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Microsatellites are polymorphic tracts of short tandem repeats (STRs) with one to six base-pair (bp) motifs and are some of the most polymorphic markers in the genome. Using 6,084 Icelandic parent-offspring trios we estimate 63.7 (95% CI: 61.9–65.4) microsatellite de novo mutations (mDNMs) per offspring per generation. Paternal mDNMs occur at longer repeats, while maternal mDNMs affect more bp. mDNMs increase by 0.97 (95% CI: 0.90–1.04) and 0.31 (95% CI: 0.25–0.37) per year of father‘s and mother‘s age at conception, respectively. We found two independent coding variants associated with an increased number of mDNMs transmitted to offspring; A missense variant (allele frequency (AF) = 1.9%) in MSH2, a mismatch repair gene, increases transmitted mDNMs from both parents (effect: 13.1 paternal and 7.8 maternal mDNMs). A synonymous variant (AF = 20.3%) in NEIL2, a DNA damage repair gene, increases paternally transmitted mDNMs (effect: 4.4 mDNMs). Thus, the microsatellite mutation rate in humans is in part under genetic control.

Objectives: The spread of SARS-CoV-2 is dependent on several factors, both biological and behavioural. The effectiveness of nonpharmaceutical interventions can be attributed largely to changes in human behaviour, but quantifying this effect remains challenging. Reconstructing the transmission tree of the third wave of SARS-CoV-2 infections in Iceland using contact tracing and viral sequence data from 2522 cases enables us to directly compare the infectiousness of distinct groups of persons. Methods: The transmission tree enables us to model the effect that a given population prevalence of vaccination would have had on the third wave had one of three different vaccination strategies been implemented before that time. This allows us to compare the effectiveness of the strategies in terms of minimizing the number of cases, deaths, critical cases, and severe cases. Results: We found that people diagnosed outside of quarantine (Ȓ = 1.31) were 89% more infectious than those diagnosed while in quarantine (Ȓ = 0.70) and that infectiousness decreased as a function of time spent in quarantine before diagnosis, with people diagnosed outside of quarantine being 144% more infectious than those diagnosed after ≥3 days in quarantine (Ȓ = 0.54). People of working age, 16 to 66 years (Ȓ = 1.08), were 46% more infectious than those outside of that age range (Ȓ = 0.74). Discussion: We found that vaccinating the population in order of ascending age or uniformly at random would have prevented more infections per vaccination than vaccinating in order of descending age, without significantly affecting the expected number of deaths, critical cases, or severe cases.

Despite the important role that monozygotic twins have played in genetics research, little is known about their genomic differences. Here we show that monozygotic twins differ on average by 5.2 early developmental mutations and that approximately 15% of monozygotic twins have a substantial number of these early developmental mutations specific to one of them. Using the parents and offspring of twins, we identified pre-twinning mutations. We observed instances where a twin was formed from a single cell lineage in the pre-twinning cell mass and instances where a twin was formed from several cell lineages. CpG>TpG mutations increased in frequency with embryonic development, coinciding with an increase in DNA methylation. Our results indicate that allocations of cells during development shapes genomic differences between monozygotic twins.

We describe the analysis of whole genome sequences (WGS) of 150,119 individuals from the UK biobank (UKB). This constitutes a set of high quality variants, including 585,040,410 SNPs, representing 7.0% of all possible human SNPs, and 58,707,036 indels. The large set of variants allows us to characterize selection based on sequence variation within a population through a Depletion Rank (DR) score for windows along the genome. DR analysis shows that coding exons represent a small fraction of regions in the genome subject to strong sequence conservation. We define three cohorts within the UKB, a large British Irish cohort (XBI) and smaller African (XAF) and South Asian (XSA) cohorts. A haplotype reference panel is provided that allows reliable imputation of most variants carried by three or more sequenced individuals. We identified 895,055 structural variants and 2,536,688 microsatellites, groups of variants typically excluded from large scale WGS studies. Using this formidable new resource, we provide several examples of trait associations for rare variants with large effects not found previously through studies based on exome sequencing and/or imputation.

Detailed knowledge of how diversity in the sequence of the human genome affects phenotypic diversity depends on a comprehensive and reliable characterization of both sequences and phenotypic variation. Over the past decade, insights into this relationship have been obtained from whole-exome sequencing or whole-genome sequencing of large cohorts with rich phenotypic data

The spread of SARS-CoV-2 is dependent on several factors, both biological and behavioral. The effectiveness of various non-pharmaceutical interventions can largely be attributed to changes in human behavior, but quantifying this effect remains challenging. Reconstructing the transmission tree of the third wave of SARS-CoV-2 infections in Iceland using contact tracing and viral sequence data from 2522 cases enables us to compare the infectiousness of distinct groups of persons directly. We find that people diagnosed outside of quarantine are 89% more infectious than those diagnosed while in quarantine, and infectiousness decreases as a function of the time spent in quarantine. Furthermore, we find that people of working age, 16-66 years old, are 47% more infectious than those outside that age range. Lastly, the transmission tree enables us to model the effect that given population prevalence of vaccination would have had on the third wave had they been administered before that time using several different strategies. We find that vaccinating in order of ascending age or uniformly at random would have prevented more infections per vaccination than vaccinating in order of descending age.

A pressing concern in the SARS-CoV-2 epidemic and other viral outbreaks, is the extent to which the containment measures are halting the viral spread. A straightforward way to assess this is to tally the active cases and the recovered ones throughout the epidemic. Here, we show how epidemic control can be assessed with molecular information during a well characterized epidemic in Iceland. We demonstrate how the viral concentration decreased in those newly diagnosed as the epidemic transitioned from exponential growth phase to containment phase. The viral concentration in the cases identified in population screening decreased faster than in those symptomatic and considered at high risk and that were targeted by the healthcare system. The viral concentration persists in recovering individuals as we found that half of the cases are still positive after two weeks. We demonstrate that accumulation of mutations in SARS-CoV-2 genome can be exploited to track the rate of new viral generations throughout the different phases of the epidemic, where the accumulation of mutations decreases as the transmission rate decreases in the containment phase. Overall, the molecular signatures of SARS-CoV-2 infections contain valuable epidemiological information that can be used to assess the effectiveness of containment measures., The concentration of SARS-CoV-2 changes during an individual’s infection, and mutations accumulate as viruses are transmitted between people. Here, the authors use data from Iceland to demonstrate how this information can be exploited at the population-level to determine the phase of the epidemic.

Despite the important role that monozygotic twins have played in genetics research, little is known about their genomic differences. Here we show that monozygotic twins differ on average by 5.2 early developmental mutations and that approximately 15% of monozygotic twins have a substantial number of these early developmental mutations specific to one of them. Using the parents and offspring of twins, we identified pre-twinning mutations. We observed instances where a twin was formed from a single cell lineage in the pre-twinning cell mass and instances where a twin was formed from several cell lineages. CpGTpG mutations increased in frequency with embryonic development, coinciding with an increase in DNA methylation. Our results indicate that allocations of cells during development shapes genomic differences between monozygotic twins.