A genome-wide study of Hardy–Weinberg equilibrium with next generation sequence data

Statistical tests for Hardy–Weinberg equilibrium have been an important tool for detecting genotyping errors in the past, and remain important in the quality control of next generation sequence data. In this paper, we analyze complete chromosomes of the 1000 genomes project by using exact test procedures for autosomal and X-chromosomal variants. We find that the rate of disequilibrium largely exceeds what might be expected by chance alone for all chromosomes. Observed disequilibrium is, in about 60% of the cases, due to heterozygote excess. We suggest that most excess disequilibrium can be explained by sequencing problems, and hypothesize mechanisms that can explain exceptional heterozygosities. We report higher rates of disequilibrium for the MHC region on chromosome 6, regions flanking centromeres and p-arms of acrocentric chromosomes. We also detected long-range haplotypes and areas with incidental high disequilibrium. We report disequilibrium to be related to read depth, with variants having extreme read depths being more likely to be out of equilibrium. Disequilibrium rates were found to be 11 times higher in segmental duplications and simple tandem repeat regions. The variants with significant disequilibrium are seen to be concentrated in these areas. For next generation sequence data, Hardy–Weinberg disequilibrium seems to be a major indicator for copy number variation.Peer ReviewedPostprint (published version

Using compositional mixed-effects models to evaluate responses to amino acid supplementation in milk replacers for calves

The consequences of supplementing Lys, Met, and Thr in milk replacers (MR) for calves have been widely studied, but scarce information exists about potential roles of other AA (whether essential or not). The effects on growth performance of supplementation of 4 different AA combinations in a mixed ration (25.4% crude protein and 20.3% fat) based on skim milk powder and whey protein concentrate were evaluated in 76 Holstein male calves (3 ± 1.7 d old). The 4 MR were as follows: CTRL with no AA supplementation; PG, supplying additional 0.3% Pro and 0.1% Gly; FY, supplying additional 0.2% Phe and 0.2% Tyr; and KMT, providing additional 0.62% Lys, 0.22% Met, and 0.61% Thr. All calves were fed the same milk allowance program and were weaned at 56 d of study. Concentrate intake was limited to minimize interference of potential differences in solid feed intake among treatments. Animals were weighed weekly, intakes recorded daily, and blood samples obtained at 2, 5, and 7 wk of study to determine serum urea and plasma AA concentrations. Plasma AA concentrations were explored using compositional data analysis, and their isometric log-ratio transformations were used to analyze their potential influence on ADG and serum urea concentration using a linear mixed-effects model. We detected no differences in calf performance and feed intake. Plasma relative concentration of the AA supplemented in the KMT and PG treatments increased in their respective treatments, and, in PG calves, a slight increase in the proportion of plasma Gly, Glu, and branched-chain AA was also observed. The proportions of plasma branched-chain AA, His, and Gln increased, and those of Thr, Arg, Lys, and Glu decreased with calves' age. A specific log-contrast balance formed by Arg, Thr, and Lys was found to be the main driver for lowering serum urea concentrations and increasing calf growth. The use of compositional mixed-effects models identified a cluster formed by the combination of Arg, Thr, and Lys, as a potential AA to optimize calf growth.info:eu-repo/semantics/publishedVersio

Testing for Hardy–Weinberg equilibrium at biallelic genetic markers on the X chromosome

Testing genetic markers for Hardy–Weinberg equilibrium (HWE) is an important tool for detecting genotyping errors in large-scale genotyping studies. For markers at the X chromosome, typically the ¿2 or exact test is applied to the females only, and the hemizygous males are considered to be uninformative. In this paper we show that the males are relevant, because a difference in allele frequency between males and females may indicate HWE not to hold. The testing of markers on the X chromosome has received little attention, and in this paper we lay down the foundation for testing biallelic X-chromosomal markers for HWE. We develop four frequentist statistical test procedures for X-linked markers that take both males and females into account: the ¿2 test, likelihood ratio test, exact test and permutation test. Exact tests that include males are shown to have a better Type I error rate. Empirical data from the GENEVA project on venous thromboembolism is used to illustrate the proposed tests. Results obtained with the new tests differ substantially from tests that are based on female genotype counts only. The new tests detect differences in allele frequencies and seem able to uncover additional genotyping error that would have gone unnoticed in HWE tests based on females onlyPeer ReviewedPostprint (published version

A bayesian test for Hardy-Weinberg equilibrium of bi-allelic X-chromosomal markers

The X chromosome is a relatively large chromosome, harboring a lot of genetic information. Much of the statistical analysis of X-chromosomal information is complicated by the fact that males only have one copy. Recently, frequentist statistical tests for Hardy–Weinberg equilibrium have been proposed specifically for dealing with markers on the X chromosome. Bayesian test procedures for Hardy–Weinberg equilibrium for the autosomes have been described, but Bayesian work on the X chromosome in this context is lacking. This paper gives the first Bayesian approach for testing Hardy–Weinberg equilibrium with biallelic markers at the X chromosome. Marginal and joint posterior distributions for the inbreeding coefficient in females and the male to female allele frequency ratio are computed, and used for statistical inference. The paper gives a detailed account of the proposed Bayesian test, and illustrates it with data from the 1000 Genomes project. In that implementation, a novel approach to tackle multiple testing from a Bayesian perspective through posterior predictive checks is used.Peer ReviewedPostprint (author's final draft

External validation of prediction models for pneumonia in primary care patients with lower respiratory tract infection: an individual patient data meta-analysis

Pneumonia remains difficult to diagnose in primary care. Prediction models based on signs and symptoms (S&S) serve to minimize the diagnostic uncertainty. External validation of these models is essential before implementation into routine practice. In this study all published S&S models for prediction of pneumonia in primary care were externally validated in the individual patient data (IPD) of previously performed diagnostic studies

Similarity in Recombination Rate Estimates Highly Correlates with Genetic Differentiation in Humans

Recombination varies greatly among species, as illustrated by the poor conservation of the recombination landscape between humans and chimpanzees. Thus, shorter evolutionary time frames are needed to understand the evolution of recombination. Here, we analyze its recent evolution in humans. We calculated the recombination rates between adjacent pairs of 636,933 common single-nucleotide polymorphism loci in 28 worldwide human populations and analyzed them in relation to genetic distances between populations. We found a strong and highly significant correlation between similarity in the recombination rates corrected for effective population size and genetic differentiation between populations. This correlation is observed at the genome-wide level, but also for each chromosome and when genetic distances and recombination similarities are calculated independently from different parts of the genome. Moreover, and more relevant, this relationship is robustly maintained when considering presence/absence of recombination hotspots. Simulations show that this correlation cannot be explained by biases in the inference of recombination rates caused by haplotype sharing among similar populations. This result indicates a rapid pace of evolution of recombination, within the time span of differentiation of modern humans

Male pygmy hippopotamus influence offspring sex ratio

Pre-determining fetal sex is against the random and equal opportunity that both conceptus sexes have by nature. Yet, under a wide variety of circumstances, populations shift their birth sex ratio from the expected unity. Here we show, using fluorescence in situ hybridization, that in a population of pygmy hippopotamus (Choeropsis liberiensis) with 42.5% male offspring, males bias the ratio of X- and Y-chromosome-bearing spermatozoa in their ejaculates, resulting in a 0.4337±0.0094 (mean±s.d.) proportion of Y-chromosome-bearing spermatozoa. Three alternative hypotheses for the shifted population sex ratio were compared: female counteract male, female indifferent, or male and female in agreement. We conclude that there appears little or no antagonistic sexual conflict, unexpected by prevailing theories. Our results indicate that males possess a mechanism to adjust the ratio of X- and Y-chromosome-bearing spermatozoa in the ejaculate, thereby substantially expanding currently known male options in sexual conflict

Common marmoset (Callithrix jacchus) personality, subjective well-being, hair cortisol level and AVPR1a, OPRM1, and DAT genotypes

We studied personality, subjective well-being, and hair cortisol level, in common marmosets Callithrix jacchus, a small, cooperatively breeding New World monkey, by examining their associations with one another and genotypes. Subjects were 68 males and 9 females that lived in the RIKEN Center for Life Science Technologies. Personality and subjective well-being were assessed by keeper ratings on two questionnaires, hair samples were obtained to assay cortisol level and buccal swabs were used to assess AVPR1a, OPRM1 and DAT genotypes. Three personality domains—Dominance, Sociability, and Neuroticism—were identified. Consistent with findings in other species, Sociability and Neuroticism were related to higher and lower subjective well-being, respectively. Sociability was also associated with higher hair cortisol levels. The personality domains and hair cortisol levels were heritable and associated with genotypes: the short form of AVPR1a was associated with lower Neuroticism and the AA genotype of the A111T SNP of OPRM1 was related to lower Dominance, lower Neuroticism, and higher hair cortisol level. Some genetic associations were not in directions that one would expect given findings in other species. These findings provide insights into the proximate and ultimate bases of personality in common marmosets, other primates and humans

No Association between Personality and Candidate Gene Polymorphisms in a Wild Bird Population

Consistency of between-individual differences in behaviour or personality is a phenomenon in populations that can have ecological consequences and evolutionary potential. One way that behaviour can evolve is to have a genetic basis. Identifying the molecular genetic basis of personality could therefore provide insight into how and why such variation is maintained, particularly in natural populations. Previously identified candidate genes for personality in birds include the dopamine receptor D4 (DRD4), and serotonin transporter (SERT). Studies of wild bird populations have shown that exploratory and bold behaviours are associated with polymorphisms in both DRD4 and SERT. Here we tested for polymorphisms in DRD4 and SERT in the Seychelles warbler (Acrocephalus sechellensis) population on Cousin Island, Seychelles, and then investigated correlations between personality and polymorphisms in these genes. We found no genetic variation in DRD4, but identified four polymorphisms in SERT that clustered into five haplotypes. There was no correlation between bold or exploratory behaviours and SERT polymorphisms/haplotypes. The null result was not due to lack of power, and indicates that there was no association between these behaviours and variation in the candidate genes tested in this population. These null findings provide important data to facilitate representative future meta-analyses on candidate personality genes