A detailed characteristics of bias associated with long runs of homozygosity identification based on medium density SNP microarrays.
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ABSTRACT:
SUBMITTER: Szmatola T
PROVIDER: S-EPMC7171384 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
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A detailed characteristics of bias associated with long runs of homozygosity identification based on medium density SNP microarrays.
Szmatoła Tomasz T Gurgul Artur A Jasielczuk Igor I Fu Weiwei W Ropka-Molik Katarzyna K
Journal of genomics 20200407
In the present study, runs of homozygosity (ROH) detected with the use of a standard bovine 54k single nucleotide polymorphism (SNP) genotyping assay and two different ROH detection approaches, based on 50 (M1) or 15 (M2) consecutive SNPs, were compared with results of whole genome sequencing. Both microarray-based methods accurately recognised medium-sized ROH, however, it was found that M2 method seemed to better than M1 identify short ROH, but highly overestimated their number, leading to num ...[more]
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Project description:BACKGROUND:PLINK is probably the most used program for analyzing SNP genotypes and runs of homozygosity (ROH), both in human and in animal populations. The last decade, ROH analyses have become the state-of-the-art method for inbreeding assessment. In PLINK, the --homozyg function is used to perform ROH analyses and relies on several input settings. These settings can have a large impact on the outcome and default values are not always appropriate for medium density SNP array data. Guidelines for a robust and uniform ROH analysis in PLINK using medium density data are lacking, albeit these guidelines are vital for comparing different ROH studies. In this study, 8 populations of different livestock and pet species are used to demonstrate the importance of PLINK input settings. Moreover, the effects of pruning SNPs for low minor allele frequencies and linkage disequilibrium on ROH detection are shown. RESULTS:We introduce the genome coverage parameter to appropriately estimate FROH and to check the validity of ROH analyses. The effect of pruning for linkage disequilibrium and low minor allele frequencies on ROH analyses is highly population dependent and such pruning may result in missed ROH. PLINK's minimal density requirement is crucial for medium density genotypes and if set too low, genome coverage of the ROH analysis is limited. Finally, we provide recommendations for the maximal gap, scanning window length and threshold settings. CONCLUSIONS:In this study, we present guidelines for an adequate and robust ROH analysis in PLINK on medium density SNP data. Furthermore, we advise to report parameter settings in publications, and to validate them prior to analysis. Moreover, we encourage authors to report genome coverage to reflect the ROH analysis' validity. Implementing these guidelines will substantially improve the overall quality and uniformity of ROH analyses.
| S-EPMC6990544 | biostudies-literature
Project description:Exome sequencing offers the potential to study the population-genomic variables that underlie patterns of deleterious variation. Runs of homozygosity (ROH) are long stretches of consecutive homozygous genotypes probably reflecting segments shared identically by descent as the result of processes such as consanguinity, population size reduction, and natural selection. The relationship between ROH and patterns of predicted deleterious variation can provide insight into the way in which these processes contribute to the maintenance of deleterious variants. Here, we use exome sequencing to examine ROH in relation to the distribution of deleterious variation in 27 individuals of varying levels of apparent inbreeding from 6 human populations. A significantly greater fraction of all genome-wide predicted damaging homozygotes fall in ROH than would be expected from the corresponding fraction of nondamaging homozygotes in ROH (p < 0.001). This pattern is strongest for long ROH (p < 0.05). ROH, and especially long ROH, harbor disproportionately more deleterious homozygotes than would be expected on the basis of the total ROH coverage of the genome and the genomic distribution of nondamaging homozygotes. The results accord with a hypothesis that recent inbreeding, which generates long ROH, enables rare deleterious variants to exist in homozygous form. Thus, just as inbreeding can elevate the occurrence of rare recessive diseases that represent homozygotes for strongly deleterious mutations, inbreeding magnifies the occurrence of mildly deleterious variants as well.
| S-EPMC3710769 | biostudies-literature
Project description:Long runs of homozygosity (ROH) are contiguous stretches of homozygous genotypes, which are a footprint of inbreeding and recessive inheritance. The presence of recessive loci is suggested for Alzheimer's disease (AD); however, their search has been poorly assessed to date. To investigate homozygosity in AD, here we performed a fine-scale ROH analysis using 10 independent cohorts of European ancestry (11,919 AD cases and 9181 controls.) We detected an increase of homozygosity in AD cases compared to controls [?AVROH (CI 95%)?=?0.070 (0.037-0.104); P?=?3.91?×?10-5; ?FROH (CI95%)?=?0.043 (0.009-0.076); P?=?0.013]. ROHs increasing the risk of AD (OR?>?1) were significantly overrepresented compared to ROHs increasing protection (p?<?2.20?×?10-16). A significant ROH association with AD risk was detected upstream the HS3ST1 locus (chr4:11,189,482?11,305,456), (? (CI 95%)?=?1.09 (0.48 ? 1.48), p value?=?9.03?×?10-4), previously related to AD. Next, to search for recessive candidate variants in ROHs, we constructed a homozygosity map of inbred AD cases extracted from an outbred population and explored ROH regions in whole-exome sequencing data (N?=?1449). We detected a candidate marker, rs117458494, mapped in the SPON1 locus, which has been previously associated with amyloid metabolism. Here, we provide a research framework to look for recessive variants in AD using outbred populations. Our results showed that AD cases have enriched homozygosity, suggesting that recessive effects may explain a proportion of AD heritability.
| S-EPMC7904832 | biostudies-literature
Project description:Gene expression microarrays measure the levels of messenger ribonucleic acid (mRNA) in a sample using probe sequences that hybridize with transcribed regions. These probe sequences are designed using a reference genome for the relevant species. However, most model organisms and all humans have genomes that deviate from their reference. These variations, which include single nucleotide polymorphisms, insertions of additional nucleotides, and nucleotide deletions, can affect the microarray's performance. Genetic experiments comparing individuals bearing different population-associated single nucleotide polymorphisms that intersect microarray probes are therefore subject to systemic bias, as the reduction in binding efficiency due to a technical artifact is confounded with genetic differences between parental strains. This problem has been recognized for some time, and earlier methods of compensation have attempted to identify probes affected by genome variants using statistical models. These methods may require replicate microarray measurement of gene expression in the relevant tissue in inbred parental samples, which are not always available in model organisms and are never available in humans.By using sequence information for the genomes of organisms under investigation, potentially problematic probes can now be identified a priori. However, there is no published software tool that makes it easy to eliminate these probes from an annotation. I present equalizer, a software package that uses genome variant data to modify annotation files for the commonly used Affymetrix IVT and Gene/Exon platforms. These files can be used by any microarray normalization method for subsequent analysis. I demonstrate how use of equalizer on experiments mapping germline influence on gene expression in a genetic cross between two divergent mouse species and in human samples significantly reduces probe hybridization-induced bias, reducing false positive and false negative findings.The equalizer package reduces probe hybridization bias from experiments performed on the Affymetrix microarray platform, allowing accurate assessment of germline influence on gene expression.
| S-EPMC4518889 | biostudies-literature
Project description:Recent studies have highlighted the potential of analyses of genomic sharing to produce insight into the demographic processes affecting human populations. We study runs of homozygosity (ROH) in 18 Jewish populations, examining these groups in relation to 123 non-Jewish populations sampled worldwide.By sorting ROH into 3 length classes (short, intermediate, and long), we evaluate the impact of demographic processes on genomic patterns in Jewish populations.We find that the portion of the genome appearing in long ROH - the length class most directly related to recent consanguinity - closely accords with data gathered from interviews during the 1950s on frequencies of consanguineous unions in various Jewish groups.The high correlation between 1950s consanguinity levels and coverage by long ROH explains differences across populations in ROH patterns. The dissection of ROH into length classes and the comparison to consanguinity data assist in understanding a number of additional phenomena, including similarities of Jewish populations to Middle Eastern, European, and Central and South Asian non-Jewish populations in short ROH patterns, relative lengths of identity-by-descent tracts in different Jewish groups, and the "population isolate" status of the Ashkenazi Jews.
| S-EPMC5698150 | biostudies-literature
Project description:BACKGROUND:Runs of Homozygosity (ROH) are genomic regions where identical haplotypes are inherited from each parent. Since their first detection due to technological advances in the late 1990s, ROHs have been shedding light on human population history and deciphering the genetic basis of monogenic and complex traits and diseases. ROH studies have predominantly exploited SNP array data, but are gradually moving to whole genome sequence (WGS) data as it becomes available. WGS data, covering more genetic variability, can add value to ROH studies, but require additional considerations during analysis. RESULTS:Using SNP array and low coverage WGS data from 1885 individuals from 20 world populations, our aims were to compare ROH from the two datasets and to establish software conditions to get comparable results, thus providing guidelines for combining disparate datasets in joint ROH analyses. By allowing heterozygous SNPs per window, using the PLINK homozygosity function and non-parametric analysis, we were able to obtain non-significant differences in number ROH, mean ROH size and total sum of ROH between data sets using the different technologies for almost all populations. CONCLUSIONS:By allowing 3 heterozygous SNPs per ROH when dealing with WGS low coverage data, it is possible to establish meaningful comparisons between data using SNP array and WGS low coverage technologies.
| S-EPMC5789638 | biostudies-literature
Project description:IMPORTANCE:Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE:To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS:Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES:The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS:The African American cohort had a low degree of inbreeding (F?~?0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P?=?.004) or greater than 3 Mb (P?=?.02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2?=?.04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2?=?.02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2?=?.03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs?>1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs?>2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs?>3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2?=?.006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2?=?.01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers. CONCLUSIONS AND RELEVANCE:To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.
| S-EPMC4641052 | biostudies-literature
Project description:BackgroundExome sequencing (ES) has been successfully applied in clinical detection of single nucleotide variants (SNVs) and small indels. However, identification of copy number variants (CNVs) using ES data remains challenging. The purpose of this study is to understand the contribution of CNVs and copy neutral runs of homozygosity (ROH) in molecular diagnosis of patients referred for ES.MethodsIn a cohort of 11,020 consecutive ES patients, an Illumina SNP array analysis interrogating mostly coding SNPs was performed as a quality control (QC) measurement and for CNV/ROH detection. Among these patients, clinical chromosomal microarray analysis (CMA) was performed at Baylor Genetics (BG) on 3229 patients, either before, concurrently, or after ES. We retrospectively analyzed the findings from CMA and the QC array.ResultsThe QC array can detect ~ 70% of pathogenic/likely pathogenic CNVs (PCNVs) detectable by CMA. Out of the 11,020 ES cases, the QC array identified PCNVs in 327 patients and uniparental disomy (UPD) disorder-related ROH in 10 patients. The overall PCNV/UPD detection rate was 5.9% in the 3229 ES patients who also had CMA at BG; PCNV/UPD detection rate was higher in concurrent ES and CMA than in ES with prior CMA (7.2% vs 4.6%). The PCNVs/UPD contributed to the molecular diagnoses in 17.4% (189/1089) of molecularly diagnosed ES cases with CMA and were estimated to contribute in 10.6% of all molecularly diagnosed ES cases. Dual diagnoses with both PCNVs and SNVs were detected in 38 patients. PCNVs affecting single recessive disorder genes in a compound heterozygous state with SNVs were detected in 4 patients, and homozygous deletions (mostly exonic deletions) were detected in 17 patients. A higher PCNV detection rate was observed for patients with syndromic phenotypes and/or cardiovascular abnormalities.ConclusionsOur clinical genomics study demonstrates that detection of PCNV/UPD through the QC array or CMA increases ES diagnostic rate, provides more precise molecular diagnosis for dominant as well as recessive traits, and enables more complete genetic diagnoses in patients with dual or multiple molecular diagnoses. Concurrent ES and CMA using an array with exonic coverage for disease genes enables most effective detection of both CNVs and SNVs and therefore is recommended especially in time-sensitive clinical situations.
| S-EPMC6525387 | biostudies-literature
Project description:Genome-wide association studies (GWASs) have identified several single-nucleotide polymorphisms (SNPs) influencing the risk of thyroid cancer (TC). Most cancer predisposition genes identified through GWASs function in a co-dominant manner, and studies have not found evidence for recessively functioning disease loci in TC. Our study examines whether homozygosity is associated with an increased risk of TC and searches for novel recessively acting disease loci.Data from a previously conducted GWAS were used for the estimation of the proportion of phenotypic variance explained by all common SNPs, the detection of runs of homozygosity (ROH) and the determination of inbreeding to unravel their influence on TC.Inbreeding coefficients were significantly higher among cases than controls. Association on a SNP-by-SNP basis was controlled by using the false discovery rate at a level of q*?< 0.05, with 34 SNPs representing true differences in homozygosity between cases and controls. The average size, the number and total length of ROHs per person were significantly higher in cases than in controls. A total of 16 recurrent ROHs of rather short length were identified although their association with TC risk was not significant at a genome-wide level. Several recurrent ROHs harbor genes associated with risk of TC. All of the ROHs showed significant evidence for natural selection (iHS, Fst, Fay and Wu's H).Our results support the existence of recessive alleles in TC susceptibility. Although regions of homozygosity were rather small, it might be possible that variants within these ROHs affect TC risk and may function in a recessive manner.
| S-EPMC4794977 | biostudies-literature
Project description:BackgroundRuns of homozygosity (ROH) are contiguous lengths of homozygous genotypes that are present in an individual due to parents transmitting identical haplotypes to their offspring. The extent and frequency of ROHs may inform on the ancestry of an individual and its population. Here we use high density (n?=?777,962) bi-allelic SNPs in a range of cattle breed samples to correlate ROH with the pedigree-based inbreeding coefficients and to validate subsequent analyses using 54,001 SNP genotypes. This study provides a first testing of the inference drawn from ROH through comparison with estimates of inbreeding from calculations based on the detailed pedigree data available for several breeds.ResultsAll animals genotyped on the HD panel displayed at least one ROH that was between 1-5 Mb in length with certain regions of the genome more likely to be involved in a ROH than others. Strong correlations (r?=?0.75, p?<?0.0001) existed between the pedigree-based inbreeding coefficient and a statistic based on sum of ROH of length?>?0.5 KB and suggests that in the absence of an animal's pedigree data, the extent of a genome under ROH may be used to infer aspects of recent population history even from relatively few samples.ConclusionsOur findings suggest that ROH are frequent across all breeds but differing patterns of ROH length and burden illustrate variations in breed origins and recent management.
| S-EPMC3502433 | biostudies-literature