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A major part of the human Y chromosome consists of palindromes with multiple copies of genes primarily expressed in testis. Here, the authors investigate copy number variation in these palindromes based on whole genome sequence data from 11,527 Icelandic men.

Agnar Helgason and colleagues report the point mutation rate for the male-specific euchromatic sequence of the Y chromosome based on 753 Icelandic males. They find that the non-recombining portions of the Y chromosome mutate at a faster rate than palindromic regions, suggesting that gene conversion acts to correct mutations in palindromic sequences.

Whole-genome sequencing of 78 Icelandic parent–offspring trios is used to study the de novo mutation rate at the genome-wide level; the rate is shown to increase by about two mutations a year as a function of the increasing age of the father at conception, highlighting the importance of father’s age on the risk of diseases such as autism and schizophrenia.

Why genetic variants that confer risk for psychiatric disorders persist in the genome is an evolutionary conundrum. Here, Mullinset al. report association of polygenic risk for autism with having fewer children and polygenic risk for ADHD with higher reproductive fitness.

Patrick Sulem, Hannes Helgason and colleagues identify homozygous and compound heterozygous loss-of-function variants of minor allele frequency <2% in 7.7% of the genotyped Icelandic population. Under transmission of some of these variants from heterozygous parents provides evidence that they are actually deleterious.

Adult height has a strong genetic component and is highly heritable. Here the authors whole-genome sequence 8,453 Icelanders and find novel parent-of-origin derived associations in IGF2-H19 and DLK1-MEG3.

Kari Stefansson and colleagues report the whole-genome sequencing of 2,636 individuals from Iceland to a median of 20× coverage, providing a valuable genomic resource for this population isolate. They characterize patterns of genetic variation and population structure and demonstrate the usefulness of this resource for genetic discovery for several disease phenotypes.

Comparisons of phenotypic and genetic association with protein levels from Icelandic and UK Biobank cohorts show that using multiple analysis platforms and stratifying populations by ancestry improves the detection of associations and allows the refinement of their location within the genome.

A barcode-based approach applied to UK Biobank and an Icelandic cohort identifies drivers of clonal hematopoiesis (CH) and finds associations between CH and multiple diseases. Genome-wide association analyses identify 25 loci associated with CH susceptibility.

Genetic risk scores derived from GWAS of psychotic disorders are greater in creative professionals unaffected by psychosis. This association cannot be explained by shared environment or education. Thus, a shared genetic architecture underlies the propensity for creativity and psychosis.

Whole-genome sequencing of monozygotic twins, along with their parents, spouses and children, identifies postzygotic mutations present in the somatic tissue of one twin, but not the other, and characterizes differences in the number and timing of these mutations.

John Perry, Ken Ong and colleagues perform a genome-wide association study for reproductive ability, behavior and success to determine underlying genetic factors. They find 38 variants associated with age of first sexual intercourse and show that both physical and neurobehavioral traits influence the onset of reproductive activity.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. Here, using genetic data for 1.52 million individuals, the authors identify 25 genes with protein-altering variants exhibiting a strong deficit of homozygosity, suggesting they are essential for successful early development.

A study reports whole-genome sequences for 490,640 participants from the UK Biobank and combines these data with phenotypic data to provide new insights into the relationship between human variation and sequence variation.

Understanding the underlying pathophysiology of obesity can help prevent this condition. Here, the authors perform a GWAS of BMI in diverse ancestries, finding four missense variants in FRS3 that affect BMI.

Bjarni Halldorsson, Kari Stefansson and colleagues analyze genomic data from 15,219 Icelanders to identify non-repetitive sequences that are missing from the reference genome. They describe 3,791 breakpoint-resolved sequence variants and find overlap with GWAS markers as well as the presence of a proportion of these variants in the chimpanzee genome.

Complete human recombination maps are presented that enable exploration of both cross-over and non-cross-over events during meiosis, with the potential to provide insight into the causes of aneuploidies and pregnancy loss.

Whole-genome sequencing identifies a rare missense variant in IKBKB associated with high risk of cutaneous and systemic lupus erythematosus among people with African ancestry.

Around 1 in 136 pregnancies is lost due to a pathogenic small sequence variant genotype in the fetus.

Sulem et al. report two previously unknown loci associated with variation in pigmentation in Northern Europeans. In two separate studies, Brown et al. and Gudbjartsson et al. report that some variants affecting human pigmentation, including variants on 20q11.22 near ASIP, also confer risk of cutaneous melanoma and basal cell carcinoma.

Here, human genome-wide single-nucleotide polymorphism (SNP) data from more than 15,000 parent–offspring pairs have been used to construct the first recombination maps that are based on directly observed recombination events. The data reveal interesting differences between the sexes: for instance, in males recombination tends to shuffle exons, whereas in females it generates new combinations of nearby genes. Comparison of these maps with others also reveals population differences.

Analysis of whole-genome sequence data of Icelandic individuals has revealed a rare nonsense mutation within the LGR4 gene that is strongly associated with, among other things, low bone mineral density, late onset of menarche, and increased risk of biliary tract cancer.

As the most common cardiac arrythmia, atrial fibrillation is of interest to physicians, and has recently been shown to have genetic components. Gudjbartsson et al. have conducted a genome-wide association scan in populations from around the globe, and find a strong link to a gene involved in early heart development. This gene, PITX2, could be a candidate for therapeutic intervention.

Whole-genome sequencing data of 14,688 Icelanders, including 1,548 parent–offspring trios, show how the age and sex of parents affect the rate and spectrum of de novo mutations.

Microsatellites are tandem repeats of short DNA motifs and represent some of the most polymorphic sites in the genome. Here, the authors report that the human germline microsatellite mutation rate is, in part, under genetic control.

Allele-specific DNA methylation data in whole blood from 7,179 individuals sequenced by Nanopore, and gene expression profiles from 896 samples, show that DNA sequence variability accounts for most of the correlation between CpG methylation and gene expression.

Archaeogenetic study of ancient DNA from medieval northwestern Europeans reveals substantial increase of continental northern European ancestry in Britain, suggesting mass migration across the North Sea during the Early Middle Ages.

Reconstructing the genome of an ancestor: 788 Icelanders are descended from a man who arrived there in 1802. 38% of his African mother’s genome has now been reconstructed from their pedigree and the genomes and genotypes of current Icelanders up to 8 generations later.

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.

A genome-wide association study of plasma protein levels measured with 4,907 aptamers in 35,559 Icelanders highlights links with over 370 disease endpoints and other traits.

Kari Stefansson, Unnur Styrkarsdottir and colleagues identify rare genotypes in COMP and CHADL associated with high risk of total hip replacement due to osteoarthritis. The high odds ratios associated with these rare risk genotypes suggest that they may represent Mendelian forms of osteoarthritis.

Analysis of Icelandic genomes reveals chromosome fragments of Neanderthal and Denisovan origin, the latter of which occurred through Denisovan gene flow either into ancestors of the Neanderthals or directly into humans.

To measure selection on variants, whole-genome sequencing of approximately 150,000 individuals from the UK Biobank is used to rank sequence variants by their level of depletion.

Unnur Thorsteinsdottir, Kari Stefansson and colleagues identify low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes. The newly discovered variants include an intronic variant associated with altered expression of CCND2, two independent missense variants in PAM and a rare frameshift variant in PDX1.

In this paper gene expression is treated as a quantitative trait in both blood and adipose tissue, and associations between specific genetic loci and body mass index are identified using a molecular network approach.

Hilma Holm et al. report a rare missense variant MYH6 that is associated with a high risk of sick sinus syndrome in Icelanders. This heart condition is found most often in elderly people and is the most frequent reason a heart pacemaker is implanted.