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1.
Sci Rep ; 9(1): 9439, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31263163

RESUMO

Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P < 5 × 10-8) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P < 0.05) associated with fasting glucose change over time. Limited power influences unambiguous interpretation, but these data suggest that genetic effects on fasting glucose change over time are likely to be small. A public version of the data provides a genomic resource to combine with future studies to evaluate shared genetic links with T2D and other metabolic risk traits.

2.
Lipids ; 53(8): 797-807, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30334266

RESUMO

It has been reported that polymorphisms within the gene-encoding enzymes related to alcohol metabolism are associated with levels of serum HDL-cholesterol (HDL-C) in East Asian populations. We evaluated the effects of genetic variants within the aldehyde dehydrogenase-2 (ALDH2) gene and the alcohol dehydrogenase-1B (ADH1B) gene on changes in the lipid profile in an 11-year longitudinal study. We genotyped rs1229984 within ADH1B and rs671 within ALDH2. We combined the genetic data with longitudinal clinical and biochemical data from 2002 to 2013 and designed a retrospective longitudinal study of 1436 Japanese males. There were significant negative relationships between rs671 within ALDH2 and HDL-C levels according to multiple linear regression analysis. Next, we assessed the association between the development of hypo-HDL cholesterolemia and rs1229984 within ADH1B or rs671 within ALDH2. In logistic regression analysis, rs671 A allele homozygote carriers have 2.65 times higher risk of developing hypo-HDL cholesterolemia than G allele homozygote carriers. Even after adjusting for possible confounding factors, a significant association was observed. However, no association between rs1229984 within ADH1B and the development of hypo-HDL cholesterolemia was observed. Rs671 within ALDH2 but not rs1229984 within ADH1B was associated with lower HDL-C levels in Japanese males.

3.
Front Genet ; 9: 210, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29963075

RESUMO

In observational cohorts, longitudinal data are collected with repeated measurements at predetermined time points for many biomarkers, along with other variables measured at baseline. In these cohorts, time until a certain event of interest occurs is reported and very often, a relationship will be observed between some biomarker repeatedly measured over time and that event. Joint models were designed to efficiently estimate statistical parameters describing this relationship by combining a mixed model for the longitudinal biomarker trajectory and a survival model for the time until occurrence of the event, using a set of random effects to account for the relationship between the two types of data. In this paper, we discuss the implementation of joint models in genetic association studies. First, we check model consistency based on different simulation scenarios, by varying sample sizes, minor allele frequencies and number of repeated measurements. Second, using genotypes assayed with the Metabochip DNA arrays (Illumina) from about 4,500 individuals recruited in the French cohort D.E.S.I.R. (Data from an Epidemiological Study on the Insulin Resistance syndrome), we assess the feasibility of implementing the joint modelling approach in a real high-throughput genomic dataset. An alternative model approximating the joint model, called the Two-Step approach (TS), is also presented. Although the joint model shows more precise and less biased estimators than its alternative counterpart, the TS approach results in much reduced computational times, and could thus be used for testing millions of SNPs at the genome-wide scale.

4.
Bioinformatics ; 34(16): 2773-2780, 2018 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-29547902

RESUMO

Motivation: Large scale genome-wide association studies (GWAS) are tools of choice for discovering associations between genotypes and phenotypes. To date, many studies rely on univariate statistical tests for association between the phenotype and each assayed single nucleotide polymorphism (SNP). However, interaction between SNPs, namely epistasis, must be considered when tackling the complexity of underlying biological mechanisms. Epistasis analysis at large scale entails a prohibitive computational burden when addressing the detection of more than two interacting SNPs. In this paper, we introduce a stochastic causal graph-based method, SMMB, to analyze epistatic patterns in GWAS data. Results: We present Stochastic Multiple Markov Blanket algorithm (SMMB), which combines both ensemble stochastic strategy inspired from random forests and Bayesian Markov blanket-based methods. We compared SMMB with three other recent algorithms using both simulated and real datasets. Our method outperforms the other compared methods for a majority of simulated cases of 2-way and 3-way epistasis patterns (especially in scenarii where minor allele frequencies of causal SNPs are low). Our approach performs similarly as two other compared methods for large real datasets, in terms of power, and runs faster. Availability and implementation: Parallel version available on https://ls2n.fr/listelogicielsequipe/DUKe/128/. Supplementary information: Supplementary data are available at Bioinformatics online.

5.
Science ; 354(6313): 760-764, 2016 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-27738015

RESUMO

Detection of recent natural selection is a challenging problem in population genetics. Here we introduce the singleton density score (SDS), a method to infer very recent changes in allele frequencies from contemporary genome sequences. Applied to data from the UK10K Project, SDS reflects allele frequency changes in the ancestors of modern Britons during the past ~2000 to 3000 years. We see strong signals of selection at lactase and the major histocompatibility complex, and in favor of blond hair and blue eyes. For polygenic adaptation, we find that recent selection for increased height has driven allele frequency shifts across most of the genome. Moreover, we identify shifts associated with other complex traits, suggesting that polygenic adaptation has played a pervasive role in shaping genotypic and phenotypic variation in modern humans.


Assuntos
Adaptação Fisiológica/genética , Lactase/genética , Complexo Principal de Histocompatibilidade/genética , Seleção Genética , Cor de Olho/genética , Frequência do Gene , Loci Gênicos , Genoma Humano , Estudo de Associação Genômica Ampla , Cor de Cabelo/genética , Haplótipos , Humanos/genética , Linhagem , Reino Unido
6.
Front Genet ; 6: 285, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26442103

RESUMO

During the past decade, findings of genome-wide association studies (GWAS) improved our knowledge and understanding of disease genetics. To date, thousands of SNPs have been associated with diseases and other complex traits. Statistical analysis typically looks for association between a phenotype and a SNP taken individually via single-locus tests. However, geneticists admit this is an oversimplified approach to tackle the complexity of underlying biological mechanisms. Interaction between SNPs, namely epistasis, must be considered. Unfortunately, epistasis detection gives rise to analytic challenges since analyzing every SNP combination is at present impractical at a genome-wide scale. In this review, we will present the main strategies recently proposed to detect epistatic interactions, along with their operating principle. Some of these methods are exhaustive, such as multifactor dimensionality reduction, likelihood ratio-based tests or receiver operating characteristic curve analysis; some are non-exhaustive, such as machine learning techniques (random forests, Bayesian networks) or combinatorial optimization approaches (ant colony optimization, computational evolution system).

7.
Diabetologia ; 57(8): 1601-10, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24893864

RESUMO

AIMS/HYPOTHESIS: Genome-wide association studies have firmly established 65 independent European-derived loci associated with type 2 diabetes and 36 loci contributing to variations in fasting plasma glucose (FPG). Using individual data from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study, we evaluated the contribution of three genetic risk scores (GRS) to variations in metabolic traits, and to the incidence and prevalence of impaired fasting glycaemia (IFG) and type 2 diabetes. METHODS: Three GRS (GRS-1, 65 type 2 diabetes-associated single nucleotide polymorphisms [SNPs]; GRS-2, GRS-1 combined with 24 FPG-raising SNPs; and GRS-3, FPG-raising SNPs alone) were analysed in 4,075 DESIR study participants. GRS-mediated effects on longitudinal variations in quantitative traits were assessed in 3,927 nondiabetic individuals using multivariate linear mixed models, and on the incidence and prevalence of hyperglycaemia at 9 years using Cox and logistic regression models. The contribution of each GRS to risk prediction was evaluated using the C-statistic and net reclassification improvement (NRI) analysis. RESULTS: The two most inclusive GRS were significantly associated with increased FPG (ß = 0.0011 mmol/l per year per risk allele, p GRS-1 = 8.2 × 10(-5) and p GRS-2 = 6.0 × 10(-6)), increased incidence of IFG and type 2 diabetes (per allele: HR GRS-1 1.03, p = 4.3 × 10(-9) and HR GRS-2 1.04, p = 1.0 × 10(-16)), and the 9 year prevalence (OR GRS-1 1.13 [95% CI 1.10, 1.17], p = 1.9 × 10(-14) for type 2 diabetes only; OR GRS-2 1.07 [95% CI 1.05, 1.08], p = 7.8 × 10(-25), for IFG and type 2 diabetes). No significant interaction was found between GRS-1 or GRS-2 and potential confounding factors. Each GRS yielded a modest, but significant, improvement in overall reclassification rates (NRI GRS-1 17.3%, p = 6.6 × 10(-7); NRI GRS-2 17.6%, p = 4.2 × 10(-7); NRI GRS-3 13.1%, p = 1.7 × 10(-4)). CONCLUSIONS/INTERPRETATION: Polygenic scores based on combined genetic information from type 2 diabetes risk and FPG variation contribute to discriminating middle-aged individuals at risk of developing type 2 diabetes in a general population.


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Homeostase/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Diabetes Mellitus Tipo 2/sangue , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
8.
Neuroendocrinology ; 97(2): 146-59, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-22538389

RESUMO

Dietary interventions involving caloric restriction represent a powerful strategy to prevent or delay age-related deteriorations and diseases. Their beneficial effects have been observed in several tissues and species. This microarray study investigated the effects of aging, long-term moderate caloric restriction (LTMCR) and long-term dietary soy on the regulation of gene expression in the anterior pituitary and hypothalamus of 20-month-old Sprague-Dawley rats. In both tissues, aging regulated genes mainly involved in cell defense and repair mechanisms related to apoptosis, DNA repair, cellular stress, inflammatory and immune response. In the aging pituitary, the highest upregulated gene was the regenerating islet-derived 3ß (5.77-fold), coding for a secretory protein involved in acute stress and inflammation. A protective effect of LTMCR on age-related change of gene expression was observed for 35 pituitary genes. In addition, beneficial effects of LTMCR in the pituitary were observed on new regulated genes mainly involved in cell death and cell stress response. In the hypothalamus, the effects of LTMCR on age-related changes were modest. Finally, changing the quality of dietary protein (20% casein for soy) had a low impact on the regulation of mRNA levels in both tissues. Genes associated with the somatotroph function were also differentially expressed in the aging pituitary. Interestingly, LTMCR prevented the effect of aging on insulin-like growth factor-binding protein-3 gene. Altogether, this study proposes novel pituitary and hypothalamic molecular targets and signaling pathways to help in understanding the mechanisms involved in aging processes and LTMCR.


Assuntos
Envelhecimento/fisiologia , Dieta , Hipotálamo/metabolismo , Adeno-Hipófise/metabolismo , Transcriptoma , Envelhecimento/sangue , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Restrição Calórica , Perfilação da Expressão Gênica , Hormônios/sangue , Hipotálamo/química , Masculino , Análise em Microsséries , Adeno-Hipófise/química , Ratos , Ratos Sprague-Dawley , Alimentos de Soja , Transcriptoma/genética , Transcriptoma/fisiologia
9.
Nat Genet ; 44(3): 297-301, 2012 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-22286214

RESUMO

Genome-wide association studies have revealed that common noncoding variants in MTNR1B (encoding melatonin receptor 1B, also known as MT(2)) increase type 2 diabetes (T2D) risk(1,2). Although the strongest association signal was highly significant (P < 1 × 10(-20)), its contribution to T2D risk was modest (odds ratio (OR) of ∼1.10-1.15)(1-3). We performed large-scale exon resequencing in 7,632 Europeans, including 2,186 individuals with T2D, and identified 40 nonsynonymous variants, including 36 very rare variants (minor allele frequency (MAF) <0.1%), associated with T2D (OR = 3.31, 95% confidence interval (CI) = 1.78-6.18; P = 1.64 × 10(-4)). A four-tiered functional investigation of all 40 mutants revealed that 14 were non-functional and rare (MAF < 1%), and 4 were very rare with complete loss of melatonin binding and signaling capabilities. Among the very rare variants, the partial- or total-loss-of-function variants but not the neutral ones contributed to T2D (OR = 5.67, CI = 2.17-14.82; P = 4.09 × 10(-4)). Genotyping the four complete loss-of-function variants in 11,854 additional individuals revealed their association with T2D risk (8,153 individuals with T2D and 10,100 controls; OR = 3.88, CI = 1.49-10.07; P = 5.37 × 10(-3)). This study establishes a firm functional link between MTNR1B and T2D risk.


Assuntos
Diabetes Mellitus Tipo 2/genética , Variação Genética , Receptor MT2 de Melatonina/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Sequência de Bases , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Éxons/genética , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Modelos Logísticos , Modelos Moleculares , Dados de Sequência Molecular , Razão de Chances , Análise de Sequência de DNA
10.
Nat Genet ; 42(2): 105-16, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20081858

RESUMO

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.


Assuntos
Glicemia/genética , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/genética , Jejum/sangue , Loci Gênicos/genética , Predisposição Genética para Doença , Homeostase/genética , Adolescente , Adulto , Alelos , Criança , Variações do Número de Cópias de DNA/genética , Bases de Dados Genéticas , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Metanálise como Assunto , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Característica Quantitativa Herdável , Reprodutibilidade dos Testes
11.
Nat Genet ; 41(10): 1110-5, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19734900

RESUMO

Genome-wide association studies have identified common variants that only partially explain the genetic risk for type 2 diabetes (T2D). Using genome-wide association data from 1,376 French individuals, we identified 16,360 SNPs nominally associated with T2D and studied these SNPs in an independent sample of 4,977 French individuals. We then selected the 28 best hits for replication in 7,698 Danish subjects and identified 4 SNPs showing strong association with T2D, one of which (rs2943641, P = 9.3 x 10(-12), OR = 1.19) was located adjacent to the insulin receptor substrate 1 gene (IRS1). Unlike previously reported T2D risk loci, which predominantly associate with impaired beta cell function, the C allele of rs2943641 was associated with insulin resistance and hyperinsulinemia in 14,358 French, Danish and Finnish participants from population-based cohorts; this allele was also associated with reduced basal levels of IRS1 protein and decreased insulin induction of IRS1-associated phosphatidylinositol-3-OH kinase activity in human skeletal muscle biopsies.


Assuntos
Diabetes Mellitus Tipo 2/genética , Genoma Humano , Hiperinsulinismo/genética , Proteínas Substratos do Receptor de Insulina/genética , Resistência à Insulina , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Biópsia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hiperinsulinismo/complicações , Hiperinsulinismo/metabolismo , Hiperinsulinismo/patologia , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Fosfatidilinositol 3-Quinases/metabolismo
12.
Nat Genet ; 41(1): 89-94, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19060909

RESUMO

In genome-wide association (GWA) data from 2,151 nondiabetic French subjects, we identified rs1387153, near MTNR1B (which encodes the melatonin receptor 2 (MT2)), as a modulator of fasting plasma glucose (FPG; P = 1.3 x 10(-7)). In European populations, the rs1387153 T allele is associated with increased FPG (beta = 0.06 mmol/l, P = 7.6 x 10(-29), N = 16,094), type 2 diabetes (T2D) risk (odds ratio (OR) = 1.15, 95% CI = 1.08-1.22, P = 6.3 x 10(-5), cases N = 6,332) and risk of developing hyperglycemia or diabetes over a 9-year period (hazard ratio (HR) = 1.20, 95% CI = 1.06-1.36, P = 0.005, incident cases N = 515). RT-PCR analyses confirm the presence of MT2 transcripts in neural tissues and show MT2 expression in human pancreatic islets and beta cells. Our data suggest a possible link between circadian rhythm regulation and glucose homeostasis through the melatonin signaling pathway.


Assuntos
Glicemia/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Jejum/sangue , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Receptor MT2 de Melatonina/genética , Receptores de Melatonina/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Criança , Cromossomos Humanos Par 11/genética , Estudos de Coortes , Diabetes Mellitus Tipo 2/enzimologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Glucoquinase/genética , Humanos , Resistência à Insulina/genética , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Metanálise como Assunto , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor MT2 de Melatonina/metabolismo , Receptores de Melatonina/metabolismo , Reprodutibilidade dos Testes
13.
Science ; 320(5879): 1085-8, 2008 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-18451265

RESUMO

Several studies have shown that healthy individuals with fasting plasma glucose (FPG) levels at the high end of the normal range have an increased risk of mortality. To identify genetic determinants that contribute to interindividual variation in FPG, we tested 392,935 single-nucleotide polymorphisms (SNPs) in 654 normoglycemic participants for association with FPG, and we replicated the most strongly associated SNP (rs560887, P = 4 x 10(-7)) in 9353 participants. SNP rs560887 maps to intron 3 of the G6PC2 gene, which encodes glucose-6-phosphatase catalytic subunit-related protein (also known as IGRP), a protein selectively expressed in pancreatic islets. This SNP was associated with FPG (linear regression coefficient beta = -0.06 millimoles per liter per A allele, combined P = 4 x 10(-23)) and with pancreatic beta cell function (Homa-B model, combined P = 3 x 10(-13)) in three populations; however, it was not associated with type 2 diabetes risk. We speculate that G6PC2 regulates FPG by modulating the set point for glucose-stimulated insulin secretion in pancreatic beta cells.


Assuntos
Glicemia/metabolismo , Glucose-6-Fosfatase/genética , Polimorfismo de Nucleotídeo Único , Alelos , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/genética , Jejum , Feminino , Predisposição Genética para Doença , Glucose-6-Fosfatase/metabolismo , Humanos , Insulina/sangue , Insulina/metabolismo , Células Secretoras de Insulina/fisiologia , Íntrons , Modelos Lineares , Masculino , Metanálise como Assunto
14.
Nature ; 445(7130): 881-5, 2007 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-17293876

RESUMO

Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants was recently made possible by the development of high-density arrays that permit the genotyping of hundreds of thousands of polymorphisms. We tested 392,935 single-nucleotide polymorphisms in a French case-control cohort. Markers with the most significant difference in genotype frequencies between cases of type 2 diabetes and controls were fast-tracked for testing in a second cohort. This identified four loci containing variants that confer type 2 diabetes risk, in addition to confirming the known association with the TCF7L2 gene. These loci include a non-synonymous polymorphism in the zinc transporter SLC30A8, which is expressed exclusively in insulin-producing beta-cells, and two linkage disequilibrium blocks that contain genes potentially involved in beta-cell development or function (IDE-KIF11-HHEX and EXT2-ALX4). These associations explain a substantial portion of disease risk and constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Genoma Humano , Estudos de Casos e Controles , Proteínas de Transporte de Cátions/genética , Cromossomos Humanos Par 10/genética , Cromossomos Humanos Par 8/genética , França , Humanos , Desequilíbrio de Ligação , Transportador 8 de Zinco
15.
Theor Popul Biol ; 66(4): 287-306, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15560908

RESUMO

We consider family specific fitnesses that depend on mixed strategies of two basic phenotypes or behaviours. Pairwise interactions are assumed, but they are restricted to occur between sibs. To study the change in frequency of a rare mutant allele, we consider two different forms of weak selection, one applied through small differences in genotypic values determining individual mixed strategies, the other through small differences in viabilities according to the behaviours chosen by interacting sibs. Under these two specific forms of weak selection, we deduce conditions for initial increase in frequency of a rare mutant allele for autosomal genes in the partial selfing model as well as autosomal and sex-linked genes in the partial sib-mating model with selection before mating or selection after mating. With small differences in mixed strategies, we show that conditions for protection of a mutant allele are tantamount to conditions for initial increase in frequency obtained in additive kin selection models. With particular reference to altruism versus selfishness, we provide explicit ranges of values for the selfing or sib-mating rate based on a fixed cost-benefit ratio and the dominance scheme that allow the spreading of a rare mutant allele into the population. This study confirms that more inbreeding does not necessarily promote the evolution of altruism. Under the hypothesis of small differences in viabilities, the situation is much more intricate unless an additive model is assumed. In general however, conditions for initial increase in frequency of a mutant allele can be obtained in terms of fitness effects that depend on the genotypes of interacting individuals or their mates and generalized conditional coefficients of relatedness according to the inbreeding condition of the interacting individuals.


Assuntos
Endogamia , Animais , Dinâmica Populacional , Reprodução/genética , Seleção Genética
16.
J Math Biol ; 46(1): 71-94, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12525936

RESUMO

We deduce and prove a general formula to approximate the change in frequency of a mutant allele under weak selection, when this allele is introduced in small frequency into a population which was previously at a fixation state. We apply the formula to autosomal genes in partial selfing models and to autosomal as well as sex-linked genes in partial sib mating models. It is shown that the fate of a rare mutant allele depends not only on the selection parameters, the inbreeding coefficient and the reproductive values of the sexes in sex-differentiated populations, but also on coefficients of relatedness between mates. This is interpreted as a kin selection effect caused by inbreeding per se.


Assuntos
Alelos , Frequência do Gene/genética , Endogamia , Modelos Genéticos , Mutação/genética , Seleção Genética
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