Rank-invariant estimation of inbreeding coefficients

The two alleles an individual carries at a locus are identical by descent (ibd) if they have descended from a single ancestral allele in a reference population, and the probability of such identity is the inbreeding coefficient of the individual. Inbreeding coefficients can be predicted from pedigrees with founders constituting the reference population, but estimation from genetic data is not possible without data from the reference population. Most inbreeding estimators that make explicit use of sample allele frequencies as estimates of allele probabilities in the reference population are confounded by average kinships with other individuals. This means that the ranking of those estimates depends on the scope of the study sample and we show the variation in rankings for common estimators applied to different subdivisions of 1000 Genomes data. Allele-sharing estimators of within-population inbreeding relative to average kinship in a study sample, however, do have invariant rankings across all studies including those individuals. They are unbiased with a large number of SNPs. We discuss how allele sharing estimates are the relevant quantities for a range of empirical applications.

An outbreak report of the two autochthonous cases of airport malaria in Belgium in 2020

We report an outbreak investigation of two fatal cases of autochthonous Plasmodium falciparum that occurred in Belgium in September 2020. Various hypotheses of potential source of infection were investigated. Based on the collected information, the most likely route of transmission was through an infectious exotic Anopheles mosquito that arrived via the international airport of Brussels or the Military airport Melsbroek and infected the cases who lived at five kilometres from the airports. Based on a genomic analysis of the parasites collected from the two cases, the most likely origin of the Plasmodium was Gabon or Cameroon. Further, the parasites collected from the two Belgian patients were identical-by-descent, which supports the assumption that the two infections originated from the bite of the same mosquito, during an interrupted feeding. Despite these cases, airport malaria remains a rare event. Yet, it has significant implications, particularly for the patient, as delayed or missed diagnosis of the cause of illness often results in high rates of complications and mortality. Therefore, to prevent such severe or fatal outcomes, a number of public health actions are suggested including increased awareness among health practitioners especially those working in the vicinity of airports and increased surveillance of exotic mosquito species at airports.

A frameshift insertion in FA2H causes a recessively inherited form of ichthyosis congenita in Chianina cattle

The aim of this study was to characterize the phenotype and to identify the genetic etiology of a syndromic form of ichthyosis congenita (IC) observed in Italian Chianina cattle and to estimate the prevalence of the deleterious allele in the population. Sporadic occurrence of different forms of ichthyosis including IC have been previously reported in cattle. However, so far, no causative genetic variant has been found for bovine IC. Nine affected cattle presenting congenital xerosis, hyperkeratosis and scaling of the skin as well as urolithiasis and cystitis associated with retarded growth were examined. Skin histopathology revealed a severe, diffuse orthokeratotic hyperkeratosis with mild to moderate epidermal hyperplasia. The pedigree records indicated a monogenic recessive trait. Homozygosity mapping and whole-genome sequencing allowed the identification of a homozygous frameshift 1 bp insertion in the FA2H gene (c.9dupC; p.Ala4ArgfsTer142) located in a 1.92 Mb shared identical-by-descent region on chromosome 18 present in all cases, while the parents were heterozygous as expected for obligate carriers. These findings enable the selection against this sub-lethal allele showing an estimated frequency of ~ 7.5% in Chianina top sires. A sporadic incidence of mild clinical signs in the skin of heterozygous carriers was observed. So far, pathogenic variants affecting the encoded fatty acid 2-hydroxylase catalyzing the synthesis of 2-hydroxysphingolipids have been associated with myelin disorders. In conclusion, this study represents the first report of an FA2H-related autosomal recessive inherited skin disorder in a mammalian species and adds FA2H to the list of candidate genes for ichthyosis in humans and animals. Furthermore, this study provides a DNA-based diagnostic test that enables selection against the identified pathogenic variant in the Chianina cattle population. However, functional studies are needed to better understand the expression of FA2H in IC-affected Chianina cattle.

Rapid detection of identity-by-descent tracts for mega-scale datasets

The ability to identify segments of genomes identical-by-descent (IBD) is a part of standard workflows in both statistical and population genetics. However, traditional methods for finding local IBD across all pairs of individuals scale poorly leading to a lack of adoption in very large-scale datasets. Here, we present iLASH, an algorithm based on similarity detection techniques that shows equal or improved accuracy in simulations compared to current leading methods and speeds up analysis by several orders of magnitude on genomic datasets, making IBD estimation tractable for millions of individuals. We apply iLASH to the PAGE dataset of ~52,000 multi-ethnic participants, including several founder populations with elevated IBD sharing, identifying IBD segments in ~3 minutes per chromosome compared to over 6 days for a state-of-the-art algorithm. iLASH enables efficient analysis of very large-scale datasets, as we demonstrate by computing IBD across the UK Biobank (~500,000 individuals), detecting 12.9 billion pairwise connections.

Chromosome-scale and haplotype-resolved genome assembly of a tetraploid potato cultivar

Potato is the third most important food crop in the world. Despite its social and economic importance, the autotetraploid genome of cultivated potato has not been assembled yet. The distinct reconstruction all of four haplotypes remained an unsolved challenge. Here, we report the 3.1 Gb haplotype-resolved, chromosome-scale assembly of the autotetraploid potato cultivar, Otava. We assembled the genome with high-quality long reads coupled with single-cell sequencing of 717 pollen genomes and chromosome conformation capture data at a haplotyping precision of 99.6%. Unexpectedly, we found that almost 50% of the tetraploid genome were identical-by-descent with at least one of the other haplotypes. This high level of inbreeding contrasted with the extreme level of structural rearrangements encompassing nearly 20% of the genome. Overall, we annotated 148,577 gene models, where only 54% of the genes were present in all four haplotypes with an average of 3.2 copies per gene. Our work showcases how accurate assemblies of complex and partially inbred autotetraploid genomes can be generated. The newly established resource gives novel insights in the breeding history of autotetraploid potato and has the potential to change the future of genomics-assisted potato breeding.

Novel Approach for Parallelizing Pairwise Comparison Problems as Applied to Detecting Segments Identical By Decent in Whole-Genome Data

Motivation Pairwise comparison problems arise in many areas of science. In genomics, datasets are already large and getting larger, and so operations that require pairwise comparisons—either on pairs of SNPs or pairs of individuals—are extremely computationally challenging. We propose a generic algorithm for addressing pairwise comparison problems that breaks a large problem (of order n2 comparisons) into multiple smaller ones (each of order n comparisons), allowing for massive parallelization. Results We demonstrated that this approach is very efficient for calling identical by descent (IBD) segments between all pairs of individuals in the UK Biobank dataset, with a 250-fold savings in time and 750-fold savings in memory over the standard approach to detecting such segments across the full dataset. This efficiency should extend to other methods of IBD calling and, more generally, to other pairwise comparison tasks in genomics or other areas of science.

Obelisc: an identical-by-descent mapping tool based on SNP streak

Motivation Genetic linkage analysis has made a huge contribution to the genetic mapping of Mendelian diseases. However, most previously available linkage analysis methods have limited applicability. Since parametric linkage analysis requires predefined model of inheritance with a fixed set of parameters, it is inapplicable without fully structured pedigree information. Furthermore, the analytical results are dependent on the specification of model parameters. While non-parametric linkage analysis can avoid these problems, the runs of homozygosity (ROH) mapping, a widely used non-parametric linkage analysis method, can only deal with recessive inheritance. The implementation of non-parametric linkage analyses capable of dealing with both dominant and recessive inheritance has been required. Results We have developed the Obelisc (Observational linkage scan), a flexibly applicable user-friendly non-parametric linkage analysis tool, which also provides an intuitive visualization of the analytical results. Obelisc is based on the SNP streak approach, which does not require any predefined inheritance model with parameters. In contrast to the ROH mapping, the SNP streak approach is applicable to both dominant and recessive traits. To illustrate the performance of Obelisc, we generated a pseudo-pedigree from the publicly available BioBank Japan Project genome-wide genotype dataset (n > 180 000). By applying Obelisc to this pseudo-pedigree, we successfully identified the regions with inherited identical-by-descent haplotypes shared among the members of the pseudo-pedigree, which was validated by the population-based haplotype phasing approach. Availability and implementation Obelisc is feely available at https://github.com/qsonehara/Obelisc as a python package with example datasets. Supplementary information Supplementary data are available at Bioinformatics online.

Controlling the false discovery rate in GWAS with population structure

This paper proposes a novel statistical method to address population structure in genome-wide association studies while controlling the false discovery rate, which overcomes some limitations of existing approaches. Our solution accounts for linkage disequilibrium and diverse ancestries by combining conditional testing via knockoffs with hidden Markov models from state-of-the-art phasing methods. Furthermore, we account for familial relatedness by describing the joint distribution of haplotypes sharing long identical-by-descent segments with a generalized hidden Markov model. Extensive simulations affirm the validity of this method, while applications to UK Biobank phenotypes yield many more discoveries compared to BOLT-LMM, most of which are confirmed by the Japan Biobank and FinnGen data.