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PubMed2004

Effects on phenotypic variability of directional selection arising through genetic differences in residual variability.

In standard models of quantitative traits, genotypes are assumed to differ in mean but not variance of the trait. Here we consider directional selection for a quantitative trait for which genotypes also confer differences in variability, viewed either as differences in residual phenotypic variance when individual loci are concerned or as differences in environmental variability when the whole genome is considered. At an individual locus with additive effects, the selective value of the increasing allele is given by ia/sigma + 1/2 ixb/sigma2, where i is the selection intensity, x is the standardized truncation point, sigma2 is the phenotypic variance, and a/sigma and b/sigma2 are the standardized differences in mean and variance respectively between genotypes at the locus. Assuming additive effects on mean and variance across loci, the response to selection on phenotype in mean is isigma2(Am)/sigma + 1/2 ixcov(Amv)/sigma2 and in variance is icov(Amv)/sigma + 1/2 ixsigma2(Av)/sigma2, where sigma2(Am) is the (usual) additive genetic variance of effects of genes on the mean, sigma2(Av) is the corresponding additive genetic variance of their effects on the variance, and cov(Amv) is the additive genetic covariance of their effects. Changes in variance also have to be corrected for any changes due to gene frequency change and for the Bulmer effect, and relevant formulae are given. It is shown that effects on variance are likely to be greatest when selection is intense and when selection is on individual phenotype or within family deviation rather than on family mean performance. The evidence for and implications of such variability in variance are discussed.

Data Interpretation, Statistical↗
PubMed2002

Exploratory factor analysis in behavior genetics research: factor recovery with small sample sizes.

Results of a Monte Carlo study of exploratory factor analysis demonstrate that in studies characterized by low sample sizes the population factor structure can be adequately recovered if communalities are high, model error is low, and few factors are retained. These are conditions likely to be encountered in behavior genetics research involving mean scores obtained from sets of inbred strains. Such studies are often characterized by a large number of measured variables relative to the number of strains used, highly reliable data, and high levels of communality. This combination of characteristics has special consequences for conducting factor analysis and interpreting results. Given that limitations on sample size are often unavoidable, it is recommended that researchers limit the number of expected factors as much as possible.

Animals↗
PubMed2003

Searching for statistically significant regulatory modules.

MOTIVATION: The regulatory machinery controlling gene expression is complex, frequently requiring multiple, simultaneous DNA-protein interactions. The rate at which a gene is transcribed may depend upon the presence or absence of a collection of transcription factors bound to the DNA near the gene. Locating transcription factor binding sites in genomic DNA is difficult because the individual sites are small and tend to occur frequently by chance. True binding sites may be identified by their tendency to occur in clusters, sometimes known as regulatory modules. RESULTS: We describe an algorithm for detecting occurrences of regulatory modules in genomic DNA. The algorithm, called mcast, takes as input a DNA database and a collection of binding site motifs that are known to operate in concert. mcast uses a motif-based hidden Markov model with several novel features. The model incorporates motif-specific p-values, thereby allowing scores from motifs of different widths and specificities to be compared directly. The p-value scoring also allows mcast to only accept motif occurrences with significance below a user-specified threshold, while still assigning better scores to motif occurrences with lower p-values. mcast can search long DNA sequences, modeling length distributions between motifs within a regulatory module, but ignoring length distributions between modules. The algorithm produces a list of predicted regulatory modules, ranked by E-value. We validate the algorithm using simulated data as well as real data sets from fruitfly and human. AVAILABILITY: http://meme.sdsc.edu/MCAST/paper

Algorithms↗
PubMed2003

Bayesian analysis of a previously published genome screen for panic disorder reveals new and compelling evidence for linkage to chromosome 7.

This article presents a Bayesian re-analysis of a linkage study of panic disorder Crowe et al. [2001: Am J Med Genet (Neuropsychiatr Genet) 105:105-109]. In the initial analysis Crowe et al. failed to find compelling evidence for linkage based on either LOD scores or NPL scores anywhere in the genome. The maximum LOD score was 2.23 on chromosome 7 at marker D7S2846 (57.79 cM according to Marshfield). Over the past several years we have been developing a Bayesian alternative approach to linkage analysis, based on direct measurement of the posterior probability of linkage (PPL), and have shown elsewhere that this approach has several advantages over the available alternatives for mapping complex-disease genes Vieland [1998: Am J Med Genet 63:947-954]; Wang et al. [1999: Genet Epidemiol 17(Suppl 1):S749-S754]; Wang et al. [2000: Ann Hum Genet 64:533-553]; and Vieland et al. [2001: Hum Hered 51:199-208]. One limitation of this approach in previous applications has been that it required the investigator to specify a fixed genetic model for the trait. We employ a new implementation of the PPL that treats the unknown trait model as a vector of nuisance parameters, which is integrated out of the PPL equation. When we apply this new model-integrated version of the PPL to the data of Crowe et al. [2001: Am J Med Genet (Neuropsychiatr Genet) 105:105-109] we obtain much clearer evidence than previously reported for a locus on chromosome 7, with an 80% probability of linkage to marker D7S521. A second location is also identified on chromosome 16 near marker D16S749 (PPL = 24%). The results for the remainder of the genome are consistently low. The two loci identified here are also supported by independent evidence from other studies.

Bayes Theorem↗
PubMed2002

Quantitative structure/property relationship analysis on aqueous solubility using genetic algorithm-combined partial least squares method.

The present study was initiated to generate a model of predicting aqueous solubility of substances from their molecular structure. For 211 drugs or drug-like compounds, their topological indices were calculated by Molconn-Z software. The optimal subset of the descriptors for the prediction of aqueous solubility was determined by genetic algorithm in combination with partial least squares (PLS) method. Thirty-four descriptors were selected by this method. Using 29 of the descriptors selected, of which the scaled PLS coefficient was significant, the cross-validated predictive q2 was 0.785 with 19 principal components that was the optimal and the standard error of prediction was 0.676. Thus, it is suggested that the model obtained would exhibit a good performance in predicting the aqueous solubility of compounds.

Algorithms↗
PubMedDate not supplied

DetSel 1.0: a computer program to detect markers responding to selection.

Estimating population parameters from polymorphism frequency data requires neutral genetic markers. Any departure from neutrality may invalidate the inferences drawn from such analyses. We recently discussed the possibility of identifying markers that show deviation from neutral expectations in pairwise comparisons of diverging populations. We are now releasing a user-friendly software package that implements all the necessary steps to identify the signature of selection among molecular markers in a set of polymorphism data. This software can be downloaded free of charge at http://www.univ-montp2.fr/~genetix/detsel/detsel.html.

Data Interpretation, Statistical↗
PubMed1983

Genetic counseling for skin diseases. A statistical analysis of 182 cases.

A statistical study was carried out on 182 cases who seeked out genetic counseling about skin diseases. The size of the latent demand for the counseling was assessed to be as much as 3.0% of the outpatients. Most clients were in their twenties. A representative consultand was the patient's child or sibling. The main diseases in question were cleft lip and palate (16%), nevus pigmentosus (12%), Recklinghausen's diseases (8%) and psoriasis (8%). Estimation of the recurrence risk was impossible in 3%, approximate in 54% and accurate in 43%. This defective estimation is due to the insufficiency of the available genetic data, e.g. carrier frequency, penetrance rate, contraction rate by age, etc. The high-risk cases were found to be 36%. In 9 cases (5% of all the counselings) the client decided to avoid reproduction. In 30 cases (16%), the clients asked for counseling after having conceived or given birth to a consultand. They were thought to be too late from the standpoint of prophylaxis of inherited diseases. Our conclusion is that genetic counseling offers some measure of disease prevention and therefore will become an essential branch or dermatology in the future.

Adolescent↗
PubMed2003

Informativeness of genetic markers for inference of ancestry.

Inference of individual ancestry is useful in various applications, such as admixture mapping and structured-association mapping. Using information-theoretic principles, we introduce a general measure, the informativeness for assignment (I(n)), applicable to any number of potential source populations, for determining the amount of information that multiallelic markers provide about individual ancestry. In a worldwide human microsatellite data set, we identify markers of highest informativeness for inference of regional ancestry and for inference of population ancestry within regions; these markers, which are listed in online-only tables in our article, can be useful both in testing for and in controlling the influence of ancestry on case-control genetic association studies. Markers that are informative in one collection of source populations are generally informative in others. Informativeness of random dinucleotides, the most informative class of microsatellites, is five to eight times that of random single-nucleotide polymorphisms (SNPs), but 2%-12% of SNPs have higher informativeness than the median for dinucleotides. Our results can aid in decisions about the type, quantity, and specific choice of markers for use in studies of ancestry.

Algorithms↗
PubMed2002

Distinguishing between selection and population expansion in an experimental lineage of bacteriophage T7.

Experimental evolution of short-lived organisms offers the opportunity to study the dynamics of polymorphism over time in a controlled environment. Here, we characterize DNA polymorphism data over time for four genes in bacteriophage T7. Our experiment ran for 2500 generations and populations were sampled after 500, 2000, and 2500 generations. We detect positive selection, purifying ("negative") selection, and population expansion in our experiment. We also present a statistical test that is able to distinguish demographic from selective events, processes that are hard to identify individually because both often produce an excess of rare mutations. Our "heterogeneity test" modifies common statistics measuring the frequency spectrum of polymorphism (e.g., Fu and Li's D) by looking for processes producing different patterns on nonsynonymous and synonymous mutations. Test results agree with the known conditions of the experiment, and we are therefore confident that this test offers a tool to evaluate natural populations. Our results suggest that instances of segregating deleterious mutations may be common, but as yet undetected, in nature.

Bacteriophage T7↗
PubMed2001

Genetic consequences of population decline in the European otter (Lutra lutra): an assessment of microsatellite DNA variation in Danish otters from 1883 to 1993.

The European otter (Lutra lutra) was common in Denmark until the 1960s, but its present distribution encompasses only a minor part of the country. The aim of this study was to assess whether the recent population decline has resulted in loss of genetic variability and to gain further insight into the dynamics of the population decline. This was done by analysing microsatellite DNA variation in contemporary and historical samples, the latter encompassing DNA samples extracted from museum specimens covering a time-span from the 1880s to the 1960s. Tests for differences in expected heterozygosity and the numbers of alleles in contemporary versus historical samples and a test for detecting population bottlenecks provided few indications of a recent bottleneck and loss of variability. However, a procedure for detecting population expansions and declines, based on the genealogical history of microsatellite alleles, suggested that a drastic long-term population decline has taken place, which could have started more than 2000 years ago, possibly due to ancient anthropogenic pressure. Finally, assignment tests and pairwise F(ST) values suggested weak but statistically significant genetic differentiation between the extant population and historical samples of otters from other regions in Denmark, more likely reflecting differentiation among original populations rather than recent drift.

Animals↗
PubMed2005

Use of AFLP markers in surveys of plant diversity.

The collection of the available range of genetic variation in a gene pool, usually made of the cultivated species and their undomesticated relatives, is referred to as a germplasm collection. Increasingly, discriminator data generated using molecular genetic markers are either complementing or completely replacing those from morphological characters (known as descriptors) in surveys of genetic diversity. In addition to highlighting the state of knowledge on the specific applications of amplified fragment length polymorphisms (AFLPs) in surveys of plant genetic diversity, an attempt at a brief description and comparison of the different marker systems in use has also been made in this chapter. We have also attempted a description of the AFLP marker technology, its strengths and weaknesses, methodologies for generating reliable AFLP data, available resources (hardware, software, consumables); the kinds of questions for which AFLP data provide valid answers; and data management options. This chapter also highlights salient considerations that would guide decisions on the adoption of molecular marker assays.

DNA, Complementary↗
PubMed2004

Assessing whether an allele can account in part for a linkage signal: the Genotype-IBD Sharing Test (GIST).

To fine map genes, investigators often test for disease-marker association in chromosomal regions with evidence for linkage. Given a marker allele tentatively associated with disease, one would ask if this allele, or one in linkage disequilibrium (LD) with it, could account in part for the observed linkage signal. This question can be addressed by determining if families selected on the basis of the presence of the tentatively associated allele show stronger evidence of linkage as measured by increased allele sharing identical by descent (IBD) by affected family members. However, common selection strategies can be biased for or against linkage in the marker region, even given no disease-marker association. We define unbiased selection schemes and extend the definition to allow weighted selection on the basis of all genotyped family members. For affected-sibship data, we describe three genotype-based weight variables, corresponding to dominant, recessive, and additive models. We then introduce a test for association of a family weight variable with excess IBD sharing. This test allows us to determine if the linkage signal in a region can be attributed in part to the presence of a marker allele, either because of direct involvement in disease etiology or because of LD with a predisposing genetic variant. For samples of 500 affected sib pairs, the tests are powerful in detection of genotype-IBD sharing association, even for disease models with sib relative risk as low as lambda S=1.1, or when evidence for linkage is absent because of sampling variation. This makes our method a new tool for detecting linkage as well as association, especially in regions harboring a candidate gene. We have implemented these methods in the software package GIST (Genotype-IBD Sharing Test).

Computer Simulation↗
PubMed1996

[Variation of a complex of wing characters in natural populations of Drosophila melanogaster].

Genetic variation of a set of morphometric wing characters in natural populations of Drosophila melanogaster from different regions of the former USSR was examined. It was shown that the proximal-distal ratio of characters of the posterior compartment significantly differs in southern and northern populations. These results suggest the operation of natural selection for wing shape in natural populations of Drosophila. Contributions of different characters into the geographic differentiation is considered.

Animals↗
PubMedDate not supplied

Genetic alterations of INK4alpha/ARF locus and p53 in human hepatocellular carcinoma.

The INK4alpha/ARF locus encodes p14(ARF) and p16(INK4alpha) , that function to arrest the cell cycle through the p53 and RB pathways, respectively. Genetic alterations of p14ARF and their relationship with p16(INK4a) or p53 inactivation have not been characterized in hepatocellular carcinoma (HCC). We examined 40 pairs of HCCs/noncancerous liver tissues for homozygous deletions (HD), methylation and mutations of the INK4a/ARF locus and for mutations of p53, and analyzed their clinicopathological correlation. p16(INK4a), p53 and p14(ARF) were inactivated in 62.5% (25 out of 40), 42.5% (17 out of 40) and 20% (8 out of 40) of HCCs, respectively. Inactivation of p14(ARF) was always associated with the concomitant inactivation of p16(INK4a) and occurred more frequently in hepatitis C virus (HCV)-associated HCC (p=0.042). Inactivation of p16INK4a) occurred more frequently in older patients (p=0.0027. The predominant mechanism of inactivation of p14(ARF) was homozygous deletion (7 out of 8), while that of p16(INK4a) was methylation (21 out of 25). Although statistically insignificant, genetic alterations of p14(ARF) tended to occur in tumors with wild-type p53. Genetic alterations of the INK4alpha/ARF locus could occur in small HCCs. In contrast, p53 mutations occurred more frequently in advanced HCCs (p=0.041). Inactivation of either p14(ARF)/p53 or p16(INK4a) occurred in 80% (32 out of 40) and concomitant disruption of both pathways occurred in 40% (16 out of 40) of HCCs, respectively. These results suggest that p14(ARF), p16(INK4a) and p53 are differentially disrupted through distinct molecular mechanisms at different stages in HCC and that p14(ARF) and p53 appear to function in the same tumor suppression pathway in HCC

Adult↗
PubMed2004

Genetic design of feature spaces for pattern classifiers.

Functional piecewise approximation seeks data representation that is compact, highly simplified and meaningful. This study presents a genetic algorithm (GA)-based approach for computing a piecewise polynomial representation of functions, with the focus being on piecewise linear approximation in an application of biomedical spectral data. The area of piecewise linear approximation has been researched in the past four decades approximately, and the method presented here is compared with another well-known approach. The expansion of this method to piecewise polynomial representation is shown to be straightforward. Finally, the application of this method as a feature extraction method for classification of a dataset of feature vectors, specifically biomedical spectra, is demonstrated.

Algorithms↗
PubMed2006

Aldosterone synthase (CYP11B2) -344T/C polymorphism is not associated with the initiation and progression of diabetic nephropathy in Caucasian Type 1 diabetic patients.

AIMS: Aldosterone is one of the main effectors of the renin-angiotensin-aldosterone system regulating blood pressure. Previous studies have shown that the aldosterone synthase promoter polymorphism -344T/C influences aldosterone levels and is associated with hypertension, a risk factor for the initiation and progression of diabetic nephropathy. Therefore, we investigated whether the -344T/C polymorphism is associated with the development and progression of diabetic nephropathy in Type 1 diabetes mellitus. METHODS: The -344T/C polymorphism was determined using standard PCR techniques in 422 Type 1 diabetic patients with overt diabetic nephropathy [mean age 43 years (SD 11)], and in 479 patients with persistent normoalbuminuria and long-standing Type 1 diabetes [age 47 years (SD 12), duration of diabetes 27 years (SD 10)]. Furthermore, we genotyped 163 Type 1 diabetic patients with overt diabetic nephropathy treated with angiotensis-converting enzyme inhibitors (ACE-I). These patients were followed for a median of 6 years (range 3-14), with nine measurements (range 3-29) of glomerular filtration rate (GFR), and had a decline in GFR of 3.1 (-3.2; 23.7) ml/min per year. RESULTS: There was no significant difference between cases and controls in either genotype distributions (cases TT 0.33, TC 0.48, CC 0.19; controls TT 0.32, TC 0.48, CC 0.20) or allele frequencies (cases T/C 0.57/0.43; controls T/C 0.56/0.44). Furthermore, a genotype-phenotype interaction analysis in the normoalbuminuric patients revealed no differences in sex distribution, age, duration of diabetes, blood pressure, HbA(1c,) or urinary albumin excretion rate across genotypes. In the observational follow-up study, the rate of decline in GFR did not differ between groups of patients with different -344T/C genotype (P = 0.41). However, the T-allele made a statistically significant contribution to both systolic and diastolic pressure during follow-up (P = 0.006 and 0.032, respectively). CONCLUSIONS: The -344T/C polymorphism of the aldosterone synthase gene is not associated with initiation or progression of diabetic nephropathy in Caucasian Type 1 diabetic patients, but modulates blood pressure variation.

Adult↗
PubMed2005

The IgA nephropathy Biobank. An important starting point for the genetic dissection of a complex trait.

BACKGROUND: IgA nephropathy (IgAN) or Berger's disease, is the most common glomerulonephritis in the world diagnosed in renal biopsied patients. The involvement of genetic factors in the pathogenesis of the IgAN is evidenced by ethnic and geographic variations in prevalence, familial clustering in isolated populations, familial aggregation and by the identification of a genetic linkage to locus IGAN1 mapped on 6q22-23. This study seems to imply a single major locus, but the hypothesis of multiple interacting loci or genetic heterogeneity cannot be ruled out. The organization of a multi-centre Biobank for the collection of biological samples and clinical data from IgAN patients and relatives is an important starting point for the identification of the disease susceptibility genes. DESCRIPTION: The IgAN Consortium organized a Biobank, recruiting IgAN patients and relatives following a common protocol. A website was constructed to allow scientific information to be shared between partners and to divulge obtained data (URL: http://www.igan.net). The electronic database, the core of the website includes data concerning the subjects enrolled. A search page gives open access to the database and allows groups of patients to be selected according to their clinical characteristics. DNA samples of IgAN patients and relatives belonging to 72 multiplex extended pedigrees were collected. Moreover, 159 trios (sons/daughters affected and healthy parents), 1068 patients with biopsy-proven IgAN and 1040 healthy subjects were included in the IgAN Consortium Biobank. Some valuable and statistically productive genetic studies have been launched within the 5th Framework Programme 1998-2002 of the European project No. QLG1-2000-00464 and preliminary data have been published in "Technology Marketplace" website: http://www.cordis.lu/marketplace. CONCLUSION: The first world IgAN Biobank with a readily accessible database has been constituted. The knowledge gained from the study of Mendelian diseases has shown that the genetic dissection of a complex trait is more powerful when combined linkage-based, association-based, and sequence-based approaches are performed. This Biobank continuously expanded contains a sample size of adequately matched IgAN patients and healthy subjects, extended multiplex pedigrees, parent-child trios, thus permitting the combined genetic approaches with collaborative studies.

Databases, Nucleic Acid↗
PubMedDate not supplied

The effect of using approximate gametic variance covariance matrices on marker assisted selection by BLUP.

Under additive inheritance, the Henderson mixed model equations (HMME) provide an efficient approach to obtaining genetic evaluations by marker assisted best linear unbiased prediction (MABLUP) given pedigree relationships, trait and marker data. For large pedigrees with many missing markers, however, it is not feasible to calculate the exact gametic variance covariance matrix required to construct HMME. The objective of this study was to investigate the consequences of using approximate gametic variance covariance matrices on response to selection by MABLUP. Two methods were used to generate approximate variance covariance matrices. The first method (Method A) completely discards the marker information for individuals with an unknown linkage phase between two flanking markers. The second method (Method B) makes use of the marker information at only the most polymorphic marker locus for individuals with an unknown linkage phase. Data sets were simulated with and without missing marker data for flanking markers with 2, 4, 6, 8 or 12 alleles. Several missing marker data patterns were considered. The genetic variability explained by marked quantitative trait loci (MQTL) was modeled with one or two MQTL of equal effect. Response to selection by MABLUP using Method A or Method B were compared with that obtained by MABLUP using the exact genetic variance covariance matrix, which was estimated using 15,000 samples from the conditional distribution of genotypic values given the observed marker data. For the simulated conditions, the superiority of MABLUP over BLUP based only on pedigree relationships and trait data varied between 0.1% and 13.5% for Method A, between 1.7% and 23.8% for Method B, and between 7.6% and 28.9% for the exact method. The relative performance of the methods under investigation was not affected by the number of MQTL in the model.

Chromosome Mapping↗