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

Profiling allele-specific gene expression in brains from individuals with autism spectrum disorder reveals preferential minor allele usage.

One fundamental but understudied mechanism of gene regulation in disease is allele-specific expression (ASE), the preferential expression of one allele. We leveraged RNA-sequencing data from human brain to assess ASE in autism spectrum disorder (ASD). When ASE is observed in ASD, the allele with lower population frequency (minor allele) is preferentially more highly expressed than the major allele, opposite to the canonical pattern. Importantly, genes showing ASE in ASD are enriched in those downregulated in ASD postmortem brains and in genes harboring de novo mutations in ASD. Two regions, 14q32 and 15q11, containing all known orphan C/D box small nucleolar RNAs (snoRNAs), are particularly enriched in shifts to higher minor allele expression. We demonstrate that this allele shifting enhances snoRNA-targeted splicing changes in ASD-related target genes in idiopathic ASD and 15q11-q13 duplication syndrome. Together, these results implicate allelic imbalance and dysregulation of orphan C/D box snoRNAs in ASD pathogenesis

Risk-Aware Multi-stakeholder Next Release Planning Using Multi-objective Optimization

[Context and motivation]: Software requirements selection is an essential task in the software development process. It consists of finding the best requirement set for each software release, considering several requirements characteristics, such as precedences and multiple conflicting objectives, such as stakeholders’ perceived value, cost and risk. [Question/Problem]: However, in this scenario, important information about the variability involved in the requirements values estimation are discarded and might expose the company to a risk when selecting a solution. [Principal ideas/results]: We propose a novel approach to the risk-aware multi-objective next release problem and implemented our approach by means of a satisfiability modulo theory solver. We aim at improving the decision quality by reducing the risk associated with the stakeholder dissatisfaction as related to the variability of the value estimation made by these stakeholders. [Contribution]: Results show that Pareto-optimal solutions exist where a major risk reduction can be achieved at the price of a minor penalty in the value-cost trade-off

Sex chromosome aneuploidies and copy-number variants: a further explanation for neurodevelopmental prognosis variability?

Sex chromosome aneuploidies (SCA) is a group of conditions in which individuals have an abnormal number of sex chromosomes. SCA, such as Klinefelter's syndrome, XYY syndrome, and Triple X syndrome are associated with a large range of neurological outcome. Another genetic event such as another cytogenetic abnormality may explain a part of this variable expressivity. In this study, we have recruited fourteen patients with intellectual disability or developmental delay carrying SCA associated with a copy-number variant (CNV). In our cohort (four patients 47,XXY, four patients 47,XXX, and six patients 47,XYY), seven patients were carrying a pathogenic CNV, two a likely pathogenic CNV and five a variant of uncertain significance. Our analysis suggests that CNV might be considered as an additional independent genetic factor for intellectual disability and developmental delay for patients with SCA and neurodevelopmental disorder