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Genetic models with reduced penetrance related to the Y chromosome.

Classical statistical genetics models of a quantitative trait depending on an autosomal gene indicate that father-to-daughter and mother-to-son correlations should be the same. If phenotypes are not sex-dependent, father-to-son and mother-to-daughter correlations also share this common value. On the other hand, if the gene is sex-linked, then the father-to-son correlation is zero. Such models do not explain genetic variation in pulmonary artery pressure (PAP) of cattle--important because cattle with high PAP are known to develop brisket disease, pulmonary heart disease, and congestive heart failure when taken to high altitudes. Data on 966 calves at a ranch in Colorado showed positive correlation (0.2) between sire PAP and male calf PAP but slightly negative correlation (-0.01) between sire PAP and female calf PAP; the dam-to-male calf and dam-to-female calf correlations are both about 0.1. The model presented here postulates an autosomal gene with reduced penetrance (i.e., the trait may remain at a normal level even when the genotype suggests abnormality) and that, in males, the rate of penetrance is related to an abnormality in the Y chromosome and is therefore passed on from father to son. Then under plausible selective breeding assumptions, the pairwise correlation between fathers and daughters can become zero or negative. Explicit formulas are computed for the model covariances, and numerical computations indicate that plausible parameter values can be chosen for the model.

Altitude↗

A multivariate analysis of neuroanatomic relationships in a genetically informative pediatric sample.

An important component of brain mapping is an understanding of the relationships between neuroanatomic structures, as well as the nature of shared causal factors. Prior twin studies have demonstrated that much of individual differences in human anatomy are caused by genetic differences, but information is limited on whether different structures share common genetic factors. We performed a multivariate statistical genetic analysis on volumetric MRI measures (cerebrum, cerebellum, lateral ventricles, corpus callosum, thalamus, and basal ganglia) from a pediatric sample of 326 twins and 158 singletons. Our results suggest that the great majority of variability in cerebrum, cerebellum, thalamus and basal ganglia is determined by a single genetic factor. Though most (75%) of the variability in corpus callosum was explained by additive genetic effects these were largely independent of other structures. We also observed relatively small but significant environmental effects common to multiple neuroanatomic regions, particularly between thalamus, basal ganglia, and lateral ventricles. These findings are concordant with prior volumetric twin studies and support radial models of brain evolution.

Adolescent↗

A review of the 'Statistical Analysis for Genetic Epidemiology' (S.A.G.E.) software package.

The 'Statistical Analysis for Genetic Epidemiology' (S.A.G.E.) software package is an integrated, comprehensive package of computer programs designed to perform many of the different analyses required in the study of genetic epidemiology. It offers a graphical user interface for most platforms and, unlike many programs available in the public domain, is flexible in both receiving many types of input files and in allowing the user to choose among output files. All of the programs accept the same data files and together provide the means to perform familial correlation, segregation, linkage and association analyses, as well as many of the ancillary analyses that help achieve these goals. Many, but not all, of the same or similar analyses can be performed (with more difficulty) using publicly available freeware. The primary limitations of S.A.G.E. at present are the lack of software for estimating haplotypes or for identifying probable double recombinants in linkage analysis. S.A.G.E. is continually being extended and upgraded, however, with automatic downloading of the latest version always available to users.

Databases, Genetic↗

Estimates of genetic variance in an F2 maize population.

Maize (Zea mays L.) breeders have used several genetic-statistical models to study the inheritance of quantitative traits. These models provide information on the importance of additive, dominance, and epistatic genetic variance for a quantitative trait. Estimates of genetic variances are useful in understanding heterosis and determining the response to selection. The objectives of this study were to estimate additive and dominance genetic variances and the average level of dominance for an F2 population derived from the B73 x Mo17 hybrid and use weighted least squares to determine the importance of digenic epistatic variances relative to additive and dominance variances. Genetic variances were estimated using Design III and weighted least squares analyses. Both analyses determined that dominance variance was more important than additive variance for grain yield. For other traits, additive genetic variance was more important than dominance variance. The average level of dominance suggests either overdominant gene effects were present for grain yield or pseudo-overdominance because of linkage disequilibrium in the F2 population. Epistatic variances generally were not significantly different from zero and therefore were relatively less important than additive and dominance variances. For several traits estimates of additive by additive epistatic variance decreased estimates of additive genetic variance, but generally the decrease in additive genetic variance was not significant.

Genetic Variation↗

Genetic dissection of proteinuria in the Sabra rat.

The pathophysiology underlying proteinuria remains incompletely understood and warrants further research. We currently initiated the investigation of the genetic basis of proteinuria in the Sabra rat, a model of salt susceptibility that we showed previously to be also a model of spontaneous proteinuria that is unrelated to salt loading or development of hypertension. We applied the total genome scan strategy in 75 F2 male animals derived from a cross between SBH/y, which are prone to develop proteinuria, and SBN/y, which are relatively resistant to the development of proteinuria. Animals were subjected to uninephrectomy (UNx) to accelerate the development of proteinuria and were provided chow with a low salt content, thus avoiding the development of hypertension. Urinary protein excretion was monitored before UNx and monthly thereafter for 8 mo. The genotype of F2 was determined with microsatellite markers. The data were analyzed for cosegregation by ANOVA and for genetic linkage with a novel multifaceted statistical genetic paradigm. We detected three proteinuria-related quantitative trait loci (QTL) that were associated with the salt sensitivity (H) alleles from SBH/y: SUP2, SUP17, and SUP20 on rat chromosomes (Chr) 2, 17, and 20. We detected an additional QTL on Chr 3, SUP3, that was associated with the salt resistance (N) alleles from SBN/y. A temporal effect was noted: QTL SUP2 and SUP17 surfaced at months 7-8, QTL SUP20 at months 6-8, and QTL SUP3 at months 5-6. The QTL emerging from this study lead us a step closer to identifying the genes associated with and elucidating the pathophysiology of proteinuria.

Animals↗

Are genetically informed designs genetically informative? Comment on McGue, Elkins, Walden, and Iacono (2005) and quantitative behavioral genetics.

M. McGue, I. Elkins, B. Walden, and W. G. Iacono presented the findings from a twin study examining the relative contributions of genetic and environmental factors to the developmental trajectories of parent-adolescent relationships. From a behavioral genetics perspective, this study is well conceptualized, is well implemented, and raises some interesting developmental questions. Yet, the classic twin methodology and heritability estimates obfuscate the dynamic gene-ecology transactions that underlie these social developmental trajectories. There is a growing divide between the findings of quantitative behavioral genetics, with its foundational estimate of a statistical genetic influence, and developmental molecular genetics. This comment provides a brief overview of this divide and its implications for the findings of McGue et al. as well as quantitative behavioral genetics more broadly.

Adolescent↗

The distribution of some polymorphisms in Italy.

A wide data collection on blood group gene frequencies in Italian regions and provinces is presented. This report is the result of a joint collaboration of human geneticists and forensic haematologists started in 1979 and updates a previous work by the same group. The following genetic polymorphisms have been examined: red-cell antigens (ABO, FY, Kell, Kidd, Lewis, Lutheran, MNSs, P, Rhesus), red-cell enzymes (ACP1, ADA, AK1, ESD, GLO1, GPT, PGD, PGM1), plasma proteins (BF, C3, GC, HP, IGK, PI, TF). Data have been classified according to genetic systems, Italian regions and provinces. Gene frequencies were estimated by the maximum likelihood method. The goodness of fit to Hardy-Weinberg proportions has been evaluated by the likelihood ratio statistics. Genetic heterogeneity of provinces and regions is reported.

Blood Group Antigens↗

Genetic epidemiology: a review of the statistical basis.

Genetic epidemiology is the analysis of the familial distributions of traits, with a view to understanding any possible genetic basis; the fundamentals of this area are reviewed. The terminology of genetic models is fully described, since it is this wealth of terminology which can make it difficult for a statistician to enter the area. The statistical approaches to the analysis of data on sets of interrelated individuals are then discussed, and resulting problems of sampling design and analysis are considered.

Biometry↗

Comparison of biochemical polymorphisms and short tandem repeat (STR) DNA markers for paternity testing in rhesus monkeys (Macaca mulatta).

Genetic markers are indispensable for molecular and statistical genetic research involving nonhuman primates. Genetic markers must be used to ascertain parentage and to confirm the accuracy of pedigrees based solely on housing or demographic records; otherwise, the results of pedigree, linkage, or quantitative genetic analyses may be unreliable. Until recently, most genetic markers used in nonhuman primates were plasma proteins or isozyme polymorphisms, which were required in large numbers, because levels of genetic variation revealed by these markers were rather low. We compared the newer, PCR-amplified short tandem repeat markers (STRs) with a panel of classical biochemical polymorphic markers, for paternity determination among captive-bred rhesus monkeys. The STR markers exhibited an average genetic diversity of 64% and an expected paternity exclusion probability of 0.443. Both of these were greater than the average 54.5% genetic diversity and 0.298 exclusion probability exhibited by the biochemical markers. The STRs were much more efficient than the biochemical markers for parentage determination, since they required only half the amount of genetic typing data to resolve an average paternity case. Thus, the results of applying these two classes of genetic markers in paternity tests were somewhat different than expected on the basis of theoretical exclusion probabilities. These differences were probably due to inbreeding and other genetic differences among breeding colonies. Because they are more informative and provide rapid and efficient genetic data, STRs are now the method of choice for parentage determination and pedigree corroboration among nonhuman primates.

Animals↗

Biochemical genetic variability in brown hares (Lepus europaeus) from Greece.

Allozyme variability of 91 brown hares (Lepus europaeus) from seven regions in Greece was compared to existing data of Bulgarian populations to test the hypothesis of the occurrence ofspecific alleles in Greece, likely stemming from an isolated Late Pleistocene refugial population in the southern Balkans. This hypothesis is particularly suggested by some subfossil Late Pleistocene hare remains in Greece and the reported high mtDNA diversity in Greek hares. Allozymic diversity could be higher in Greek hares than in hares from neighboring regions as a result of the accumulation of variants in a long-lasting Pleistocene refugium. Conversely, Greek hares could exhibit reduced genetic diversity because of long-lasting low effective population sizes during the Late Glacial Maximum and a lower chance of postglacial gene flow from other populations into this rather marginal part in the southern Balkans. Horizontal starch gel electrophoresis of proteins from 35 loci revealed three alleles (Es-1(-162), Pep-2(114), Mpi(88)) at low frequencies, which were not found in Bulgarian or any other brown hare population. In contrast, some alleles from the populations from Bulgaria and other regions of Europe were absent in the Greek samples. Population genetic statistics indicated only a slight tendency of increased gene pool diversity in Greek hares, little substructuring in Greek and Bulgarian populations, respectively, as well as an only slightly lower level of gene flow between the two neighboring regions, as compared to the gene flow within each region. The results conform to the hypothesis of a Late Pleistocene refugial population in the southern Balkans, with some few specific nuclear gene pool characteristics, but little effect on the overall genetic differentiation between Greek and Bulgarian hares.

Alleles↗

Genetic diversity among alfalfa (Medicago sativa) cultivars coming from a breeding program, using SSR markers.

Alfalfa (Medicago sativa) is an autotetraploid, allogamous and heterozygous species whose cultivars are synthetic populations. The breeders apply selection pressure for some agronomic traits within a breeding pool to increase the frequency of favorable individuals. The objective of this study was to investigate the differentiation level among seven cultivars originating from one breeding program, and between these cultivars and the breeding pool, with eight SSR markers. These highly polymorphic and codominant markers, together with recent population genetic statistics extended to autotetraploids, offer tools to analyse genetic diversity in alfalfa. The number of alleles per locus varied between 3 and 24. All loci were at a panmictic equilibrium in the cultivars, except one, probably because of null alleles. With seven SSR loci, each cultivar was at panmictic equilibrium. The mean gene diversity was high, ranging from 0.665 to 0.717 in the cultivars. The parameter F(ST) indicated a low but significant diversity among cultivars. Among 21 pairs of cultivars, 15 were significantly different. The breeding pool also had a high diversity, and was significantly different from each cultivar except the most recent one. Considering the characteristics of the breeding program and the mode of cultivar elaboration, we found that they were unable to generate a large variety differentiation. Estimation of population genetics parameters at SSR loci can be applied for assessing the differences between cultivars or populations, either for variety distinction or the management of genetic resources.

Breeding↗

Heterogeneity of genetic control of blood pressure in ethnically different populations.

We review the literature on statistical genetic analyses of blood pressure in samples from various ethnic backgrounds using different statistical methods and packages. We then provide the results of a complex segregation analysis performed on familial data on systolic and diastolic blood pressure in 2 ethnically different populations, Chuvashans and Turkmenians. Two types of major gene models were tested in the segregation analysis: Model type 1 tests for a Mendelian mode of transmission and estimates genotype-specific averages regardless of age and sex effect, and model type 2 estimates age and sex effects on each of 3 genotypes within the putative major genotype. In both total samples, by both types of segregation analysis, familial aggregation of both systolic and diastolic blood pressure was inconsistent with the Mendelian mode of inheritance. In the next step of analysis the pedigrees in both samples were sorted into 2 groups on the basis of 2 likelihoods as obtained under Mendelian and nontransmission models for each entire sample. This procedure resulted in the appearance of 2 subsamples (large and small) in each ethnic sample. The segregation analysis that was carried out then on the larger subsample provided consistent evidence to support the major gene effect on systolic and diastolic blood pressure in 2 ethnic groups. Interestingly, model type 2 showed that in both ethnically different large subsamples, for each sex the genotype predisposing to a larger mean value of systolic (or diastolic) blood pressure also displayed the highest rate of blood pressure increase with age. We discuss in detail possible sources of heterogeneity in familial transmission of blood pressure observed in our 2 samples, and we suggest a method to improve the analysis of heterogeneity for trait inheritance.

Adolescent↗

A new paradigm for drug discovery: integrating clinical, genetic, genomic and molecular phenotype data to identify drug targets.

Application of statistical genetics approaches to variations in mRNA transcript abundances in segregating populations can be used to identify genes and pathways associated with common human diseases. The combination of this genetic information with gene expression and clinical trait data can also be used to identify subtypes of a disease and the genetic loci specific to each subtype. Here we highlight results from some of our recent work in this area and further explore the many possibilities that exist in employing a more comprehensive genetics and functional genomics approach to the functional annotation of genomes, and in applying such methods to the validation of targets for complex traits in the drug discovery process.

Animals↗

Substantial genetic effects involved in determination of circulating levels of calciotropic hormones in human pedigrees.

This paper reports the results of a series of univariate and bivariate statistical genetic analyses that were performed on a sample of nuclear and more complex pedigrees (N = 567 individuals) of an ethnically homogenous White population. Our major objectives were: (1) To quantitatively evaluate the extent and pattern of the putative genetic effects on plasma level variation and covariation of the intact parathyroid hormone (PTH) and 25-hydroxyvitamin D [25(OH)D]; (2) To evaluate the extent of the possible genetic covariation between each of the two calciotropic hormones and two important bone mass traits, namely radiographic hands bone mineral density (BMD) and cortical index (CI). Variance component analysis, as implemented in the statistical package FISHER unambigously demonstrated that in addition to age, genetic factors contribute significantly to interindividual variation of both calciotropic hormones (37.5% for PTH and 53.3% for 25(OH)D). Complex segregation analysis strongly suggested the involvement of major gene effects into the determination of 25(OH)D levels, but was not clear cut with respect to PTH. Significant correlations between circulating levels of study hormones were found (-0.146, P < 0.05 in men and -0.194, P < 0.01 in women). However, no genetic correlation was revealed between PTH and 25(OH)D plasma concentrations. Bivariate analyses showed that familial cross correlations between PTH and BMD and CI measured at the bones of the hand were consistently statistically significant, suggesting moderate, but detectable pleiotropic genetic effects. The corresponding genetic correlations were -0.461 +/- 0.153 and -0.223 +/- 0.113, respectively. Circulating levels of 25(OH)D showed neither phenotypic nor genetic correlation with any of the BMD or CI variation.

Adolescent↗

Haplotype-sharing analysis using Mantel statistics for combined genetic effects.

We applied a new approach based on Mantel statistics to analyze the Genetic Analysis Workshop 14 simulated data with prior knowledge of the answers. The method was developed in order to improve the power of a haplotype sharing analysis for gene mapping in complex disease. The new statistic correlates genetic similarity and phenotypic similarity across pairs of haplotypes from case-control studies. The genetic similarity is measured as the shared length between haplotype pairs around a genetic marker. The phenotypic similarity is measured as the mean corrected cross-product based on the respective phenotypes. Cases with phenotype P1 and unrelated controls were drawn from the population of Danacaa. Power to detect main effects was compared to the X2-test for association based on 3-marker haplotypes and a global permutation test for haplotype association to test for main effects. Power to detect gene x gene interaction was compared to unconditional logistic regression. The results suggest that the Mantel statistics might be more powerful than alternative tests.

Haplotypes↗

Genetics of Latin American Diversity Project: Insights into population genetics and association studies in admixed groups in the Americas.

Latin Americans are underrepresented in genetic studies, increasing disparities in personalized genomic medicine. Despite available genetic data from thousands of Latin Americans, accessing and navigating the bureaucratic hurdles for consent or access remains challenging. To address this, we introduce the Genetics of Latin American Diversity (GLAD) Project, compiling genome-wide information from 53,738 Latin Americans across 39 studies representing 46 geographical regions. Through GLAD, we identified heterogeneous ancestry composition and recent gene flow across the Americas. Additionally, we developed GLAD-match, a simulated annealing-based algorithm, to match the genetic background of external samples to our database, sharing summary statistics (i.e., allele and haplotype frequencies) without transferring individual-level genotypes. Finally, we demonstrate the potential of GLAD as a critical resource for evaluating statistical genetic software in the presence of admixture. By providing this resource, we promote genomic research in Latin Americans and contribute to the promises of personalized medicine to more people.

Humans↗