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Inclusive fitness theory predicts that parental care will vary with relatedness between potentially caring parents and offspring, potentially shaping mating system evolution. Systems with extra-pair paternity (EPP), and hence variable parent-brood relatedness, provide valuable opportunities to test this prediction. However, existing theoretical and empirical studies assume that a focal male is either an offspring's father with no inbreeding, or is completely unrelated. We highlight that this simple dichotomy does not hold given reproductive interactions among relatives, complicating the effect of EPP on parent-brood relatedness yet providing new opportunities to test inclusive fitness theory. Accordingly, we tested hierarchical hypotheses relating parental feeding rate to parent-brood relatedness, parent kinship and inbreeding, using song sparrows (Melospiza melodia) experiencing natural variation in relatedness. As predicted, male and female feeding rates increased with relatedness to a dependent brood, even controlling for brood size. Male feeding rate tended to decrease as paternity loss increased, and increased with increasing kinship and hence inbreeding between socially paired mates. We thereby demonstrate that variation in a key component of parental care concurs with subtle predictions from inclusive fitness theory. We additionally highlight that such effects can depend on the underlying social mating system, potentially generating status-specific costs of extra-pair reproduction.
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Endogamia , Passeriformes/fisiología , Conducta Sexual Animal , Animales , Femenino , MasculinoAsunto(s)
Diabetes Mellitus Tipo 2 , Glucosuria , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/efectos adversos , Creatinina , Hipoglucemiantes/uso terapéutico , Albúminas , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/orinaRESUMEN
PURPOSE: Demographic, environmental, and genetic risk factors for age-related macular degeneration (AMD) have been identified; however, a substantial portion of the variance in AMD disease risk and heritability remains unexplained. To identify AMD risk variants and generate hypotheses for future studies, we performed whole exome sequencing for 75 individuals whose phenotype was not well predicted by their genotype at known risk loci. We hypothesized that these phenotypically extreme individuals were more likely to carry rare risk or protective variants with large effect sizes. METHODS: A genetic risk score was calculated in a case-control set of 864 individuals (467 AMD cases, 397 controls) based on 19 common (≥1% minor allele frequency, MAF) single nucleotide variants previously associated with the risk of advanced AMD in a large meta-analysis of advanced cases and controls. We then selected for sequencing 39 cases with bilateral choroidal neovascularization with the lowest genetic risk scores to detect risk variants and 36 unaffected controls with the highest genetic risk score to detect protective variants. After minimizing the influence of 19 common genetic risk loci on case-control status, we targeted single variants of large effect and the aggregate effect of weaker variants within genes and pathways. Single variant tests were conducted on all variants, while gene-based and pathway analyses were conducted on three subsets of data: 1) rare (≤1% MAF in the European population) stop, splice, or damaging missense variants, 2) all rare variants, and 3) all variants. All analyses controlled for the effects of age and sex. RESULTS: No variant, gene, or pathway outside regions known to be associated with risk for advanced AMD reached genome-wide significance. However, we identified several variants with substantial differences in allele frequency between cases and controls with strong additive effects on affection status after controlling for age and sex. Protective effects trending toward significance were detected at two loci identified in single-variant analyses: an intronic variant in FBLN7 (the gene encoding fibulin 7) and at three variants near pyridoxal (pyridoxine, vitamin B6) kinase (PDXK). Aggregate rare-variant analyses suggested evidence for association at ASRGL1, a gene previously linked to photoreceptor cell death, and at BSDC1. In known AMD loci we also identified 29 novel or rare damaging missense or stop/splice variants in our sample of cases and controls. CONCLUSIONS: Identified variants and genes may highlight regions important in the pathogenesis of AMD and are key targets for replication.
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Predisposición Genética a la Enfermedad/genética , Degeneración Macular/genética , Polimorfismo de Nucleótido Simple , Anciano , Femenino , Frecuencia de los Genes , Técnicas de Genotipaje , Humanos , Masculino , Fenotipo , Factores de Riesgo , Secuenciación del ExomaRESUMEN
PURPOSE: To evaluate the heritability of choroidal thickness and its relationship to age-related macular degeneration (AMD). DESIGN: Cohort study. PARTICIPANTS: Six hundred eighty-nine individuals from Amish families with early or intermediate AMD. METHODS: Ocular coherence tomography was used to quantify choroidal thickness, and fundus photography was used to classify eyes into categories using a modified Clinical Age-Related Maculopathy Staging (CARMS) system. Repeatability and heritability of choroidal thickness and its phenotypic and genetic correlations with the AMD phenotype (CARMS category) were estimated using a generalized linear mixed model (GLMM) approach that accounted for relatedness, repeated measures (left and right eyes), and the effects of age, gender, and refraction. MAIN OUTCOME MEASURES: Heritability of choroidal thickness and its phenotypic and genetic correlation with the AMD phenotype (CARMS category). RESULTS: Phenotypic correlation between choroidal thickness and CARMS category was moderate (Spearman's rank correlation, rs = -0.24; n = 1313 eyes) and significant (GLMM posterior mean, -4.27; 95% credible interval [CI], -7.88 to -0.79; P = 0.02) after controlling for relatedness, age, gender, and refraction. Eyes with advanced AMD had thinner choroids than eyes without AMD (posterior mean, -73.8; 95% CI, -94.7 to -54.6; P < 0.001; n = 1178 eyes). Choroidal thickness was highly repeatable within individuals (repeatability, 0.78; 95% CI, 0.68 to 0.89) and moderately heritable (heritability, 0.40; 95% CI, 0.14 to 0.51), but did not show significant genetic correlation with CARMS category, although the effect size was moderate (genetic correlation, -0.18; 95% CI, -0.49 to 0.16). Choroidal thickness also varied with age, gender, and refraction. The CARMS category showed moderate heritability (heritability, 0.49; 95% CI, 0.26 to 0.72). CONCLUSIONS: We quantify the heritability of choroidal thickness for the first time, highlighting a heritable, quantitative trait that is measurable in all individuals regardless of AMD affection status, and moderately phenotypically correlated with AMD severity. Choroidal thickness therefore may capture variation not captured by the CARMS system. However, because the genetic correlation between choroidal thickness and AMD severity was not significant in our data set, genes associated with the 2 traits may not overlap substantially. Future studies should therefore test for genetic variation associated with choroidal thickness to determine the overlap in genetic basis with AMD.
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Amish/genética , Coroides/patología , Carácter Cuantitativo Heredable , Adulto , Anciano , Anciano de 80 o más Años , Coroides/diagnóstico por imagen , Estudios de Cohortes , Femenino , Humanos , Degeneración Macular/genética , Masculino , Persona de Mediana Edad , Tamaño de los Órganos/genética , Tomografía de Coherencia ÓpticaRESUMEN
The differential allocation hypothesis predicts increased investment in offspring when females mate with high-quality males. Few studies have tested whether investment varies with mate relatedness, despite evidence that non-additive gene action influences mate and offspring genetic quality. We tested whether female lekking lance-tailed manakins (Chiroxiphia lanceolata) adjust offspring sex and egg volume in response to mate attractiveness (annual reproductive success, ARS), heterozygosity and relatedness. Across 968 offspring, the probability of being male decreased with increasing parental relatedness but not father ARS or heterozygosity. This correlation tended to diminish with increasing lay-date. Across 162 offspring, egg volume correlated negatively with parental relatedness and varied with lay-date, but was unrelated to father ARS or heterozygosity. Offspring sex and egg size were unrelated to maternal age. Comparisons of maternal half-siblings in broods with no mortality produced similar results, indicating differential allocation rather than covariation between female quality and relatedness or sex-specific inbreeding depression in survival. As males suffer greater inbreeding depression, overproducing females after mating with related males may reduce fitness costs of inbreeding in a system with no inbreeding avoidance, while biasing the sex of outbred offspring towards males may maximize fitness via increased mating success of outbred sons.
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Óvulo/citología , Passeriformes/fisiología , Procesos de Determinación del Sexo , Conducta Sexual Animal , Animales , Femenino , Genotipo , Endogamia , Masculino , Preferencia en el Apareamiento Animal , Repeticiones de Microsatélite , Passeriformes/genéticaRESUMEN
Indirect benefits of mate choice result from increased offspring genetic quality and may be important drivers of female behaviour. 'Good-genes-for-viability' models predict that females prefer mates of high additive genetic value, such that offspring survival should correlate with male attractiveness. Mate choice may also vary with genetic diversity (e.g. heterozygosity) or compatibility (e.g. relatedness), where the female's genotype influences choice. The relative importance of these nonexclusive hypotheses remains unclear. Leks offer an excellent opportunity to test their predictions, because lekking males provide no material benefits and choice is relatively unconstrained by social limitations. Using 12 years of data on lekking lance-tailed manakins, Chiroxiphia lanceolata, we tested whether offspring survival correlated with patterns of mate choice. Offspring recruitment weakly increased with father attractiveness (measured as reproductive success, RS), suggesting attractive males provide, if anything, only minor benefits via offspring viability. Both male RS and offspring survival until fledging increased with male heterozygosity. However, despite parent-offspring correlation in heterozygosity, offspring survival was unrelated to its own or maternal heterozygosity or to parental relatedness, suggesting survival was not enhanced by heterozygosity per se. Instead, offspring survival benefits may reflect inheritance of specific alleles or nongenetic effects. Although inbreeding depression in male RS should select for inbreeding avoidance, mates were not less related than expected under random mating. Although mate heterozygosity and relatedness were correlated, selection on mate choice for heterozygosity appeared stronger than that for relatedness and may be the primary mechanism maintaining genetic variation in this system despite directional sexual selection.
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Aptitud Genética , Variación Genética , Preferencia en el Apareamiento Animal , Passeriformes/genética , Animales , Femenino , Heterocigoto , Modelos Lineales , Masculino , Modelos Genéticos , Passeriformes/fisiologíaRESUMEN
BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are recommended treatment for adults with chronic kidney disease (CKD), but uncertainty exists regarding their use in patients with frailty and/or multimorbidity, among whom polypharmacy is common. We derived a multivariable logistic regression model to predict hospitalization (reflecting frailty) and assessed empagliflozin's risk-benefit profile in a post-hoc analysis of the double-blind, placebo-controlled EMPA-KIDNEY trial. METHODS: The EMPA-KIDNEY trial randomized 6609 patients with CKD (estimated glomerular filtration rate [eGFR] ≥20<45 mL/min/1.73m2, or ≥45<90 mL/min/1.73m2 with urinary albumin-to-creatinine ratio ≥200 mg/g) to receive either empagliflozin 10 mg daily or matching placebo and followed for two years (median). Additional characteristics analysed in subgroups were multimorbidity, polypharmacy and health-related quality of life (HRQoL) at baseline. Cox regression analyses were performed with subgroups defined by approximate thirds of each variable. RESULTS: The strongest predictors of hospitalization were N-terminal prohormone of brain natriuretic peptide, poor mobility and diabetes; then eGFR and other comorbidities. Empagliflozin was generally well-tolerated independent of predicted risk of hospitalization. In relative terms, allocation to empagliflozin reduced the risk of the primary outcome of kidney disease progression or cardiovascular death by 28% (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.64-0.82); and all-cause hospitalization by 14% (HR 0.86, 95% CI 0.78-0.95); with broadly consistent effects across subgroups of predicted risk of hospitalization, multimorbidity, polypharmacy or HRQoL. In absolute terms, the estimated benefits of empagliflozin were greater in those at highest predicted risk of hospitalization (reflecting frailty) and outweighed potential serious harms. CONCLUSIONS: These findings support the use of SGLT2 inhibitors in CKD, irrespective of frailty, multimorbidity or polypharmacy.
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The forces driving extra-pair reproduction by socially monogamous females, and the resulting genetic polyandry, remain unclear. A testable prediction of the hypothesis that extra-pair reproduction partly reflects indirect selection on females is that extra-pair young (EPY) will be fitter than their within-pair young (WPY) maternal half-siblings. This prediction has not been comprehensively tested in a wild population, requiring data on the lifetime reproductive success (LRS) of maternal half-sib EPY and WPY. We used 17 years of genetic parentage data from song sparrows, Melospiza melodia, to compare the LRS of hatched EPY and WPY maternal half-siblings measured as their lifetime number of hatched offspring, recruited offspring, and hatched grandoffspring. EPY hatchlings were not significantly fitter than WPY hatchlings for any of three measures of LRS. Furthermore, opposite to prediction, EPY hatchlings tended to have lower LRS than their maternal half-sibling WPY hatchlings on average. EPY also tended to be less likely to survive to hatch than their maternal half-sibling WPY. Taken together, these results fail to support one key hypothesis explaining the evolution of genetic polyandry by socially monogamous females and suggest there may be weak indirect selection against female extra-pair reproduction in song sparrows.
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Endogamia , Conducta Sexual Animal , Gorriones/fisiología , Animales , Colombia Británica , Femenino , Geografía , Modelos Lineales , Masculino , ReproducciónRESUMEN
Numerous studies have tested for indirect selection on female extra-pair reproduction (EPR) by quantifying whether extra-pair young (EPY) are fitter than their within-pair young (WPY) maternal half-siblings. In contrast, the hypothesis that offspring of EPY and WPY (rather than the EPY and WPY themselves) differ in fitness has not been tested, even though inter-generational effects of parental extra-pair status on offspring fitness could alter the magnitude and direction of indirect selection on EPR. We tested whether offspring of EPY song sparrows, Melospiza melodia, were more likely to recruit or produce hatched or recruited offspring over their lifetimes than offspring of WPY. Hatchlings with one or two EPY parents were more likely to recruit and produce hatched offspring than hatchlings with two WPY parents. Furthermore, these relationships differed between maternal versus paternal extra-pair status. Hatchlings with EPY fathers were more likely to recruit and produce offspring than hatchlings with WPY fathers. In contrast, hatchlings with EPY mothers were as likely to recruit as hatchlings with WPY mothers and tended to be less likely to produce recruited offspring. Depending on the causal genetic and environmental mechanisms, such conflicting inter-generational relationships between parental extra-pair status and offspring fitness could substantially influence the evolutionary dynamics of EPR.
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Aptitud Genética , Preferencia en el Apareamiento Animal , Pájaros Cantores/fisiología , Animales , Colombia Británica , Femenino , Modelos Lineales , Masculino , Reproducción , Estaciones del AñoRESUMEN
One specific hypothesis explaining the evolution of extra-pair reproduction (EPR) by socially monogamous females is that EPR is under indirect selection because extra-pair offspring (EPO) sired by extra-pair males have higher additive genetic value for fitness than the within-pair offspring (WPO) a female would have produced had she solely mated with her socially paired male. This hypothesis has not been explicitly tested by comparing additive genetic value between EPO and the WPO they replaced. We show that the difference in additive genetic breeding value (BV) between EPO and the WPO they replaced is proportional to the genetic covariance between offspring fitness and male net paternity gain through EPR, and estimate this covariance with respect to offspring recruitment in free-living song sparrows (Melospiza melodia). Recruitment and net paternity gain showed non-zero additive genetic variance and heritability, and negative genetic covariance. Opposite to prediction, EPO therefore had lower BV for recruitment than the WPO they replaced. We thereby demonstrate an explicit quantitative genetic approach to testing the hypothesis that EPR allows polyandrous females to increase offspring additive genetic value, and suggest that there may be weak indirect selection against female EPR through reduced additive genetic value for recruitment of EPO versus WPO in song sparrows.
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Endogamia , Apareamiento , Reproducción/genética , Reproducción/fisiología , Selección Genética/genética , Conducta Sexual Animal/fisiología , Gorriones/genética , Animales , Femenino , Variación Genética , Masculino , FenotipoRESUMEN
The hypothesis that female extra-pair reproduction in socially monogamous animals reflects indirect genetic benefits requires that there be additive and/or nonadditive genetic variance in fitness. However, the specific hypotheses that male extra-pair reproductive success (EPRS) shows additive genetic variance (V(A)), heritability (h2), or inbreeding depression, and hence that females could acquire indirect genetic benefits through increased EPRS of sons, have not been explicitly tested. We used comprehensive genetic pedigree data from song sparrows (Melospiza melodia) to estimate V(A), h2, and inbreeding depression in the number of extra-pair offspring a male sired per year and the probability that a male would sire any extra-pair offspring per year. Inbreeding depression was substantial: more inbred males sired fewer extra-pair offspring and were less likely to sire any extra-pair offspring. In contrast, estimates of V(A) and h2 were close to 0, although 95% credible intervals were relatively wide. These data suggest that females could accrue indirect genetic benefits, in terms of increased EPRS of outbred sons, by mating with unrelated social or extra-pair mates. In contrast, any indirect benefit of extra-pair reproduction in terms of producing sons with high additive genetic value for EPRS is most likely to be small.
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Variación Genética , Endogamia , Reproducción/fisiología , Conducta Sexual Animal/fisiología , Gorriones/genética , Gorriones/fisiología , Animales , Femenino , Masculino , Apareamiento , Reproducción/genéticaRESUMEN
It is widely hypothesized that the evolution of female extra-pair reproduction in socially monogamous species reflects indirect genetic benefits to females. However, a critical prediction of this hypothesis, that extra-pair young (EPY) are fitter than within-pair young (WPY), has rarely been rigorously tested. We used 18 years of data from free-living song sparrows, Melospiza melodia, to test whether survival through major life-history stages differed between EPY and WPY maternal half-siblings. On average, survival of hatched chicks to independence from parental care and recruitment, and their total lifespan, did not differ significantly between EPY and WPY. However, EPY consistently tended to be less likely to survive, and recruited EPY survived for significantly fewer years than recruited WPY. Furthermore, the survival difference between EPY and WPY was sex-specific; female EPY were less likely to survive to independence and recruitment and lived fewer years than female WPY, whereas male EPY were similarly or slightly more likely to survive and to live more years than male WPY. These data indicate that extra-pair paternity may impose an indirect cost on females via their female offspring and that sex-specific genetic, environmental or maternal effects may shape extra-pair reproduction.
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Evolución Biológica , Aptitud Genética/fisiología , Longevidad/fisiología , Conducta Sexual Animal/fisiología , Gorriones/fisiología , Animales , Colombia Británica , Femenino , Genética de Población , Funciones de Verosimilitud , Masculino , Factores Sexuales , Análisis de SupervivenciaRESUMEN
The forces driving the evolution of extra-pair reproduction in socially monogamous animals remain widely debated and unresolved. One key hypothesis is that female extra-pair reproduction evolves through indirect genetic benefits, reflecting increased additive genetic value of extra-pair offspring. Such evolution requires that a female's propensity to produce offspring that are sired by an extra-pair male is heritable. However, additive genetic variance and heritability in female extra-pair paternity (EPP) rate have not been quantified, precluding accurate estimation of the force of indirect selection. Sixteen years of comprehensive paternity and pedigree data from socially monogamous but genetically polygynandrous song sparrows (Melospiza melodia) showed significant additive genetic variance and heritability in the proportion of a female's offspring that was sired by an extra-pair male, constituting major components of the genetic architecture required for extra-pair reproduction to evolve through indirect additive genetic benefits. However, estimated heritabilities were moderately small (0.12 and 0.18 on the observed and underlying latent scales, respectively). The force of selection on extra-pair reproduction through indirect additive genetic benefits may consequently be relatively weak. However, the additive genetic variance and non-zero heritability observed in female EPP rate allow for multiple further genetic mechanisms to drive and constrain mating system evolution.
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Variación Genética , Preferencia en el Apareamiento Animal , Gorriones/genética , Animales , Evolución Biológica , Colombia Británica , Femenino , Masculino , Modelos Biológicos , Paternidad , Linaje , Gorriones/fisiologíaRESUMEN
Sex ratio theory proposes that the equal sex ratio typically observed in birds and mammals is the result of natural selection. However, in species with chromosomal sex determination, the same 1 : 1 sex ratio is expected under random Mendelian segregation. Here, we present an analysis of 14 years of sex ratio data for a population of song sparrows (Melospiza melodia) on Mandarte Island, at the nestling stage and at independence from parental care. We test for the presence of variance in sex ratio over and above the binomial variance expected under Mendelian segregation, and thereby quantify the potential for selection to shape sex ratio. Furthermore, if sex ratio variation is to be shaped by selection, we expect some of this extra-binomial variation to have a genetic basis. Despite ample statistical power, we find no evidence for the existence of either genetic or environmentally induced variation in sex ratio, in the nest or at independence. Instead, the sex ratio variation observed matches that expected under random Mendelian segregation. Using one of the best datasets of its kind, we conclude that female song sparrows do not, and perhaps cannot, adjust the sex of their offspring. We discuss the implications of this finding and make suggestions for future research.
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Razón de Masculinidad , Gorriones/genética , Gorriones/fisiología , Animales , Ecosistema , Femenino , Variación Genética , MasculinoRESUMEN
Comprehensive, accurate paternity assignment is critical to answering numerous questions in evolutionary ecology. Yet, most studies of species with extra-pair paternity (EPP) fail to assign sires to all offspring. Common limitations include incomplete and biased sampling of offspring and males, particularly with respect to male location and social status, potentially biasing estimated patterns of paternity. Studies that achieve comprehensive sampling and paternity assignment are therefore required. Accordingly, we genotyped virtually all males and >99% of 6-day-old offspring over 16 years in a song sparrow (Melospiza melodia) population and used three complementary statistical methodologies to attempt complete paternity assignment for all 2207 offspring. Assignments were highly consistent across maximum likelihood methods that used solely genotype data, and heuristic and integrated Bayesian analyses that included data describing individual locations. Sires were assigned to >99% of all genotyped offspring with ≥95% confidence, revealing an EPP rate of c. 28%. Extra-pair sires primarily occupied territories neighbouring their extra-pair offspring; spatial location was therefore highly informative for paternity assignment. EPP was biased towards paired territorial males, although unpaired territorial and floater males sired c. 13% of extra-pair offspring. Failing to sample and include unpaired males as candidate sires would therefore substantially reduce assignment rates. These analyses demonstrate the integration of genetic and ecological information to achieve comprehensive paternity assignment and direct biological insight, illustrate the potential biases that common forms of incomplete sampling could have on estimated patterns of EPP, and provide an essential basis for understanding the evolutionary causes and consequences of EPP.
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Genética de Población , Conducta Sexual Animal , Gorriones/genética , Territorialidad , Animales , Teorema de Bayes , Colombia Británica , Genotipo , Funciones de Verosimilitud , Masculino , Repeticiones de Microsatélite , Modelos Genéticos , Análisis de Secuencia de ADNRESUMEN
Heterozygosity-fitness correlations use molecular measures of heterozygosity as proxy estimates of individual inbreeding coefficients (f) to examine relationships between inbreeding and fitness traits. Heterozygosity-fitness correlations partly depend on the assumption that individual heterozygosity and f are strongly and negatively correlated. Although theory predicts that this relationship will be strongest when mean f and variance in f are high, few studies of heterozygosity-fitness correlations include estimates of f based on pedigrees, which allow for more thorough examinations of the relationship between f, heterozygosity and fitness in nature. We examined relationships between pedigree-based estimates of f, multilocus heterozygosity (MLH) and the probability of survival to hatch in song sparrow nestmates. f and MLH were weakly, but significantly negatively correlated. Inbreeding coefficient predicted the probability of survival to hatch. In contrast, MLH did not predict the probability of survival to hatch nor did it account for residual variation in survival to hatch after statistically controlling for the effects of f. These results are consistent with the expectation that heterozygosity-f correlations will be weak when mean and variance in f are low. Our results also provide empirical support for recent simulation studies, which show that variation in MLH among siblings with equal f can be large and may obscure MLH-fitness relationships.
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Aptitud Genética , Genética de Población , Heterocigoto , Endogamia , Gorriones/genética , Animales , Colombia Británica , Óvulo , Análisis de Secuencia de ADNRESUMEN
Age-related macular degeneration (AMD), a highly prevalent and impactful disease of aging, is inarguably influenced by complex interactions between genetic and environmental factors. Various risk scores have been tested that assess measurable genetic and environmental contributions to disease. We herein summarize and review the ability and utility of these numerous models for prediction of AMD and suggest additional risk factors to be incorporated into clinically useful predictive models of AMD.
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PURPOSE: Progression rate of age-related macular degeneration (AMD) varies substantially, yet its association with genetic variation has not been widely examined. METHODS: We tested whether progression rate from intermediate AMD to geographic atrophy (GA) or choroidal neovascularization (CNV) was correlated with genotype at seven single nucleotide polymorphisms (SNPs) in the four genes most strongly associated with risk of advanced AMD. Cox proportional hazards survival models examined the association between progression time and SNP genotype while adjusting for age and sex and accounting for variable follow-up time, right censored data, and repeated measures (left and right eyes). RESULTS: Progression rate varied with the number of risk alleles at the CFH:rs10737680 but not the CFH:rs1061170 (Y402H) SNP; individuals with two risk alleles progressed faster than those with one allele (hazard ratio [HR] = 1.61, 95% confidence interval [CI] = 1.08-2.40, P < 0.02, n = 547 eyes), although this was not significant after Bonferroni correction. This signal was likely driven by an association at the correlated protective variant, CFH:rs6677604, which tags the CFHR1-3 deletion; individuals with at least one protective allele progressed more slowly. Considering GA and CNV separately showed that the effect of CFH:rs10737680 was stronger for progression to CNV. CONCLUSIONS: Results support previous findings that AMD progression rate is influenced by CFH, and suggest that variants within CFH may have different effects on risk versus progression. However, since CFH:rs10737680 was not significant after Bonferroni correction and explained only a relatively small portion of variation in progression rate beyond that explained by age, we suggest that additional factors contribute to progression.
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Factor H de Complemento/genética , ADN/genética , Predisposición Genética a la Enfermedad , Degeneración Macular/genética , Polimorfismo de Nucleótido Simple , Anciano , Anciano de 80 o más Años , Alelos , Factor H de Complemento/metabolismo , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Degeneración Macular/diagnóstico , Degeneración Macular/metabolismo , Masculino , Persona de Mediana Edad , Curva ROC , Estudios Retrospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.
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Estudio de Asociación del Genoma Completo , Degeneración Macular/genética , Predisposición Genética a la Enfermedad , Humanos , MutaciónRESUMEN
Understanding the evolutionary dynamics of inbreeding and inbreeding depression requires unbiased estimation of inbreeding depression across diverse mating systems. However, studies estimating inbreeding depression often measure inbreeding with error, for example, based on pedigree data derived from observed parental behavior that ignore paternity error stemming from multiple mating. Such paternity error causes error in estimated coefficients of inbreeding (f) and reproductive success and could bias estimates of inbreeding depression. We used complete "apparent" pedigree data compiled from observed parental behavior and analogous "actual" pedigree data comprising genetic parentage to quantify effects of paternity error stemming from extra-pair reproduction on estimates of f, reproductive success, and inbreeding depression in free-living song sparrows (Melospiza melodia). Paternity error caused widespread error in estimates of f and male reproductive success, causing inbreeding depression in male and female annual and lifetime reproductive success and juvenile male survival to be substantially underestimated. Conversely, inbreeding depression in adult male survival tended to be overestimated when paternity error was ignored. Pedigree error stemming from extra-pair reproduction therefore caused substantial and divergent bias in estimates of inbreeding depression that could bias tests of evolutionary theories regarding inbreeding and inbreeding depression and their links to variation in mating system.