was investigated in F1 and backcross populations of two wild diploid potato species (Solanum commersonii and Solanum cardiophyllum) exhibiting extremes of freezing tolerance and acclimation capacity. Precise assessment of these two traits allowed distinction of small but significant differences among genotypes. The two traits were not correlated in segregating populations, suggesting independent genetic control. Analyses of generation means indicate that all of the variance for acclimation capacity and a major proportion of the variance for the nonacclimated freezing tolerance can be best explained by an additive-dominance model with both traits being partially recessive. Recovery of parental phenotypes in limited populations suggests that both traits are controlled by relatively few genes. To our knowledge this is the first study demonstrating independent genetic control of the two main traits associated with frost or winter survival. Our results show that it should be possible to incorporate these traits from wild germ plasm into cultivated crop plants by independent selection. These results help explain the lack of progress in improving winter survival through field selection. Furthermore, our study demonstrates relative simplicity of the inheritance of cold acclimation, thus providing avenues for understanding the link between biochemical and genetic aspects of low-temperature stress in crop plants.

Journal Article↗
PubMed1995

Efficient high-resolution genetic mapping of mouse interspersed repetitive sequence PCR products, toward integrated genetic and physical mapping of the mouse genome.

The ability to carry out high-resolution genetic mapping at high throughput in the mouse is a critical rate-limiting step in the generation of genetically anchored contigs in physical mapping projects and the mapping of genetic loci for complex traits. To address this need, we have developed an efficient, high-resolution, large-scale genome mapping system. This system is based on the identification of polymorphic DNA sites between mouse strains by using interspersed repetitive sequence (IRS) PCR. Individual cloned IRS PCR products are hybridized to a DNA array of IRS PCR products derived from the DNA of individual mice segregating DNA sequences from the two parent strains. Since gel electrophoresis is not required, large numbers of samples can be genotyped in parallel. By using this approach, we have mapped > 450 polymorphic probes with filters containing the DNA of up to 517 backcross mice, potentially allowing resolution of 0.14 centimorgan. This approach also carries the potential for a high degree of efficiency in the integration of physical and genetic maps, since pooled DNAs representing libraries of yeast artificial chromosomes or other physical representations of the mouse genome can be addressed by hybridization of filter representations of the IRS PCR products of such libraries.

Animals↗
PubMed2001

The major murine systemic lupus erythematosus susceptibility locus, Sle1, is a cluster of functionally related genes.

The major murine systemic lupus erythematosus (SLE) susceptibility locus Sle1 is syntenic to a chromosomal region linked with SLE susceptibility in multiple human studies. Congenic analyses have shown that Sle1 breaks tolerance to chromatin, a necessary step for full disease induction that can be suppressed by specific modifier loci. In the present study, our fine mapping analysis of the location of Sle1 has determined that three loci within this congenic interval, termed Sle1a, Sle1b, and Sle1c, can independently cause a loss of tolerance to chromatin. Each displays a distinctive profile of serological and cellular characteristics, with T and B cell functions being more affected by Sle1a and Sle1b, respectively. The epistatic interactions of Sle1 with other susceptibility loci to cause severe nephritis cannot be accounted, however, by these three loci alone, suggesting the existence of an additional locus, termed Sle1d. These findings indicate that the potent autoimmune phenotype caused by the Sle1 genomic interval reflects the combined impact of four, separate, susceptibility genes. This level of genetic complexity, combined with similar findings in other systems, supports the possibility that many complex trait loci reflect the impact of polymorphisms in linked clusters of genes with related functions.

Animals↗
PubMed1999

Catecholamine storage vesicle protein expression in genetic hypertension.

Chromogranin A expression is heritable in humans, and both plasma chromogranin A concentration and its releasable adrenal and sympathetic neuronal pools are augmented in established essential (hereditary) hypertension. To evaluate chromogranin A further as a simpler or "intermediate phenotype" in the complex trait of hypertension, we studied chromogranin A expression in the spontaneously hypertensive rat (SHR), a rodent model of essential hypertension. Both plasma (p < 0.0001) and adrenal medullary (p = 0.003 to p < 0.0001) chromogranin A were elevated in the SHR, even at the earliest stages (3-4 weeks of age). In the adult adrenal gland, both chromogranin A (p=0.005) and norepinephrine (p=0.011) were increased in the SHR, while dopamine beta-hydroxylase activity was diminished (p < 0.0001). Chromogranin A mRNA expression was also elevated in the SHR adrenal medulla (p = 0.017). Differences in chromogranin A processing were not noted between SHR and Wistar Kyoto control (WKY) rats. In an SHR x WKY genetic intercross, control of the adrenal chromogranin A phenotype by a single major locus was suggested by comparison of phenotypic variance of the F2 vs F1 generations, and by bimodal frequency histogram (3:1 ratio), confirmed by maximum likelihood analysis (chi2 = 74.6, p < 0.000001) in the F2 generation. However, microsatellite alleles at a surrogate locus (Ighe) 12.7 cM from chromogranin A (Chga), on rat chromosome 6, failed to co-segregate with blood pressure in an F2 generation (F = 0.06, p = 0.94). In another rodent model of hereditary hypertension, the genetically hypertensive mouse (BPH/2), adrenal chromogranin A (p=0.018) and norepinephrine (p = 0.004) were actually diminished. We conclude that over-expression of chromogranin A is a variable feature of mammalian genetic hypertension. In one rodent model (the SHR), over-expression of chromogranin A is largely controlled by a single genetic locus, but the chromogranin A locus itself is not directly linked to determination of the blood pressure elevation of the SHR.

Adrenal Medulla↗
PubMed2005

Lack of association between endometriosis and the CYP17 MspA1 polymorphism in UK and Japanese populations.

Endometriosis is a complex trait, which means that multiple susceptibility genes interact with one another and the environment to produce the phenotype. One of the genes previously implicated in the disease is CYP17; this encodes the enzyme P450c17alpha, which plays a vital role in steroid biosynthesis in the ovary. The presence of a single nucleotide polymorphism (T-->C) in the 5'-promoter region of the gene creates a new recognition site for the restriction enzyme MspA1 producing a mutant allele (A2), which affects circulating estrogen levels. In this study, we compared the frequency of the CYP17 MspA1 polymorphism in two different ethnic populations. DNA was obtained from (1) 94 women with revised American Fertility Society (rAFS) stage III-IV endometriosis and 97 male blood donors in the UK, and (2) 130 women with rAFS stage III-IV endometriosis and 179 female newborn infants in Japan. No significant differences in allele or genotype frequencies were seen in either population. The genotype distribution in the UK population was 33/94 [35.1%] (cases) and 39/97 [40.2%] (controls) for A1A1 (homozygous wild-type); 43/94 [45.7%] (cases) and 44/97 [45.4%] (controls) for A1A2; and 18/94 [19.1%] (cases) and 14/97 [14.4%] (controls) for A2A2. The genotype distribution in the Japanese population was 31/130 [23.9%] (cases) and 57/179 [31.8%] (controls) for A1A1; 73/130 [56.2%] (cases) and 89/179 [49.7%] (controls) for A1A2; and 26/130 [20.0%] (cases) and 33/179 [18.4%] (controls) for A2A2. The CYP17 MspA1 polymorphism is probably not associated with endometriosis in either the UK or the Japanese population.

Asian People↗
PubMed2003

CCR5 and CCR2 gene polymorphisms in hypertensive patients.

Essential hypertension is a complex trait under polygenic control. Evidences suggests immune system involvement during pathogenesis. CC-chemokine receptor (CCR)5 and CCR2 are characterised by gene polymorphism. Variant alleles are derived from a deletion in the CCR5 gene (CCR5delta32) and a substitution mutation at the CCR2 locus (CCR264I). CCR polymorphic forms have been studied extensively as invasion cofactors for HIV-1, but they have also been implicated in immuno-related disorders. Here, we evaluate the allelic distribution of CCR5 and CCR2 genes in essential hypertension in a case-control study. Genotype frequency in a group of essential hypertensive patients (stage I-II; n=120) and a group of unrelated, healthy Caucasian subjects (n=340) is compared. CCR gene polymorphism is analysed by polymerase chain reaction and restriction enzyme digestion. A statistically significant difference was observed for CCR5 and CCR2 mutant alleles in essential hypertensive patients, compared with the controls (P=0.004 and P=0.003, respectively). CCR5delta32 and CCR264I alleles showed a 0.096 and 0.10 frequency among cases. To date, a role for the immune system in hypertension has not been clarified, nor has the predictive value of CCR polymorphisms.

Alleles↗
PubMed2004

Evaluation of the ARMD1 locus on 1q25-31 in patients with age-related maculopathy: genetic variation in laminin genes and in exon 104 of HEMICENTIN-1.

The age-related maculopathy (ARM) genetics program at Columbia University utilizes comprehensive genetic analysis of candidate genes in large case-control studies to determine genotypes associated with the ARM complex trait. Genes encoding laminins, a class of extracellular matrix proteins, represent attractive candidates for two reasons. First, the presence of laminins in the basal lamina of the retinal pigment epithelium (RPE), Bruch's membrane, and choriocapillaris suggests a possible role in the pathophysiology of ARM. Second, three laminin genes, LAMC1, LAMC2, and LAMB3, are located in the 1q25-31 region, within the previously mapped ARMD1 locus. The entire open reading frame of the three laminin genes was screened for variants by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing in at least 92, and up to 368 ARM patients and matched unaffected controls. Sixty-nine sequence variants were detected in the 69 exons of the LAMC1, LAMC2, and LAMB3 genes. Screening of exon 104 of the recently proposed ARMD1 gene, HEMICENTIN-1, residing in the 1q25-31 locus, did not detect the suggested causal variant, Q5345R, in 632 study subjects. Overall, we did not find statistically significant differences in the frequency of variants between ARM-affected individuals and age-matched controls. Four rare, non-synonymous, variants were detected in single cases of ARM patients. Our data on relatively limited numbers of study subjects do not suggest a significant role for genetic variation in the three laminin genes and in exon 104 of HEMICENTIN-1 in predisposing individuals to ARM. However, as in many instances in similar studies, involvement of rare amino acid-changing variants in a fraction of ARM cannot be ruled out.

Aged↗
PubMed1999

The genetic epidemiology of smoking.

The enormous personal and societal costs associated with tobacco are well documented. Unlike the large literature on the prevalence and consequences of tobacco use, there are fewer data on the genetic epidemiology (family, adoption, and twin studies) of tobacco use initiation and nicotine dependence. This review is limited to smoking as this has been the overwhelming focus of the literature. The data from family, adoption, and twin studies strongly support a substantial genetic influence on the initiation and maintenance of smoking. The literature supports the following hypothesis of the development of nicotine dependence. Smoking initiation is the obligatory first step. Liability to initiating smoking results from genetic influences (approximately 60%) and from environmental influences shared by members of a twin pair (approximately 20%) and that are specific to an individual (approximately 20%). The impact of shared environment may be particularly pronounced in mid-adolescence when many begin smoking. A subset of those who initiate smoking progress to nicotine dependence: genetic factors appear to be more prominent in this transition (approximately 70%) and shared environmental influences appear to be negligible. The genetic factors that predispose to smoking initiation appear to overlap substantially but not completely with those for nicotine dependence. The substantial impact of genetic factors on smoking behavior has engendered molecular genetic studies of this complex trait. We need to localize and identify the specific genes involved-which genes predispose to smoking initiation and which to nicotine dependence? If such genes are located, by what biological mechanisms do they operate? Do these genes act directly by altering or enhancing the pharmacokinetics or pharmacodynamics of nicotine? Do they act indirectly via personality or depression? Are these genes specific to nicotine or are they also involved in dependence on other licit and illicit psychoactive substances? Are there different mechanisms in men and women? What are the specific environmental factors and how do genes and environment interact?

Adoption↗
PubMed1999

Phenotypic selection: a successful strategy to fix major genes of hypertension.

Hypertension is dominantly inherited in cross hybrids between hypertensive SHR/Mol and normotensive BB/OK rats. We used these cross hybrids for repeated backcrossing of selected hypertensive animals onto normotensive BB/OK rats to fix high blood pressure and to generate a hypertensive and diabetic BB/OK rat subline. After 8 backcrosses, the backcross parents were genetically analysed with the aid of 259 microsatellite markers to identify SHR genes causing blood pressure of 177 +/- 10 mmHg in this BB/OK rat subline. Loci on chromosomes 1, 14 and 18 showed longest heterozygosity. These loci might contain major genes of the SHR rat causing hypertension in this BB/OK rat subline. This classical strategy seems to be most suitable to fix major genes of hypertension in particular and complex traits in general and therefore to generate new animal models.

Animals↗