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This study showed an association of loss-of-function mutations in ANGPTL4 with low triglyceride levels and protection against coronary artery disease. Inhibition of Angptl4 in mice and monkeys with a monoclonal antibody reduced triglyceride levels. The level of serum triglycerides is, in part, heritable, and elevated levels are associated with a risk of ischemic cardiovascular disease. 1 – 3 Mendelian randomization studies of genetically determined triglyceride levels have suggested that this association is causal. 4 Two lines of genetic evidence have further established a causal role for serum triglycerides in the risk of cardiovascular disease. First, inactivating mutations in the gene encoding apolipoprotein C3 ( APOC3 ), a component of remnant particles, were reported to be associated with decreased serum triglyceride levels, a decreased burden of subclinical atherosclerosis, and a reduced risk of ischemic cardiovascular disease, which suggests . . .

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca 2+ -impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission. Genetic variants in ionotropic glutamate receptors have been implicated in neurodevelopmental disorders. Here, the authors report heterozygous de novo mutations in the GRIA2 gene in 28 individuals with intellectual disability and neurodevelopmental abnormalities associated with reduced Ca 2+ transport and AMPAR currents.”

Approximately 5% of patients with cystic fibrosis express one allele with some retained CFTR function. In a prospective trial, tezacaftor–ivacaftor had a greater effect on increasing FEV 1 than ivacaftor alone, and both ivacaftor alone and the combination were more effective than placebo.

Engineered gene drives based on a homing mechanism could rapidly spread genetic alterations through a population. However, such drives face a major obstacle in the form of resistance against the drive. In addition, they are expected to be highly invasive. Here, we introduce the Toxin-Antidote Recessive Embryo (TARE) drive. It functions by disrupting a target gene, forming recessive lethal alleles, while rescuing drive-carrying individuals with a recoded version of the target. Modeling shows that such drives will have threshold-dependent invasion dynamics, spreading only when introduced above a fitness-dependent frequency. We demonstrate a TARE drive in Drosophila with 88-95% transmission by female heterozygotes. This drive was able to spread through a large cage population in just six generations following introduction at 24% frequency without any apparent evolution of resistance. Our results suggest that TARE drives constitute promising candidates for the development of effective, flexible, and regionally confinable drives for population modification. CRISPR homing gene drives are highly invasive and can fail due to the rapid evolution of resistance. Here the authors present TARE drive, inspired by naturally occurring selfish genetic elements, which is less vulnerable to resistance and can potentially be confined to a target population.

AbstractObjectiveTo compare prevalent and incident morbidity and mortality between those with the HFE p.C282Y genetic variant (responsible for most hereditary haemochromatosis type 1) and those with no p.C282Y mutations, in a large UK community sample of European descent.DesignCohort study.Setting22 centres across England, Scotland, and Wales in UK Biobank (2006-10).Participants451 243 volunteers of European descent aged 40 to 70 years, with a mean follow-up of seven years (maximum 9.4 years) through hospital inpatient diagnoses and death certification.Main outcome measureOdds ratios and Cox hazard ratios of disease rates between participants with and without the haemochromatosis mutations, adjusted for age, genotyping array type, and genetic principal components. The sexes were analysed separately as morbidity due to iron excess occurs later in women.ResultsOf 2890 participants homozygous for p.C282Y (0.6%, or 1 in 156), haemochromatosis was diagnosed in 21.7% (95% confidence interval 19.5% to 24.1%, 281/1294) of men and 9.8% (8.4% to 11.2%, 156/1596) of women by end of follow-up. p.C282Y homozygous men aged 40 to 70 had a higher prevalence of diagnosed haemochromatosis (odds ratio 411.1, 95% confidence interval 299.0 to 565.3, P<0.001), liver disease (4.30, 2.97 to 6.18, P<0.001), rheumatoid arthritis (2.23, 1.51 to 3.31, P<0.001), osteoarthritis (2.01, 1.71 to 2.36, P<0.001), and diabetes mellitus (1.53, 1.16 to 1.98, P=0.002), versus no p.C282Y mutations (n=175 539). During the seven year follow-up, 15.7% of homozygous men developed at least one incident associated condition versus 5.0% (P<0.001) with no p.C282Y mutations (women 10.1% v 3.4%, P<0.001). Haemochromatosis diagnoses were more common in p.C282Y/p.H63D heterozygotes, but excess morbidity was modest.ConclusionsIn a large community sample, HFE p.C282Y homozygosity was associated with substantial prevalent and incident clinically diagnosed morbidity in both men and women. As p.C282Y associated iron overload is preventable and treatable if intervention starts early, these findings justify re-examination of options for expanded early case ascertainment and screening.

Purpose While cancer phenotypes in carriers of a single mutant allele in most major cancer susceptibility genes are well-established, there is a paucity of data on the phenotype of carriers of two pathogenic variants—double heterozygotes (DH) or homozygous carriers. Here, we describe the phenotype of carriers of homozygous and DH pathogenic sequence variants (PSVs) in major cancer susceptibility genes. Methods Individuals referred for multigene panel testing at Blueprint Genetics laboratory were included. Ethically approved comparison of cancer type and age at diagnosis between DH, homozygous, and single PSV carriers was performed per gene. Results Of 6,685 eligible participants, 928 (13.9%) were single heterozygous PSV carriers, 6 (0.09%) were homozygous PSV carriers, and 17 (0.25%) were DH PSV carriers. Mean age at diagnosis of any cancer among single PSV age was 46.8 ± 14.9 years and among DH PSV carriers 37.6 ± 13.0 years ( P  < 0.0001). Notably, age at diagnosis for breast cancer among single BRCA1 PSV carriers ( n  = 59) was 43.8 ± 8.7 years ( p  = 0.7606), among single BRCA2 PSV carriers ( n  = 52)—47.9 ± 13.0 years ( p  = 0.2274) compared with 42.3 ± 13.0 years among DH PSV carriers ( n  = 10- 9 of whom were carriers of either BRCA1 or BRCA2 ). Conclusion DH for PSV in two cancer susceptibility genes is a rare event, and the mean age at cancer diagnosis is younger in DH PSV carriers compared with single PSV carriers.

Balancing selection refers to a variety of selective regimes that maintain advantageous genetic diversity within populations. We review the history of the ideas regarding the types of selection that maintain such polymorphism in flowering plants, notably heterozygote advantage, negative frequency-dependent selection, and spatial heterogeneity. One shared feature of these mechanisms is that whether an allele is beneficial or detrimental is conditional on its frequency in the population. We highlight examples of balancing selection on a variety of discrete traits. These include the well-referenced case of self-incompatibility and recent evidence from species with nuclear-cytoplasmic gynodioecy, both of which exhibit trans-specific polymorphism, a hallmark of balancing selection. We also discuss and give examples of how spatial heterogeneity in particular, which is often thought unlikely to allow protected polymorphism, can maintain genetic variation in plants (which are rooted in place) as a result of microhabitat selection. Lastly, we discuss limitations of the protected polymorphism concept for quantitative traits, where selection can inflate the genetic variance without maintaining specific alleles indefinitely. We conclude that while discrete-morph variation provides the most unambiguous cases of protected polymorphism, they represent only a fraction of the balancing selection at work in plants.

In numerous applications, from working with animal models to mapping the genetic basis of human disease susceptibility, knowing whether a single disrupting mutation in a gene is likely to be deleterious is useful. With this goal in mind, a number of measures have been developed to identify genes in which protein-truncating variants (PTVs), or other types of mutations, are absent or kept at very low frequency in large population samples—genes that appear ‘intolerant’ to mutation. One measure in particular, the probability of being loss-of-function intolerant (pLI), has been widely adopted. This measure was designed to classify genes into three categories, null, recessive and haploinsufficient, on the basis of the contrast between observed and expected numbers of PTVs. Such population-genetic approaches can be useful in many applications. As we clarify, however, they reflect the strength of selection acting on heterozygotes and not dominance or haploinsufficiency. This Perspective discusses how best to interpret pLI, a measure widely used to identify genes that are intolerant to a single copy of a truncating mutation, by relating this and related measures to the underlying population-genetic theory.

IntroductionDuring the first wave of the COVID- 19 pandemic many elective procedures were postponed including venesection for the treatment of haemochromatosis. On resumption of venesection, limited capacity offered the opportunity to observe the effect of prolonged cessation of maintenance in non-cirrhotic patients over 70 years who guidelines suggest should undergo lifelong venesection.Methods40 HFE haemochromatosis patients aged 70+ at Royal Derby Hospital (RDH) (25 C282Y homozygotes, 11 compound heterozygotes (CH) and 4 C282Y heterozygotes- 3 mutually exclusive groups) who had a SF< 150µg/L at the point of venesection cessation were identified. SF levels at venesection cessation and resumption were collected and the time interval used to express the change in SF over 12 months. Statistical analyses were conducted using STATA.ResultsThe median projected increase in SF in 1 year in C282Y homozygotes was 40.8(-40.9-490.2)µg/L, in C282Y heterozygotes was 36.4(11.5-157.5) µg/L, and in compound heterozygotes was 74.1(-58.2-170.5) µg/L.There was no significant difference between the projected median increase in SF in 1 year between C282Y homozygotes compared to C282Y heterozygotes (p=0.95, p>0.05), between C282Y homozygotes compared to compound heterozygotes (p=0.72, p>0.05) or between all patients with a single C282Y mutation (compound heterozygotes and C282Y heterozygotes) compared to C282Y homozygotes (p=0.75,p>0.05).Considering all patients requiring venesection, the proportion of patients whose ferritin increased over 12 months by less than 50 was 50%, < 100 was 80% and 98% remain within normal range.ConclusionsIn non-cirrhotic HFE patients age 70+ the majority of patients can safely suspend venesection for at least 1 year and continued ferritin monitoring would likely reduce the burden on the service without clinically significant consequences as long as a threshold for resumption were agreed. Since evidence suggests that reduced iron absorption may be a physiological result of ageing, some patients may not require further venesection.Abstract P321 Figure 1

The estimation of the inbreeding coefficient (F) is essential for the study of inbreeding depression (ID) or for the management of populations under conservation. Several methods have been proposed to estimate the realized F using genetic markers, but it remains unclear which one should be used. Here we used whole-genome sequence data for 245 individuals from a Holstein cattle pedigree to empirically evaluate which estimators best capture homozygosity at variants causing ID, such as rare deleterious alleles or loci presenting heterozygote advantage and segregating at intermediate frequency. Estimators relying on the correlation between uniting gametes (FUNI) or on the genomic relationships (FGRM) presented the highest correlations with these variants. However, homozygosity at rare alleles remained poorly captured. A second group of estimators relying on excess homozygosity (FHOM), homozygous-by-descent segments (FHBD), runs-of-homozygosity (FROH) or on the known genealogy (FPED) was better at capturing whole-genome homozygosity, reflecting the consequences of inbreeding on all variants, and for young alleles with low to moderate frequencies (0.10 < . < 0.25). The results indicate that FUNI and FGRM might present a stronger association with ID. However, the situation might be different when recessive deleterious alleles reach higher frequencies, such as in populations with a small effective population size. For locus-specific inbreeding measures or at low marker density, the ranking of the methods can also change as FHBD makes better use of the information from neighboring markers. Finally, we confirmed that genomic measures are in general superior to pedigree-based estimates. In particular, FPED was uncorrelated with locus-specific homozygosity.