Frequency and Complexity of De Novo Structural Mutation in Autism.

Genetic studies of autism spectrum disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variants (SVs) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping, and de novo assembly to genome sequencing of 235 subjects (71 affected individuals, 26 healthy siblings, and their parents), we compiled an atlas of 29,719 SV loci (5,213/genome), comprising 11 different classes. We found a high diversity of de novo mutations, the majority of which were undetectable by previous methods. In addition, we observed complex mutation clusters where combinations of de novo SVs, nucleotide substitutions, and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%) and propose that genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs, but not an elevated rate of genome rearrangement.

Joint effects of cancer and variants in the factor 5 gene on the risk of venous thromboembolism.

Venous thromboembolism occurs frequently in cancer patients. Two variants in the factor 5 gene (F5), rs6025 encoding for the factor V Leiden mutation R506Q, and rs4524 encoding K858R, have been found to be associated with venous thromboembolism. We assessed the joint effect of active cancer and these two F5 variants on venous thromboembolism risk in a case-cohort study. Cases with a first venous thromboembolism (n=609) and a randomly selected age-weighted cohort (n=1,691) were sampled from the general population in Tromsø, Norway. Venous thromboembolism was classified as cancer-related if it occurred in the period 6 months before to 2 years after a diagnosis of cancer. Active cancer was associated with an 8.9-fold higher risk of venous thromboembolism (95% CI 7.2-10.9). The risk of cancer-related venous thromboembolism was 16.7-fold (95% CI 9.9-28.0) higher in subjects heterozygous for rs6025 compared with non-carriers of this variant without active cancer. In subjects with active cancer the risk of venous thromboembolism was 15.9-fold higher (95% CI 9.1-27.9) in those with one risk allele at rs4524, and 21.1-fold (95% CI 12.4-35.8) higher in those with two risk alleles compared with non-carriers without active cancer. A synergistic interaction was observed between active cancer and factor V Leiden (relative excess risk due to interaction 7.0; 95% CI 0.5-14.4) and rs4524 (relative excess risk due to interaction 15.0; 95% CI 7.5-29.2). The incidence of venous thromboembolism during the initial 6 months following a diagnosis of cancer was particularly high in subjects with risk alleles at these loci. This implies that the combination of cancer and F5 variants synergistically increases venous thromboembolism risk.

Selective sweeps versus introgression - population genetic dynamics of the murine leukemia virus receptor Xpr1 in wild populations of the house mouse (Mus musculus).

BACKGROUND: The interaction between viruses and their receptors in the host can be expected to lead to an evolutionary arms race resulting in cycles of rapid adaptations. We focus here on the receptor gene Xpr1 (xenotropic and polytropic retrovirus receptor 1) for murine leukemia viruses (MLVs). In a previous screen for selective sweeps in mouse populations we discovered that a population from Germany was almost monomorphic for Xpr1 haplotypes, while a population from France was polymorphic. RESULTS: Here we analyze Xpr1 sequences and haplotypes from a broad sample of wild mouse populations of two subspecies, M. m. domesticus and M. m. musculus, to trace the origins of this distinctive polymorphism pattern. We show that the high polymorphism in the population in France is caused by a relatively recent invasion of a haplotype from a population in Iran, rather than a selective sweep in Germany. The invading haplotype codes for a novel receptor variant, which has itself undergone a recent selective sweep in the Iranian population. CONCLUSIONS: Our data support a scenario in which Xpr1 is frequently subject to positive selection, possibly as a response to resistance development against recurrently emerging infectious viruses. During such an infection cycle, receptor variants that may convey viral resistance can be captured from another population and quickly introgress into populations actively dealing with the infectious virus.

Ethics and Racial Equity in Social Welfare Policy: Social Work's Response to the COVID-19 Pandemic.

The COVID-19 pandemic has been particularly overwhelming for communities of color in the United States. In addition to the higher levels of underlying health conditions, circumstances related to a history of oppression and unequal access to opportunities and services are apparent. Social service programs will need to be re-developed to accommodate a new reality, both in terms of how people connect with services and how social work professionals provide them. Professional social work organizations' codes of ethics are analyzed, along with the theoretical framework of structural competency. It is an ethical imperative that social welfare policy and practice advance as culturally competent, racial equity, and empowerment-based programs. Child welfare is portrayed as an example where the pandemic could provide an opportunity to learn from the past to construct a more compassionate, competent, and ethical future.

Identification of Common and Rare Genetic Variation Associated With Plasma Protein Levels Using Whole-Exome Sequencing and Mass Spectrometry.

BACKGROUND: Identifying genetic variation associated with plasma protein levels, and the mechanisms by which they act, could provide insight into alterable processes involved in regulation of protein levels. Although protein levels can be affected by genetic variants, their estimation can also be biased by missense variants in coding exons causing technical artifacts. Integrating genome sequence genotype data with mass spectrometry-based protein level estimation could reduce bias, thereby improving detection of variation that affects RNA or protein metabolism. METHODS: Here, we integrate the blood plasma protein levels of 664 proteins from 165 participants of the Tromsø Study, measured via tandem mass tag mass spectrometry, with whole-exome sequencing data to identify common and rare genetic variation associated with peptide and protein levels (protein quantitative trait loci [pQTLs]). We additionally use literature and database searches to prioritize putative functional variants for each pQTL. RESULTS: We identify 109 independent associations (36 protein and 73 peptide) and use genotype data to exclude 49 (4 protein and 45 peptide) as technical artifacts. We describe 2 particular cases of rare variation: 1 associated with the complement pathway and 1 with platelet degranulation. We identify putative functional variants and show that pQTLs act through diverse molecular mechanisms that affect both RNA and protein metabolism. CONCLUSIONS: We show that although the majority of pQTLs exert their effects by modulating RNA metabolism, many affect protein levels directly. Our work demonstrates the extent by which pQTL studies are affected by technical artifacts and highlights how prioritizing the functional variant in pQTL studies can lead to insights into the molecular steps by which a protein may be regulated.

Associations Between Common and Rare Exonic Genetic Variants and Serum Levels of 20 Cardiovascular-Related Proteins: The Tromsø Study.

BACKGROUND: Genetic variation can be used to study causal relationships between biomarkers and diseases. Here, we identify new common and rare genetic variants associated with cardiovascular-related protein levels (protein quantitative trait loci [pQTLs]). We functionally annotate these pQTLs, predict and experimentally confirm a novel molecular interaction, and determine which pQTLs are associated with diseases and physiological phenotypes. METHODS AND RESULTS: As part of a larger case-control study of venous thromboembolism, serum levels of 51 proteins implicated in cardiovascular diseases were measured in 330 individuals from the Tromsø Study. Exonic genetic variation near each protein's respective gene (cis) was identified using sequencing and arrays. Using single site and gene-based tests, we identified 27 genetic associations between pQTLs and the serum levels of 20 proteins: 14 associated with common variation in cis, of which 6 are novel (ie, not previously reported); 7 associations with rare variants in cis, of which 4 are novel; and 6 associations in trans. Of the 20 proteins, 15 were associated with single sites and 7 with rare variants. cis-pQTLs for kallikrein and F12 also show trans associations for proteins (uPAR, kininogen) known to be cleaved by kallikrein and with NTproBNP. We experimentally demonstrate that kallikrein can cleave proBNP (NTproBNP precursor) in vitro. Nine of the pQTLs have previously identified associations with 17 disease and physiological phenotypes. CONCLUSIONS: We have identified cis and trans genetic variation associated with the serum levels of 20 proteins and utilized these pQTLs to study molecular mechanisms underlying disease and physiological phenotypes.