Sewall Wright (1889-1988).
The genetic contributions of Sewall Wright is briefly reviewed with special reference to J.B.S. Haldane's work. These include his work in population genetics, statistics, and animal breeding.
Animal Husbandry↗
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Results for “statistical genetics”
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Statistical analysis of the migration component of genetic drift.
Statistical methods are introduced for analysis of the migration component of genetic drift, i.e., of the stochastic changes that affect allele frequencies during migration between local groups. Attention focuses on alpha M, a parameter that measures the extent to which this component of drift departs from the ideal of independent random sampling, and which can be interpreted as a measure of the extent to which migration is kin-structured. It is shown that alpha M can be estimated from genetic data, even in the absence of information about the genealogical relationships of migrants, and Monte-Carlo simulations are used to approximate the sampling distribution of the estimator under the null hypothesis of independent random sampling. Application of these methods to data from the Aland Islands, Finland, shows that the migration pattern there is consistent with the hypothesis of independent random sampling.
Finland↗
Genetic regulation of thymic involution.
In this review, we have summarized our work using combined complex statistical genetics, bioinformatics, and functional genomics to determine the genetic basis of the age-related thymic involution in C57BL/6J X DBA/2J recombinant inbred mice and the parental B6 and D2 mice. We have shown that these mice provided a valuable genetic model that can permit resampling of thymuses from different aged but genetically identical animals and determination of the relative significance of age-associated changes in the thymus. Our results suggest that the quantitative trait loci (QTL) regulating the Con A-induced thymocyte proliferative response were mapped to mouse chromosome Chr 11 (D11Mit51 at 18 cM), a region that harbors the IL-12b gene. The importance of IL-12b in maintaining thymic integrity and function during the aging process was confirmed by a more rapid involution of the thymus in IL-12b knockout (IL-12b-/-) mice compared to wild-type (WT) mice. Functionally, IL-12 provided a strong synergistic effect to augment the IL-7 or IL-2 induced thymocyte proliferative response, especially in both aged WT and IL-12b-/- mice, but not in normal young mice. In contract to the proliferative response, the age-related decline in the total number of thymocytes was determined at different age, and mapped to loci on Chr 9, 62 cM and Chr 10, 32 cM. Using matrix-assisted laser desorption/ionisation-time of flight-mass spectrometry (MALDI-TOF-MS), increased expression of peroxiredoxin was found to be correlated with thymic involution. Our results suggest the possibility to identify the complex molecular network that can be associated with the regulation of thymic involution in aged mice using a high-dimensional functional genomics approach.
Aging↗
Meeting report. Statistical methods in genetic mapping.
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Chromosome Mapping↗
In silico phenotypic screening method of mutants based on statistical modeling of genetically mixed samples.
In comprehensive functional genomics projects, systematic analysis of phenotypes is vital. However, conventional phenotypic screening is done mainly by imprecise visual observation of qualitative traits, and, therefore, in silico screening techniques for quantitative traits are required. In this report, we propose in silico phenotypic screening method that utilizes a Gaussian mixture model for the trait distribution in the offspring of a mutagenized line and the likelihood ratio test between the estimated Gaussian mixture model and the wild-type single Gaussian model. In order to evaluate the proposed method, we performed a screening experiment using real trait data of Arabidopsis. In this experiment, the proposed screening method properly distinguished the mutant line from the wild-type line. Furthermore, we conducted power analysis of the proposed method and two conventional methods under various simulated conditions of sample size and distribution of trait frequency. The result of the power analysis confirmed the effectiveness of the proposed method compared to the conventional methods.
Algorithms↗
Genetics of manic depressive illness: current status and evolving concepts.
The bipolar affective spectrum is clinically heterogeneous and genetically complex. Current methods for assessment and analysis of familial traits with variable phenotypic expression and unclear mode of inheritance are reviewed. Recent evidence for a major gene localized on the X-chromosome is presented and other linkage findings are discussed. The limitations and prospects of psychiatric genetics are discussed in the light of recent advances in diagnostic nomenclature, statistical genetic techniques, and molecular biology. Methodological uncertainties notwithstanding, the powerful new techniques in genetic research portend well for unraveling the genetics of bipolar affective illness.
Bipolar Disorder↗
Podoconiosis: a tropical model for gene-environment interactions?
Podoconiosis (endemic non-filarial elephantiasis) is a geochemical disease occurring in individuals exposed to red clay soil derived from alkalic volcanic rock. It is a chronic, debilitating disorder and a considerable public health problem in at least 10 countries in tropical Africa, Central America and northern India. Only a small proportion of individuals exposed to red clay develop disease and familial clustering of cases occurs, so we tested the hypothesis that disease occurs in genetically susceptible individuals on exposure to an environmental element in soil. Using multiple statistical genetic techniques we estimated sibling recurrence risk ratio (lambda(s)) and heritability for podoconiosis, and conducted segregation analysis on 59 multigenerational affected families from Wolaitta Zone, southern Ethiopia. We estimated the lambda(s) to be 5.07. The heritability of podoconiosis was estimated to be 0.629 (SE 0.069, P=1x10(-7)). Segregation analysis showed that the most parsimonious model was that of an autosomal co-dominant major gene. Age and use of footwear were significant covariates in the final model. Host genetic factors are important determinants of susceptibility to podoconiosis. Identification of the gene(s) involved will lead to better understanding of the gene-environment interactions involved in the pathogenesis of podoconiosis and other complex multifactorial conditions.
Age of Onset↗
Genetic determinants of cutaneous malignant melanoma in Sinclair swine.
The role of genetic factors involved in the determination of risk of cutaneous malignant melanoma (CMM) in humans remains unclear owing to genetic heterogeneity and reliance on simplistic models of inheritance. Here, we report a statistical genetic analysis of cutaneous malignant melanoma in Sinclair swine (SSCM), a unique animal model for human CMM. Using complex segregation analysis a two-locus model involving an unknown major locus and a second locus that lies within or close to the swine leukocyte antigen (SLA) complex jointly determine risk of SSCM in pedigreed animals. These loci also influence severity of affection, accounting for approximately 20% of the phenotypic variation in quantitative tumour burden.
Animals↗
Genetics of schizophrenia: I. Familial patterns and mode of inheritance.
The purpose of this article is to review and condense the available literature on genetic modeling in schizophrenia research. The principles underlying genetic models and the various applications of these models to family data are reviewed. It is concluded that despite the advances in statistical genetics, the mode of inheritance of schizophrenia remains elusive. The conflicting results are attributed to variation in methods for data collection and analysis and to the heterogeneous nature of the disorder. The possibility is also raised that most previous genetic analyses of schizophrenia may have been compromised by methodological drawbacks. Although the use of advanced genetic models in conjunction with adequate data may shed more light on the genetic contribution to schizophrenia, the limitations of this approach in genetically heterogeneous disorders must be recognized. Alternative methods, such as studies with biological susceptibility traits and genetic markers, may be more useful in unraveling the specific genetic components that underlie the transmission of schizophrenia.
Genetic Counseling↗
Sex-specific QTL effects on variation in paraoxonase 1 (PON1) activity in Mexican Americans.
Paraoxonase 1 (PON1), a high-density lipoprotein-associated enzyme known to protect against cellular damage from toxic agents, may also have antioxidant properties. PON1 activity levels have been reported to differ by sex in human and animal studies with females exhibiting higher basal levels. We measured PON1 activity frozen serum for 1,406 individuals in over 40 extended pedigrees from the San Antonio Family Heart Study (SAFHS). We used a maximum likelihood-based, variance decomposition approach implemented in SOLAR to test for genotype-by-sex (G x S) interaction on variation in PON1 activity and to determine if any of the four PON1 quantitative trait loci (QTL) previously reported by us for this population might account for sex differences in PON1 activity levels. The residual additive genetic correlation (rho(G) = 0.82) between males and females is significantly different from 1 (P = 0.009), suggesting that some of the genes that influence PON1 activity act differently in females and males or, possibly, that a different combination of genes influences this trait in each sex. In addition to the QTL at or near the PON structural locus on 7q21-22, three other potential QTLs were evaluated for sex-specific effects: one each on chromosomes 12, 17 and 19. The QTL on chromosome 17 (LOD = 2.32, P = 0.0003; flanked by microsatellite marker loci D17S974 and D17S969) shows a significant (P = 0.005) sex-specific effect on PON1 activity; accounting for 6% of the additive genetic variance in males and 20% in females. This study represents the first formal statistical genetic test for G x S interactions on normal quantitative variation in PON1 activity in humans.
Adult↗
[Estimation of diversity by morphological markers].
A genetic statistical method for estimation of intraspecific diversity of cultivated plants with respect to morphological genes is proposed. The method may be used for estimation of probability distributions of morphological (marker) mutations with respect to the frequencies of their expression and for prediction of experimental parameter such as the total number of markers, the scale (duration) of the experiment that is necessary for detection of a given proportion of the total marker diversity of the species, etc. The method was tested on tomato Lycopersicon esculentum Mill. using data from the SolGenes Internet databank.
Biomarkers↗
A simulation model including ovulation rate, potential embryonic viability, and uterine capacity to explain litter size in mice: I. Model development and implementation.
Litter size in mice was studied using a model including ovulation rate, potential embryonic viability, and uterine capacity. Simulated results were compared with experimental results from a selection experiment with mice. The four criteria of selection were selection on number born (LS), selection on an index of ovulation rate and ova success (IX), selection on number born to unilaterally ovariectomized females (UT), and unselected control (LC). Comparisons were made to statistics of the base generation and to responses after 13 generations of selection. Phenotypic and genetic statistics for uterine capacity were generated so that simulations produced the experimental means, standard deviations, and correlations between left and right litter size, as well as responses in number born using the LS, IX, and UT criteria. Statistics for the simulated data generally agreed with observed values. Simulated heritability in the base generation for uterine capacity was .065. Experimental and simulated responses per generation in litter size through 13 generations of selection were .15 and .16, .17 and .18, and .10 and .11 for LS, IX, and UT, respectively. Simulated responses in uterine capacity after 13 generations were 2.19, 1.60, and 3.40 for LS, IX, and UT, respectively. Simulated means for the base generation were 13.22 and 16.30 for ovulation rate and uterine capacity, respectively. Uterine capacity was an important component of the variability in litter size; however, ovulation rate was the more limiting component.
Algorithms↗
SPC: a SPectral Component approach leveraging Identity-by-Descent graphs to address recent population structure in genomic analysis.
Population structure is a well-known confounder in statistical genetics, particularly in genome-wide association studies (GWAS), where it can lead to inflated test statistics and spurious associations. Traditional methods, such as principal components (PCs), commonly used to adjust for population structure, are limited in capturing fine-scale, non-linear patterns that arise from recent demographic events - patterns that are crucial for understanding rare variant effects. To address this challenge, we propose a novel method called SPectral Components (SPCs), which leverages identity-by-descent (IBD) graphs to capture and transform local, non-linear fine-scale population structure into continuous representations that can be seamlessly integrated into genetic analysis pipelines. Using both simulated datasets and empirical data from the UK Biobank (N ≈ 420,000), we demonstrate that SPCs outperform PCs in adjusting for fine-scale population structure. In simulations, SPCs explained over 90% of the fine-scale population structure with fewer components, while PCs captured less than 5%. In the UK Biobank, SPCs reduced the inflation of p-values in the GWAS of an environmental-driven phenotype by 12% compared to PCs, while maintaining a similar performance to PCs in height, a highly heritable phenotype. Additionally, SPCs improved rare variant association analyses, reducing genomic inflation (e.g., from 7.6 to 1.2 in one analysis), and provided more accurate heritability estimates. Spatial autocorrelation analysis further confirmed the ability of SPCs to account for environmental effects, reducing Moran's I for both environmental and heritable phenotypes more effectively than PCs. Overall, our findings demonstrate that SPCs provide a robust, scalable adjustment for recent population structure, offering a powerful alternative or complement to PCs in large-scale biobank studies.
GWAS↗
Gene mapping in the 20th and 21st centuries: statistical methods, data analysis, and experimental design.
In the 20th century geneticists began to unravel some of the simpler aspects of the etiology of inherited diseases in humans. The theory of linkage analysis was developed and applied long before the advent of molecular biology, but only the technological advances of the second half of the 20th century made large-scale gene mapping with a dense genome-spanning set of markers a reality. More recently, the primary topic of interest has shifted from simple Mendelian diseases, for which genotypes of some gene are the cause of disease, to more complex diseases, for which genotypes of some set of genes together with environmental factors merely alter the probability that an individual gets the disease, although individual factors are typically insufficient to cause the disease outright. To this end, a great deal of dogma has evolved about the best way to skin this cat, although to date success has been minimal with any approach. We postulate that the main reason for this is a lack of attention to experimental design. Once the data have been ascertained, the most powerful statistical methods will not be able to salvage an inappropriately designed study (Andersen 1990). Each phenotype and/or population mandates its own individually tailored study design to maximize the chances of successful gene mapping. We suggest that careful consideration of the available data from real genotype-phenotype correlation studies (as opposed to oversimplified theoretically tractable models), and the practical feasibility of different ascertainment schemes dictate how one should proceed. In this review we review the theory and practice of gene mapping at the close of the 20th century, showing that most methods of linkage and linkage disequilibrium analysis are similar in a fundamental sense, with the differences being related more to study design and ascertainment than to technical details of the underlying statistical analysis. To this end, we propose a new focus in the field of statistical genetics that more explicitly highlights the primacy of study design as the means to increase power for gene mapping.
Algorithms↗
Expression of HGF/SF and Met protein is associated with genetic alterations of VHL gene in primary renal cell carcinomas.
We analyzed the genetic alterations of VHL, HGF/SF, and Met genes and the expression pattern of HGF/SF and Met protein in 26 renal cell carcinomas (RCCs). We found five mutations of the VHL gene and frequent LOH (50%) only in non-papillary clear cell RCC. We found six cases in which the CpG island of VHL was methylated. In addition, one missense mutation of the HGF/SF gene was detected in clear cell RCC. HGF/SF and Met protein were expressed in 84.6% and 80.7% of RCCs, respectively. All of the cases with the genetic alterations of VHL or HGF/SF demonstrated strong expression of HGF/SF and Met protein in RCC cells. Statistically, genetic alterations of VHL and HGF/SF were significantly correlated with HGF/SF and Met expression (Fisher's exact test, p=0.022 and p=0.0070). Thus, these results strongly suggest that the expression of HGF/SF and Met protein is closely associated with the genetic alterations of VHL and HGF/SF in primary RCCs.
Adult↗
Host-associated genetic structure of Mexican populations of the cabbage aphid Brevicoryne brassicae L. (Homoptera: Aphididae).
Phytophagous insects can use different host plant species across their geographic distribution. Within a locality, however, their feeding can be restricted to one or two plant species. If host species constitute different selective regimes to herbivorous insects, genetic differentiation and host-associated local adaptation may occur. In this study, we describe the genetic structure of the aphid Brevicoryne brassicae L. associated to Brassica campestris L. and B. oleraceae var. capitata L., two plant species that occur sympatrically in four localities in the highlands of Chiapas, Mexico. The aim was to determine if the aphid populations are genetically structured in relation to the plant host species, and if such differentiation is consistent among localities. The genetic description of populations was made using 11 enzyme loci using cellulose acetate electrophoresis. Aphid genotypes were surveyed in two host plant species-associated populations within each of four localities at seven polymorphic loci (eight subpopulations in total). The genetic structure was assessed at the level of subpopulations, among localities, between hosts, and pairwise comparisons of hosts within locality, using Wright F-statistics. Genetic distance among localities and between host-associated populations within each locality was also estimated. We found that overall genetic differentiation was high (FST=0.22), and that differentiation among localities (FST=0.13) was higher than differentiation between hosts (FST=0.03). All FST estimates were statistically significant. Pairwise comparisons of FST between hosts in each locality suggest high differentiation in two of them, and low but still significant differentiation in two other localities. Given that general environmental conditions are similar within localities, selection on each host species may produce genetic divergence within and among subpopulations of B. brassicae.
Animals↗
The use of neurophysiological endophenotypes to understand the genetic basis of schizophrenia.
Specifying the complex genetic architecture of the "fuzzy" clinical phenotype of schizophrenia is an imposing problem. Utilizing metabolic, neurocognitive, and neurophysiological "intermediate" endophenotypic measures offers significant advantages from a statistical genetics standpoint. Endophenotypic measures are amenable to quantitative genetic analyses, conferring upon them a major methodological advantage compared with largely qualitative diagnoses using the Diagnostic and Statistical Manual of Mental Health, 4th Edition (DSM-IV). Endophenotypic deficits occur across the schizophrenia spectrum in schizophrenia patients, schizotypal patients, and clinically unaffected relatives of schizophrenia patients. Neurophysiological measures, such as P50 event-related suppression and the prepulse inhibition (PPI) of the startle response, are endophenotypes that can be conceptualized as being impaired because of a single genetic abnormality in the functional cascade of DNA to RNA to protein. The "endophenotype approach" is also being used to understand other medical disorders, such as colon cancer, hemochromatosis, and hypertension, where there is interplay between genetically conferred vulnerability and nongenetic stressors. The power and utility of utilizing endophenotypes to understand the genetics of schizophrenia is discussed in detail in this article.
Animals↗
Statistical methods in genetics.
In recent years, a very large variety of statistical methodologies, at various levels of complexity, have been put forward to analyse genotype data and detect genetic variations that may be responsible for increasing the susceptibility to disease. This review provides a concise account of a number of selected statistical methods for population-based association mapping, from single-marker tests of association to multi-marker data mining techniques for gene-gene interaction detection.
Genetic Markers↗